Document:

<PAGE>

                                                                   EXHIBIT 10.13

                                                                  August 5, 2002

Penn National Gaming, Inc.
825 Berkshire Boulevard
Suite 200
Wyomissing, Pennsylvania 19610

Attention: Robert S. Ippolito

                       RE: PROJECT LA--COMMITMENT LETTER

Ladies and Gentlemen:

     Penn National Gaming, Inc. ("YOU" or "BORROWER") has advised Bear, Stearns
& Co. Inc. ("BEAR STEARNS"), Bear Stearns Corporate Lending Inc. ("BSCL") and
Merrill Lynch Capital Corporation ("MERRILL Lynch"; together with Bear Stearns
and BSCL, "WE" or "US") that you and a newly formed subsidiary of yours intend
to enter into a merger agreement (the "ACQUISITION AGREEMENT") with Hollywood
Casino Corporation ("TARGET") pursuant to which, you will acquire through merger
(the "ACQUISITION") all of the capital stock of Target for cash. In addition,
you have advised us of the following: (1) on the closing date of the Acquisition
(the "CLOSING DATE"), you will repay all outstanding borrowings under your
existing revolving credit facility and terminate the commitments in connection
therewith, (2) on the Closing Date, you will redeem (or irrevocably deposit into
trust sufficient funds with an irrevocable notice of redemption to cause the
obligations under the indenture in respect thereof to be discharged) Target's
outstanding floating rate senior secured notes due 2006, (3) on the Closing
Date, you will consummate a cash tender offer for not less than 85% of Target's
11.25% senior secured notes due 2007 (the "NON-CALLABLE NOTES"), obtain consents
to eliminate all significant covenants from the governing indenture in
connection therewith and modify the indenture governing the Non-Callable Notes
to permit the Credit Facilities referred to below to be secured by the
collateral securing the Non-Callable Notes on an equal and ratable basis or
otherwise discharge or defease the Non-Callable Notes with the same effect, (4)
you may commence change of control tender offers under the terms of the
indentures governing the first mortgage notes and senior secured notes
(collectively, the "EXISTING TARGET SUBSIDIARY BONDS") of Target's Shreveport
subsidiary (such subsidiary and its subsidiaries are referred to as the "TARGET
UNRESTRICTED GROUP") at a price of 101% of the principal amount thereof, plus
accrued and unpaid interest and (5) approximately $17.6 million of personal
property subject to capital leases at Target may be purchased and the associated
leases terminated, if necessitated by the Acquisition. The refinancing or
replacement of all of the foregoing debt (and related consent solicitations) of
Borrower, Target and their respective subsidiaries are referred to collectively
as the "REFINANCING." The sources and uses of funds necessary to consummate the
Transactions (as defined below) will be as set forth in Annex A hereto.

     In order to effectuate the foregoing, you have advised us that you intend
to enter into senior secured credit facilities in the amount of $1,000.0 million
(the "CREDIT FACILITIES").

<PAGE>

     The Acquisition, the Refinancing, the entering into and borrowings under
the Credit Facilities by the parties herein described and the other transactions
contemplated hereby entered into and consummated in connection with the
Acquisition are herein referred to as the "TRANSACTIONS."

     You have requested that BSCL and Merrill Lynch commit to provide the Credit
Facilities to finance the Acquisition and the Refinancing and to pay the related
fees and expenses.

     Accordingly, subject to the terms and conditions set forth below, each of
BSCL and Merrill Lynch hereby agrees with you as follows:

          1. COMMITMENT. Each of BSCL and Merrill Lynch (or one or more of their
     affiliates) hereby commits to provide to Borrower 50% of each of the Credit
     Facilities upon the terms and subject to the conditions set forth or
     referred to herein, in the Fee Letter (the "FEE LETTER") dated the date
     hereof and delivered to you and in the Senior Secured Credit Facilities
     Summary of Terms and Conditions attached hereto (and incorporated by
     reference herein) as EXHIBIT A (the "TERM SHEET").

          2. SYNDICATION. We reserve the right and intend, prior to or after the
     execution of the definitive documentation for the Credit Facilities (the
     "CREDIT DOCUMENTS"), to syndicate all or a portion of our commitments to
     one or more financial institutions (together with BSCL and Merrill Lynch,
     the "LENDERS"). Our commitment hereunder is subject to each of Bear Stearns
     (or one of its affiliates) and Merrill Lynch, Pierce, Fenner & Smith
     Incorporated ("MLPF&S") (or one of its affiliates) acting as a joint lead
     arrangers of and joint book-runners for the Credit Facilities and each of
     BSCL and Merrill Lynch acting as syndication agents for the Credit
     Facilities. We (or one of our affiliates) will manage all aspects of the
     syndication (in consultation with you), including decisions as to the
     selection of potential Lenders to be approached and when they will be
     approached, when their commitments will be accepted, which Lenders will
     participate and the final allocations of the commitments among the Lenders
     (which are likely not to be PRO RATA across facilities among Lenders), and
     we will exclusively perform all functions and exercise all authority as
     customarily performed and exercised in such capacities, including selecting
     counsel for the Lenders, negotiating the Credit Documents and determining
     the amount and distribution of fees among the Lenders, PROVIDED, HOWEVER,
     that we agree not to syndicate any portion of our commitments hereunder to
     Mackay-Shields. Any agent titles (including co-agents) awarded to other
     Lenders are subject to our prior approval and shall not entail any role
     with respect to the matters referred to in this paragraph without our prior
     consent. You agree that no Lender will receive compensation outside the
     terms contained herein and in the Fee Letter in order to obtain its
     commitment to participate in the Credit Facilities. We may select (with
     your consent, not to be unreasonably withheld, delayed or conditioned) a
     Lender to act as an administrative agent (the "ADMINISTRATIVE AGENT") for
     the Credit Facilities to perform such ministerial and administrative
     functions as we shall reasonably designate.

          You understand that we intend to commence the syndication of the
     Credit Facilities promptly, and you agree to assist us actively in
     achieving a timely syndication that is satisfactory to us. The syndication
     efforts will be accomplished by a variety of means, including direct
     contact during the syndication between senior management, advisors and
     affiliates of Borrower and Target on the one hand, and the proposed Lenders
     on the other hand and Borrower hosting, with us, at least one

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<PAGE>

     meeting with prospective Lenders at such times and places as we may
     reasonably request. You agree to, upon our request, (a) provide, and cause
     your affiliates and advisors to provide, and use your reasonable best
     efforts to have Target provide, to us all information reasonably requested
     by us to successfully complete the syndication, including the information
     and projections (including updated projections) contemplated hereby, and
     (b) assist, and cause your affiliates and advisors to assist, and use your
     reasonable best efforts to have Target assist, us in the preparation of a
     Confidential Information Memorandum and other marketing materials (the
     contents of which you shall be solely responsible for) to be used in
     connection with the syndication, including making available representatives
     of Borrower and Target. You also agree to use your reasonable best efforts
     to ensure that our syndication efforts benefit materially from your (and
     your affiliates') existing lending relationships. You further agree that,
     at your expense, you will work with us to procure a rating for the Credit
     Facilities by Moody's Investor's Service, Inc. and Standard & Poor's
     Ratings Group promptly after the execution of the Acquisition Agreement.

          3. FEES. As consideration for our commitment hereunder and our
     agreement to arrange, manage, structure and syndicate the Credit
     Facilities, you agree to pay to us the nonrefundable fees as set forth in
     the Fee Letter as and when specified in such document.

          4. CONDITIONS. Each of Bear Stearns', BSCL's and Merrill Lynch's
     commitment hereunder is subject to the conditions set forth elsewhere
     herein and in the Term Sheet.

          Our commitment hereunder is also subject to (a) other than with
     respect to changes in the Illinois gaming tax law enacted in June 2002,
     there not having occurred or becoming known any material adverse change or
     any condition or event that could reasonably be expected to result in a
     material adverse change in the business, operations, condition (financial
     or otherwise), assets, properties, liabilities (contingent or otherwise) or
     prospects of either (1) Borrower and its subsidiaries taken as a whole
     (before or after giving effect to the Transactions) since December 31, 2001
     or (2) Target and its subsidiaries taken as a whole (before giving effect
     to the Transactions) since December 31, 2001 (it being acknowledged that
     neither (i) the existence of the Notice of Violation and Hearing from the
     State of Louisiana Gaming Control Board dated July 22, 2002 addressed to
     Hollywood Casino Shreveport nor (ii) the existence of the lawsuits by and
     against Target and Jack E. Pratt et al shall, by itself, constitute a
     material adverse change); (b) there not having occurred and be continuing
     in or affecting current loan syndication or financial, banking or capital
     market conditions generally that, individually or in the aggregate, in our
     good faith judgment would materially adversely affect our ability to
     syndicate the Credit Facilities; (c) our reasonable satisfaction that,
     after the date hereof and prior to and during the syndication of the Credit
     Facilities, none of Borrower, Target or any of their respective
     subsidiaries or affiliates shall have syndicated or issued, attempted to
     syndicate or issue, announced or authorized the announcement of, or engaged
     in discussions concerning the syndication or issuance of, any debt facility
     or debt security of any of them, including renewals thereof (other than the
     Credit Facilities (including the Incremental Facility as defined in the
     Term Sheet) and any debt financing which we have requested to replace the
     Second Priority Facility and the Second Term Loan B Draw (each as defined
     in the Term Sheet)) that shall have disrupted or interfered with the
     syndication of the Credit Facilities; (d) our reasonable satisfaction that
     the Acquisition will be consummated in all material respects in accordance
     with the terms of the Acquisition Agreement (without the waiver or
     amendment of any material condition unless consented to by the Lead
     Arrangers), which terms, along with the

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<PAGE>

     conditions and structure of the Acquisition and the Acquisition Agreement,
     shall be in form and substance satisfactory to the Lead Arrangers (it being
     acknowledged that the Acquisition Agreement as in effect on the date
     hereof, and all exhibits, schedules, appendices and attachments thereto are
     satisfactory); (e) our receipt of (i) quarterly consolidated financial
     statements of Borrower and Target within 45 days of the end of each fiscal
     quarter to the extent not previously filed with the Securities and Exchange
     Commission and (ii) monthly consolidated financial statements of Borrower
     and Target within 30 days of the end of each month subsequent to June 30,
     2002 (which date will be extended to 35 days for the month for which the
     SAS 71 review for the last twelve month period is being conducted and 45
     days for the month ended December 31, 2002) (collectively, the "REQUIRED
     FINANCIALS"); (f) you, Bear Stearns and MLPF&S shall have executed and
     delivered the engagement letter (the "ENGAGEMENT LETTER") dated the date
     hereof and you shall not be in breach thereof or in breach of the Fee
     Letter; and (g) none of the Information and Projections (each as defined
     below in Section 5 hereof) shall be misleading or incorrect in any material
     respect taken as a whole, in light of the circumstances under which such
     statements were made.

          5. INFORMATION AND INVESTIGATIONS. You hereby represent and covenant
     that (a) all information and data (excluding financial projections) that
     have been or will be made available by you or any of your affiliates,
     representatives or advisors to us or any Lender (whether prior to or on or
     after the date hereof) in connection with the Transactions (including, to
     our knowledge with respect to Target), taken as a whole (the
     "INFORMATION"), is and will be complete and correct in all material
     respects and does not and will not, taken as a whole, contain any untrue
     statement of a material fact or omit to state any material fact necessary
     in order to make the statements contained therein not misleading in light
     of the circumstances under which such statements are made, and (b) all
     financial projections concerning Borrower and its subsidiaries and, to our
     knowledge, Target and its subsidiaries and the transactions contemplated
     hereby (the "PROJECTIONS") that have been made or will be prepared by or on
     behalf of you or any of your affiliates, representatives or advisors and
     that have been or will be made available to us or any Lender in connection
     with the transactions contemplated hereby have been and will be prepared in
     good faith based upon assumptions believed by you to be reasonable at the
     time they were prepared (it being understood that the Projections are
     subject to significant contingencies and uncertainties, many of which are
     beyond our control, and do not constitute a guarantee or representation of
     future results). You agree to supplement the Information and the
     Projections from time to time until the date of execution and delivery of
     the Credit Documents and, if requested by us, for a reasonable period
     thereafter necessary to complete the syndication of the Credit Facilities
     so that the representation and covenant in the preceding sentence remain
     correct in all material respects and to permit us to evaluate whether the
     conditions to our commitments have been satisfied. In syndicating the
     Credit Facilities we will be entitled to use and rely primarily on the
     Information and the Projections without responsibility for independent
     check or verification thereof.

          6. INDEMNIFICATION. You agree (i) to indemnify and hold harmless each
     of Bear Stearns, BSCL and Merrill Lynch and each of the other Lenders and
     their respective officers, directors, employees, affiliates, agents and
     controlling persons (Bear Stearns, BSCL, Merrill Lynch and each such other
     person being an "INDEMNIFIED PARTY") from and against any and all losses,
     claims, damages, costs, expenses and liabilities, joint or several, to
     which any Indemnified Party may become subject under any applicable law, or
     otherwise related to or arising out of or in connection with this
     Commitment Letter, the Fee Letter, the Term Sheet, the Credit Facilities,
     the loans under the Credit Facilities, the use of proceeds

                                       4
<PAGE>

     of any such loan, any of the Transactions or any related transaction and
     the performance by any Indemnified Party of the services contemplated
     hereby and will reimburse each Indemnified Party for any and all expenses
     (including reasonable counsel fees and expenses) as they are incurred in
     connection with the investigation of or preparation for or defense of any
     pending or threatened claim or any action or proceeding arising therefrom,
     whether or not such Indemnified Party is a party and whether or not such
     claim, action or proceeding is initiated or brought by or on behalf of you,
     Target, or any of your or Target's respective affiliates and whether or not
     any of the Transactions are consummated or this Commitment Letter is
     terminated, except to the extent resulting primarily from such Indemnified
     Party's bad faith, gross negligence or willful misconduct and (ii) not to
     assert any claim against any Indemnified Party for consequential, punitive
     or exemplary damages on any theory of liability in connection in any way
     with the transactions described in or contemplated by this Commitment
     Letter.

          You agree that, without our prior written consent, neither you nor any
     of your affiliates or subsidiaries will settle, compromise or consent to
     the entry of any judgment in any pending or threatened claim, action or
     proceeding in respect of which indemnification has been or could be sought
     under the indemnification provisions hereof (whether or not any other
     Indemnified Party is an actual or potential party to such claim, action or
     proceeding), unless such settlement, compromise or consent (i) includes an
     unconditional written release in form and substance satisfactory to the
     Indemnified Parties of each Indemnified Party from all liability arising
     out of such claim, action or proceeding and (ii) does not include any
     statement as to or an admission of fault, culpability or failure to act by
     or on behalf of any Indemnified Party.

          In the event that an Indemnified Party is requested or required to
     appear as a witness in any action brought by or on behalf of or against you
     or any of your subsidiaries or affiliates in which such Indemnified Party
     is not named as a defendant, you agree to reimburse such Indemnified Party
     for all expenses incurred by it in connection with such Indemnified Party's
     appearing and preparing to appear as such a witness, including, without
     limitation, the reasonable fees and expenses of its legal counsel.

          7. EXPENSES. You agree to reimburse us and our affiliates for our and
     their reasonable expenses upon our request made from time to time
     (including, without limitation, all reasonable due diligence investigation
     expenses, fees of consultants engaged with your consent (not to be
     unreasonably withheld), syndication expenses (including printing,
     distribution and bank meetings), appraisal and valuation fees and expenses,
     travel expenses, rating agency fees, duplication fees and expenses, audit
     fees, search fees, filing and recording fees and the reasonable fees,
     disbursements and other charges of counsel (and any local counsel) and any
     sales, use or similar taxes (and any additions to such taxes) related to
     any of the foregoing) incurred in connection with the negotiation,
     preparation, execution and delivery, waiver or modification, collection and
     enforcement of this Commitment Letter, the Term Sheet, the Fee Letter and
     the Credit Documents and the security arrangements (if any) in connection
     therewith and whether or not such fees and expenses are incurred before or
     after the date hereof or any loan documentation is entered into or the
     Transactions are consummated or any extensions of credit are made under the
     Credit Facilities or this Commitment Letter is terminated or expires.

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<PAGE>

          8. CONFIDENTIALITY. This Commitment Letter, the Term Sheet, the Fee
     Letter, the contents of any of the foregoing and our and/or our affiliates'
     activities pursuant hereto or thereto are confidential and shall not be
     disclosed by or on behalf of you or any of your affiliates to any person
     without our prior written consent, except that you may disclose this
     Commitment Letter and the Term Sheet (i) to your and Target's and your and
     its respective officers, directors, employees and advisors, and then only
     in connection with the Transactions and on a confidential need-to-know
     basis and (ii) as you are required to make by applicable law or compulsory
     legal process (based on the advice of legal counsel); PROVIDED, HOWEVER,
     that in the event of any such compulsory legal process you agree to give us
     prompt notice thereof and to cooperate with us in securing a protective
     order in the event of compulsory disclosure and that any disclosure made
     pursuant to public filings shall be subject to our prior review. You agree
     that you will permit us to review and approve any reference to any of us or
     any of our affiliates in connection with the Credit Facilities or the
     transactions contemplated hereby contained in any press release or similar
     public disclosure prior to public release. You agree that we and our
     affiliates may share information concerning you, and, subject to the
     existing confidentiality agreement between Target and Borrower, Target and
     your and Target's respective subsidiaries and affiliates among ourselves
     solely in connection with the performance of our services hereunder and the
     evaluation and consummation of financings and Transactions contemplated
     hereby.

          9. TERMINATION. Our commitment hereunder is based upon the financial
     and other information regarding you and Target and your and its respective
     subsidiaries previously provided to us. In the event that by means of
     continuing review or otherwise we become aware of or discover new
     information or developments concerning conditions or events previously
     disclosed to us that is inconsistent in any material adverse respect with
     the Projections or the Information provided to us prior to the date hereof,
     or if any event or condition has occurred or become known (other than (i)
     changes in Illinois gaming tax law enacted in June 2002, (ii) the existence
     of the lawsuits by and against Target and Jack E. Pratt et al and (iii) the
     existence of the Notice of Violation and Hearing from the State of
     Louisiana Gaming Control Board dated July 22, 2002 addressed to Hollywood
     Casino Shreveport that in our judgment has had or could reasonably be
     expected to have a material adverse effect on the business, operations,
     condition (financial or otherwise), assets, properties, liabilities
     (contingent or otherwise) or prospects of either (1) Borrower and its
     subsidiaries taken as a whole (either before or after giving effect to the
     Transactions) since December 31, 2001 or (2) Target and its subsidiaries
     taken as a whole (before giving effect to the Transactions) since December
     31, 2001, this Commitment Letter and both of our commitments hereunder
     shall terminate upon written notice by either Bear Stearns, BSCL or Merrill
     Lynch. In addition, our commitments hereunder shall terminate in their
     entirety (A) on the date that is 45 days after the receipt by you of all
     requisite regulatory approvals but in any event no later than July 31, 2003
     if the Credit Documents are not executed and delivered by Borrower and the
     Lenders by such date, (B) on the date of execution and delivery of the
     Credit Documents by Borrower and the Lenders and (C) the date of
     termination or abandonment of the Acquisition or the date of the
     Acquisition if the initial funding under the Credit Facilities does not
     occur on such date. Notwithstanding the foregoing, the provisions of
     Sections 6, 7, 8 and 11 hereof shall survive any termination pursuant to
     this Section 9; PROVIDED that the provisions of Sections 6 and 7 shall be
     superceded and replaced in their entirety by the provisions in the
     definitive documentation relating to expenses and indemnification.

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          10. ASSIGNMENT; ETC. This Commitment Letter and our commitment
     hereunder shall not be assignable by any party hereto (other than by us to
     our affiliates) without the prior written consent of the other parties
     hereto, and any attempted assignment shall be void and of no effect;
     PROVIDED, HOWEVER, that nothing contained in this Section 10 shall prohibit
     us (in our sole discretion) from (i) performing any of our duties hereunder
     through any of our affiliates, and you will owe any related duties
     (including those set forth in Section 2 above) to any such affiliate, and
     (ii) granting (in consultation with you) participations in, or selling (in
     consultation with you) assignments of all or a portion of, the commitments
     or the loans under the Credit Facilities pursuant to arrangements
     satisfactory to us. Upon any such assignment, upon the request of the Lead
     Arrangers, the Company will enter into a customary assignment agreement
     with any such assignee; following the execution and delivery thereof, our
     commitments hereunder will be reduced by the amount of the commitment
     assumed in such assignment agreement. Participation will not, in any event,
     reduce commitments. This Commitment Letter is solely for the benefit of the
     parties hereto and does not confer any benefits upon, or create any rights
     in favor of, any other person.

          11. GOVERNING LAW; WAIVER OF JURY TRIAL. This Commitment Letter shall
     be governed by, and construed in accordance with, the laws of the State of
     New York. Each of the parties hereto waives all right to trial by jury in
     any action, proceeding or counterclaim (whether based upon contract, tort
     or otherwise) related to or arising out of any of the Transactions or the
     other transactions contemplated hereby, or the performance by us or any of
     our affiliates of the services contemplated hereby.

          12. AMENDMENTS; COUNTERPARTS; ETC. No amendment or waiver of any
     provision hereof or of the Term Sheet shall be effective unless in writing
     and signed by the parties hereto and then only in the specific instance and
     for the specific purpose for which given. This Commitment Letter may be
     executed in any number of counterparts and by different parties hereto in
     separate counterparts, each of which when so executed shall be deemed to be
     an original and all of which taken together shall constitute one and the
     same agreement. Delivery of an executed counterpart by telecopier shall be
     effective as delivery of a manually executed counterpart.

          13. PUBLIC ANNOUNCEMENTS; NOTICES. We may, subject to your prior
     consent (not to be unreasonably withheld, delayed or conditioned) at our
     expense, publicly announce as we may choose the capacities in which we or
     our affiliates have acted hereunder. Any notice given pursuant hereto shall
     be mailed or hand delivered in writing, if to (i) you, at your address set
     forth on page one hereof, with a copy to Peter S. Sartorius, Esq., at
     Morgan, Lewis & Bockius, LLP, 1701 Market Street, Philadelphia,
     Pennsylvania 19103; and (ii) Bear Stearns and BSCL at 383 Madison Avenue,
     New York, New York 10179, Attention: Victor Bulzacchelli and Merrill Lynch,
     at World Financial Center, North Tower, 27th Floor, 250 Vesey Street, New
     York, New York 10281, Attention: Chris Ooten, with a copy, in either case,
     to Jonathan A. Schaffzin, Esq., at Cahill Gordon & Reindel, 80 Pine Street,
     New York, New York 10005.

                            (Signature Page Follows)

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<PAGE>

     Please confirm that the foregoing correctly sets forth our agreement of the
terms hereof and the Fee Letter by signing and returning to the undersigned the
duplicate copy of this letter and the Fee Letter enclosed herewith. Unless we
receive your executed duplicate copies hereof and thereof by 5:00 p.m., New York
City time, on August 16, 2002, our commitment hereunder will expire at such
time.

     We are pleased to have this opportunity and we look forward to working with
you on this transaction.

                                 Very truly yours,

                                 BEAR, STEARNS & CO. INC.

                                 By: /s/ KEITH C. BARNISH
                                     ----------------------------------
                                     Name: Keith C. Barnish
                                     Title: Senior Managing Director

                                 BEAR STEARNS CORPORATE LENDING INC.

                                 By: /s/ KEITH C. BARNISH
                                     ----------------------------------
                                     Name:  Keith C. Barnish
                                     Title: Executive Vice President

                                 MERRILL LYNCH CAPITAL CORPORATION

                                 By: /s/ STEPHEN D. PARTS
                                     ----------------------------------
                                     Name:  Stephen D. Paras
                                     Title: Vice President

Accepted and agreed to as of the date first written above:

PENN NATIONAL GAMING, INC.

By: /s/ WILLIAM J. CLIFFORD
    ----------------------------------
    Name:  William J. Clifford
    Title: Chief Financial Officer

<PAGE>

                                                                         ANNEX A
                            SOURCES AND USES OF FUNDS
                               (IN $ IN MILLIONS)

<TABLE>
<CAPTION>

                 SOURCES                                                      USES
                 -------                                                      ----
<S>                                           <C>           <C>                                          <C>
Cash on hand at Borrower and Target           $  100.8      Cash purchase price of equity of Target      $   347.5

Revolving Facility(1)                         $   12.9      Refinance Target 11.25% Senior Secured       $   378.4
                                                            Notes, Floating Rate Senior Secured
                                                            Notes, Capital Leases and Other

Term Loan A Facility                          $  100.0      Refinancing Existing Borrower Revolving      $     5.2
                                                            Facility Debt

Term Loan B Facility(2)                       $  600.0      Pension and Severance Costs                  $    16.1

Second Priority Facility(3)                   $    0.0      Transaction and tender fees and expenses     $    66.5

                                                            Repurchase of Shreveport Notes(4)            $     0.0
                                              --------                                                   ---------
        Total Sources                         $  813.7              Total Uses                           $   813.7
                                              ========                                                   =========
</TABLE>

--------------------

1.   $100.0 million of commitments; approximately $12.9 drawn at closing
     (assuming termination of Target capital leases).

2.   $700.0 million of commitments; additional $100.0 million available draw for
     repurchase of Shreveport Notes.

3.   $100.0 million of commitments available for repurchase of Shreveport Notes.

4.   Assumes no tender for Existing Target Subsidiary Notes.

<PAGE>

CONFIDENTIAL

                        SENIOR SECURED CREDIT FACILITIES

                        SUMMARY OF TERMS AND CONDITIONS(a)

<TABLE>
<S>                                   <C>
Borrower:                             Penn National Gaming, Inc. ("BORROWER").

Joint Lead Arrangers and Joint        Bear, Stearns & Co. and MLPF&S (collectively,
   Book Runners:                      the "LEAD ARRANGERS").

Syndication Agents:                   BSCL and Merrill Lynch.

Administrative Agent:                 A Lender or other financial institution to be selected by the Lead
                                      Arrangers with the consent (not to be unreasonably withheld) of
                                      Borrower (the "ADMINISTRATIVE AGENT").

Lenders:                              BSCL (or one of its affiliates), Merrill Lynch (or one of its
                                      affiliates) and a syndicate of financial institutions (the
                                      "Lenders") arranged by the Lead Arrangers in consultation with
                                      Borrower.

Credit Facilities:                    Senior secured credit facilities (the "CREDIT FACILITIES") in an
                                      aggregate principal amount of up to $1,000.0 million, such Credit
                                      Facilities comprising:

                                             (A) TERM LOAN FACILITIES. Term loan facilities in an
                                             aggregate principal amount of $900.0 million (the "TERM LOAN
                                             FACILITIES"), such aggregate principal amount to be
                                             allocated among (i) a Term Loan A Facility in an aggregate
                                             principal amount of up to $100.0 million (the "TERM LOAN A
                                             FACILITY"), (ii) a Term Loan B Facility in an aggregate
                                             principal amount of up to $700.0 million (the "TERM LOAN B
                                             FACILITY"), of which $100.0 million will be available for
                                             the Second Term Loan B Draw (as defined below), and (iii) a
                                             Second Priority Term Loan Facility in an aggregate principal
                                             amount of up to $100.0 million
</TABLE>

-------------------
(a)  Capitalized terms used herein and not defined shall have the meanings
     assigned to such terms in the Commitment Letter (the "COMMITMENT LETTER").

<PAGE>

<TABLE>
<S>                                   <C>
                                             (the "SECOND PRIORITY FACILITY"). Loans under the Term Loan
                                             Facilities are herein referred to as "TERM LOANS."

                                             (B) REVOLVING CREDIT FACILITY. A revolving credit facility
                                             in an aggregate principal amount of $100.0 million (the
                                             "REVOLVING FACILITY"). Loans under the Revolving Facility
                                             are herein referred to as "REVOLVING LOANS"; the Term Loans
                                             and the Revolving Loans are herein referred to collectively
                                             as "LOANS." An amount to be agreed of the Revolving Facility
                                             will be available as a letter of credit subfacility.

Incremental Facility:                 In addition, the Credit Documents (as defined below) will provide
                                      for additional term loans and/or revolving loans, at Borrower's
                                      election (the "INCREMENTAL FACILITY"), in an aggregate principal
                                      amount not to exceed $100.0 million so long as (i) immediately
                                      before and immediately after the borrowing of any such loans there
                                      is no Default or Event of Default and (ii) Borrower has received
                                      gaming licenses from the State of Pennsylvania to operate slot
                                      machines at either of its existing facilities in Pennsylvania;
                                      PROVIDED, HOWEVER, that Borrower uses the funds drawn under the
                                      Incremental Facility solely to buildout such slot operations; and
                                      PROVIDED, FURTHER, that Borrower will be able to draw no more than
                                      $50.0 million per gaming facility for such buildout.

Documentation:                        Usual for facilities and transactions of this type and reasonably
                                      acceptable to Borrower and the Lenders.  The documentation for the
                                      Credit Facilities will include, among others, a credit agreement
                                      (the "CREDIT AGREEMENT"), guarantees and appropriate pledge,
                                      security interest, mortgage and other collateral documents
                                      (collectively, the "CREDIT DOCUMENTS").  Borrower and the
                                      Guarantors (as defined below under "Guarantors") are herein
                                      referred to as the "CREDIT PARTIES" and individually referred to as
                                      a "CREDIT PARTY."

Transactions:                         As set forth in the Commitment Letter.

Availability/Purpose:                 (A)   TERM LOAN FACILITIES.  Term Loans (other than $100.0 million
                                      under the Term Loan B Facility and the Second Priority Term Loan
                                      Facility) will be available to finance the Acquisition and the
                                      Refinancing and to pay related fees

                                                    2
<PAGE>

                                      and expenses, subject to the terms and conditions set forth in the
                                      Credit Documents, on the date of consummation of the Acquisition
                                      (the "CLOSING DATE") in a single draw. The remaining $100.0 million
                                      under the Term Loan B Facility (the "SECOND TERM LOAN B DRAW") and
                                      amounts under the Second Priority Facility will only be available
                                      to fund the "Change of Control Offers" hereinafter referred to. To
                                      the extent the Second Term Loan B Draw and Second Priority Facility
                                      Loans are not made on or prior to the expiration of such "Change of
                                      Control Offers," the unutilized commitments in respect thereof
                                      shall expire. Term Loans repaid or prepaid may not be reborrowed.

                                      (B) REVOLVING FACILITY. Not more than approximately $90.0 million
                                      of the Revolving Facility will be available to finance the
                                      Acquisition and the Refinancing and will otherwise be solely
                                      available for working capital and general corporate purposes on a
                                      fully revolving basis, subject to the terms and conditions set
                                      forth in the Credit Documents, in the form of revolving loans and
                                      letters of credit on and after the Closing Date until the date that
                                      is five years after the Closing Date (the "R/C MATURITY DATE").

Guarantors:                           Each of Borrower's direct and indirect domestic subsidiaries
                                      existing on the Closing Date or thereafter created or acquired
                                      shall unconditionally guarantee, on a joint and several basis, all
                                      obligations of Borrower under the Credit Facilities and (to the
                                      extent relating to the Loans) under each interest rate protection
                                      agreement entered into with a Lender or an affiliate of a Lender;
                                      PROVIDED that no guarantee need be provided by any member of the
                                      Target Unrestricted Group to the extent prohibited by the Existing
                                      Target Subsidiary Bonds and other indebtedness of Borrower; and
                                      PROVIDED, FURTHER, that no guarantee need be provided by Hollywood
                                      Casino - Aurora, Inc. to the extent such guarantee is prohibited
                                      by Illinois gaming authorities provided that Borrower has used
                                      commercially reasonable efforts with such authorities to arrange
                                      for such guarantees.  Each guarantor of any of the Credit
                                      Facilities is herein referred to as a "GUARANTOR" and its
                                      guarantee is referred to herein as a "GUARANTEE."

Security:                             The Credit Facilities, the Guarantees and (to the extent relating
                                      to the Loans) the obligations of Borrower under each interest rate
                                      protection agreement entered into with a Lender or any affiliate of
                                      a Lender will be secured by (A) a perfected

                                                    3
<PAGE>

                                      lien on, and pledge of, all of the capital stock and intercompany
                                      notes of each of the direct and indirect subsidiaries of Borrower
                                      existing on the Closing Date or thereafter created or acquired,
                                      except that with respect to foreign subsidiaries only the capital
                                      stock of direct foreign subsidiaries of Borrower or a Guarantor
                                      need be pledged and only 65% of the voting capital stock thereof
                                      need be pledged; and (B) a perfected lien on, and security interest
                                      in, all of the tangible and intangible properties and assets
                                      (including all contract rights, real property interests,
                                      trademarks, trade names, equipment and proceeds of the foregoing)
                                      of each Credit Party (collectively, the "COLLATERAL"), except for
                                      (1) in the case of clause (B), liens or security interests in the
                                      Pennwood Joint Venture, the Casino Rama management contract and the
                                      leasehold estate at Casino Rouge to the extent such liens or
                                      security interests are prohibited by the terms thereof and liens or
                                      security interests pertaining to the Aurora, Illinois facility of
                                      Target if prohibited by Illinois gaming authorities to the extent
                                      Borrower has used commercially reasonable best efforts with such
                                      authorities to arrange for such liens and security interests; and
                                      (2) in the case of clause (A) and clause (B), those properties and
                                      assets as to which the Lead Arrangers shall determine in their sole
                                      discretion that the costs of obtaining such security interest are
                                      excessive in relation to the value of the security to be afforded
                                      thereby (it being understood that none of the foregoing shall be
                                      subject to any other liens or security interests, except for
                                      certain customary exceptions to be agreed upon). All such security
                                      interests will be created pursuant to documentation satisfactory in
                                      all respects to the Lead Arrangers, and on the Closing Date, such
                                      security interests shall have become perfected (or arrangements for
                                      the perfection thereof reasonably satisfactory to the Lead
                                      Arrangers shall have been made) and the Lead Arrangers shall have
                                      received satisfactory evidence as to the enforceability and
                                      priority thereof. All liens to secure the Credit Facilities shall
                                      be equal and ratable, except that any Loans under the Second
                                      Priority Facility will be secured on a basis junior to the other
                                      Credit Facilities on a basis customary for facilities of this type.

Termination of Commitments:           The commitments in respect of the Credit Facilities (including
                                      pursuant to the Commitment Letter) will terminate in their entirety
                                      (A) on the date that is 45 days after receipt by Borrower of all
                                      requisite regulatory approvals but in any

                                                    4
<PAGE>

                                      event no later than July 31, 2003; (ii) the date of the Acquisition
                                      if the initial funding under the Credit Facilities does not occur
                                      on such date; and (iii) the termination or abandonment of the
                                      Acquisition.

Final Maturity:                       (A) TERM LOAN FACILITIES. The Term Loan A Facility will mature on
                                      the fifth anniversary of the Closing Date, the Term Loan B Facility
                                      will mature on the sixth anniversary of the Closing Date and the
                                      Second Priority Facility will mature on the seventh anniversary of
                                      the Closing Date; PROVIDED that the Term Loan B Facility and the
                                      Second Priority Facility will mature six months prior to the
                                      maturity of Borrower's outstanding 11 1/8% Senior Subordinated
                                      Notes due 2008, unless such notes are refinanced in full to a date
                                      that is at least six months after the above-referenced maturity
                                      dates of the Term Loan B Facility and the Second Priority Facility.

                                      (B) REVOLVING FACILITY. The Revolving Facility will mature on the
                                      R/C Maturity Date.

Amortization Schedule:                The Term Loan A Facility will amortize on a quarterly basis
                                      (beginning with the first full fiscal quarter after the Closing
                                      Date) in amounts to be agreed.

                                      Each of the Term Loan B Facility and the Second Priority Facility
                                      will amortize at a rate of 1.00% PER ANNUM on a quarterly basis
                                      (beginning with the first full fiscal quarter after the Closing
                                      Date) for the first five and six years, respectively, after the
                                      Closing Date with the balance paid in four equal quarterly
                                      installments thereafter.

Letters of Credit:                    Letters of credit under the Revolving Facility ("LETTERS OF
                                      CREDIT") will be issued by a Lender to be agreed by the Lead
                                      Arrangers and Borrower (in such capacity, the "L/C LENDER"). The
                                      issuance of all Letters of Credit shall be subject to the customary
                                      procedures of the L/C Lender.

Letter of Credit Fees:                Letter of Credit fees will be payable for the account of the
                                      Revolving Facility Lenders on the daily average undrawn face amount
                                      of each Letter of Credit at a rate PER ANNUM equal to the
                                      applicable margin for Revolving Loans that are LIBOR rate loans in
                                      effect at such time, which fees shall be paid quarterly in
                                      arrears.  In addition, an issuing fee on the face amount of each
                                      Letter of Credit equal to 0.25% PER ANNUM

                                                    5
<PAGE>

                                      shall be payable to the L/C Lender for its own account, which fee
                                      shall also be payable quarterly in arrears.

Interest Rates:                       Interest rates in connection with the Credit Facilities will be as
                                      specified on ANNEX I attached hereto.

Default Rate:                         Overdue principal, interest and other amounts shall bear interest
                                      at a rate PER ANNUM equal to 2% in excess of the applicable
                                      interest rate (including applicable margin).

Mandatory Prepayments/                Subject to the next paragraph, the Credit Facilities will be
  Reductions in Commitments:          required to be prepaid with (a) beginning with the fiscal year
                                      ended December 31, 2003, (i) if Total Leverage Ratio (as defined
                                      below) is greater than 4.5x, 75% of annual Excess Cash Flow (to be
                                      defined), (ii) if Total Leverage Ratio is less than 4.5x, 50% of
                                      annual Excess Cash Flow or (iii) if Total Leverage Ratio is less
                                      than 3.5x, 0% of annual Excess Cash Flow; PROVIDED, HOWEVER, that
                                      such determinations with respect to the fiscal year ended December
                                      31, 2003 shall be based on actual results from the Closing Date;
                                      and PROVIDED, FURTHER, HOWEVER, that if there are amounts
                                      outstanding under the Second Priority Facility, then, for the
                                      Deferral Period (as defined in the Fee Letter) 62.5% of annual
                                      Excess Cash Flow measured since the Closing Date will be applied to
                                      the Second Priority Facility on a monthly basis and 37.5% to the
                                      balance of the Credit Facilities as provided above, (b) 100% of the
                                      net cash proceeds (including insurance proceeds) of asset sales and
                                      other asset dispositions by Borrower or any of its subsidiaries
                                      (subject to baskets and exceptions and customary reinvestment
                                      rights), (c) 100% of the net cash proceeds of the issuance or
                                      incurrence of debt by Borrower or any of its subsidiaries (subject
                                      to baskets and exceptions to be agreed upon) and (d) (i) in the
                                      event that any of the Second Priority Facility is drawn and remains
                                      outstanding, 100% of the net proceeds from any issuance of equity
                                      securities in any public offering or private placement or from any
                                      capital contribution (subject to baskets and exceptions to be
                                      agreed upon) and (ii) if there are no amounts outstanding under the
                                      Second Priority Facility, 50% of such net proceeds until such time
                                      as the Total Leverage Ratio (as defined below) is below 4.0:1.0.

                                      Mandatory prepayments will be applied PRO RATA among the Term Loan
                                      Facilities based on the aggregate principal

                                                    6
<PAGE>

                                      amount of Term Loans then outstanding under each such Term Loan
                                      Facility; PROVIDED that (1) in the event that any of the Second
                                      Priority Facility is drawn and remains outstanding, mandatory
                                      prepayments of the type referred to in clause (c) or (d) of the
                                      immediately preceding paragraph shall be applied, first, to the
                                      Second Priority Facility and, at the Second Term Loan B Draw
                                      Lenders' option, the Second Term Loan B Draw and, second, PRO RATA
                                      among the remaining Term Loan Facilities and (2) mandatory
                                      prepayments of the type referred to in clause (b) of the
                                      immediately preceding paragraph shall be applied only to the Second
                                      Priority Facility and, at the Second Term Loan B Draw Lenders'
                                      option, the Second Term Loan B Draw, after application to the other
                                      Term Loan Facilities. Any application to any Term Loan Facility
                                      shall be applied PRO RATA to the remaining scheduled amortization
                                      payments in respect thereof. Notwithstanding the foregoing, any
                                      holder of Term Loans under the Term Loan B Facility may, to the
                                      extent that Term Loans are then outstanding under the Term Loan A
                                      Facility, elect not to have mandatory prepayments applied to such
                                      holder's Term Loans under the Term Loan B Facility, in which case
                                      the aggregate amount so declined shall be applied to the remaining
                                      scheduled amortization payments under the Term Loan A Facility or
                                      Second Priority Facility in accordance with the first sentence of
                                      this paragraph. To the extent that the amount to be applied to the
                                      prepayment of Term Loans exceeds the aggregate amount of Term Loans
                                      then outstanding, such excess shall be applied to the Revolving
                                      Facility to permanently reduce the commitments thereunder.

                                      Revolving Loans will be immediately prepaid to the extent that the
                                      aggregate extensions of credit under the Revolving Facility exceed
                                      the commitments then in effect under the Revolving Facility. To the
                                      extent that the amount to be applied to the repayment of the
                                      Revolving Loans exceeds the amount thereof then outstanding,
                                      Borrower shall cash collateralize outstanding Letters of Credit.

                                      To the extent any debt incurrence or equity issuance (subject to
                                      limited exceptions) occurs on or prior to the expiration of the
                                      "Change of Control Offers" in respect of the Existing Target
                                      Subsidiary Bonds, the net proceeds thereof shall be deposited in an
                                      escrow account with the Administrative Agent to fund the "Change of
                                      Control Offers" or Alternate

                                                    7
<PAGE>

                                      Target Subsidiary Bond Offer and the commitments for the Second
                                      Priority Facility will be correspondingly reduced.

Voluntary Prepayments/                (A) TERM LOAN FACILITIES. Term Loans may be prepaid at
  Reductions in Commitments:          any time in whole or in part at the option of Borrower, in a
                                      minimum principal amount and in multiples to be agreed upon,
                                      without premium or penalty (except, in the case of LIBOR
                                      borrowings, breakage costs related to prepayments not made on the
                                      last day of the relevant interest period). Voluntary prepayments
                                      will be applied first to the Second Priority Facility and then in
                                      amounts and to tranches as determined by Borrower.

                                      (B) REVOLVING FACILITY. The unutilized portion of the commitments
                                      under the Revolving Facility may be reduced and loans under the
                                      Revolving Facility may be repaid at any time, in each case, at the
                                      option of Borrower, in a minimum principal amount and in multiples
                                      to be agreed upon, without premium or penalty (except, in the case
                                      of LIBOR borrowings, breakage costs related to prepayments not made
                                      on the last day of the relevant interest period).

Conditions to Effectiveness           The effectiveness of the credit agreement and the making
  and to Initial Loans:               of the initial Loans under the Credit Facilities shall be subject
                                      to conditions precedent that are usual for facilities and
                                      transactions of this type, to those specified herein and in the
                                      Commitment Letter and to such additional conditions precedent as
                                      may reasonably be required by either of the Lead Arrangers (all
                                      such conditions to be satisfied in a manner satisfactory to both of
                                      the Lead Arrangers, including, but not limited to, execution and
                                      delivery of the Credit Documents reasonably acceptable in form and
                                      substance to the Lead Arrangers by each Credit Party thereto on or
                                      prior to the Closing Date; delivery of reasonably satisfactory
                                      borrowing certificates and other customary closing certificates;
                                      receipt of valid security interests as contemplated hereby; absence
                                      of defaults, prepayment events or creation of liens under debt
                                      instruments or other material agreements as a result of the
                                      transactions contemplated hereby; absence of material litigation;
                                      evidence of corporate authority; receipt of approvals or consents
                                      from governmental authorities and third parties whose approval or
                                      consent is required (i) under the Acquisition Agreement to
                                      consummate the Transaction or (ii) to consummate the financing
                                      therefor; compliance with applicable

                                                    8
<PAGE>

                                      laws, regulations and licensing requirements; delivery of
                                      reasonably satisfactory legal opinions; and adequate insurance.

                                      In addition to those conditions precedent set forth or referred to
                                      in the Commitment Letter, the making of the initial Loans will be
                                      subject to the following conditions:

                                      (A) The delivery, on or prior to the Closing Date, of a
                                          certificate on behalf of Borrower from the chief
                                          financial officer of Borrower and, at the reasonable
                                          request of the Lead Arrangers and at Borrower's
                                          expense, a nationally recognized appraisal or valuation
                                          consultant reasonably satisfactory to the Lead
                                          Arrangers and in form and substance reasonably
                                          satisfactory to the Lead Arrangers with respect to the
                                          solvency (on a consolidated basis) of Borrower and,
                                          with respect to such officer's certificate, of each
                                          Credit Party (other than HWCC - Louisiana, Inc. and its
                                          subsidiaries ("SHREVEPORT") immediately after the
                                          consummation of the Transactions to occur on the
                                          Closing Date (assuming the borrowing in full of the
                                          Second Priority Facility and the Second Term Loan B
                                          Draw).

                                      (B) Simultaneously with the making of the initial Loans,
                                          the Acquisition shall have been consummated in all
                                          material respects in accordance with the terms of the
                                          Acquisition Agreement (without the waiver or amendment
                                          of any material condition unless consented to by the
                                          Lead Arrangers), which terms, along with the conditions
                                          and structure of the Acquisition and the Acquisition
                                          Agreement, shall be in form and substance satisfactory
                                          to the Lead Arrangers (it being acknowledged that the
                                          Acquisition Agreement as in effect on the date hereof,
                                          and all exhibits, schedules, appendices and attachments
                                          thereto are satisfactory). Each of the parties thereto
                                          shall have complied in all material respects with all
                                          covenants set forth in the Acquisition Agreement to be
                                          complied with by it on or prior to the Closing Date
                                          (without the waiver or amendment of any of the material
                                          terms thereof unless consented to by the Lead
                                          Arrangers).

                                                    9
<PAGE>

                                      (C) Simultaneously with the making of the initial Loans,
                                          the Refinancing shall have been effected on terms and
                                          conditions and pursuant to documentation satisfactory
                                          to the Lead Arrangers. As part of the Refinancing, (i)
                                          not less than 85% of the Target Non-Callable Notes
                                          shall have been tendered for cash pursuant to a tender
                                          offer and consent solicitation at a price reasonably
                                          acceptable to the Lead Arrangers, and, in connection
                                          therewith, requisite consents shall have been received
                                          for the elimination of all significant restrictive
                                          covenants and the inclusion as "permitted liens" liens
                                          to secure the Credit Facilities with the collateral
                                          securing the Non-Callable Notes on an equal and ratable
                                          basis or (ii) there shall have been a legal discharge
                                          or defeasance of the Non-Callable Notes with the effect
                                          that the restrictive covenants cease to have effect and
                                          such collateral is available to secure the Credit
                                          Facilities. All liens in respect of the indebtedness
                                          subject to the Refinancing (with limited exceptions to
                                          be agreed upon) shall have been released and the Lead
                                          Arrangers shall have received evidence thereof
                                          satisfactory to the Lead Arrangers and a "pay-off"
                                          letter or letters reasonably satisfactory to the Lead
                                          Arrangers with respect to such Indebtedness.

                                      (D) The Lead Arrangers shall have received reasonably
                                          satisfactory evidence (including satisfactory
                                          supporting schedules and other data) that after giving
                                          effect to the Transactions and the financing therefor
                                          (other than the funding of the Second Term Loan B Draw
                                          and the Second Priority Facility), a closing leverage
                                          ratio (calculated in a manner satisfactory to the Lead
                                          Arrangers) to be defined as the maximum ratio of total
                                          debt (including amounts related to any off-balance
                                          sheet receivables financings or other permitted
                                          securitizations, whether or not they constitute debt
                                          but excluding debt at Shreveport and any Loans under
                                          the Incremental Facility) to pro forma EBITDA for the
                                          combined company (including $7.0 million of add-backs
                                          arising from expected synergies and including the
                                          EBITDA of Target exclusive of Shreveport's EBITDA) for
                                          the last 12 months ended for which financial statements
                                          have been delivered in accordance with the Commitment
                                          Letter for which a SAS 71 review has been completed

                                                   10
<PAGE>

                                          are available, of not greater than (i) 5.1:1.0 if such
                                          ratio is being calculated for the last 12 months ended
                                          November 30, 2002 or before and (ii) 5.0:1.0 thereafter.

                                      (E) The Transactions and the financing therefor shall be in
                                          compliance with all laws and regulations applicable to
                                          the Transactions, including without limitation, all
                                          requisite governmental authorities and third parties
                                          whose approval or consent is required (i) under the
                                          Acquisition Agreement to consummate the Transactions or
                                          (ii) to consummate the financing therefor shall have
                                          approved or consented to the Transactions and the other
                                          transactions contemplated hereby to the extent required
                                          (without the imposition of any materially burdensome
                                          condition or qualification in the judgment of the Lead
                                          Arrangers) and all such approvals shall be in full
                                          force and effect, all applicable waiting periods shall
                                          have expired and there shall be no governmental or
                                          judicial action, actual or threatened, that has or
                                          could reasonably be expected to have a reasonable
                                          likelihood of restraining, preventing or imposing
                                          materially burdensome or materially adverse conditions
                                          on any of the Transactions or the other transactions
                                          contemplated hereby.

                                      (F) No law or regulation shall be applicable in the
                                          judgment of the Lead Arrangers that restrains, prevents
                                          or imposes material adverse conditions upon the
                                          Transactions or the financing thereof, including the
                                          Credit Facilities.

                                      (G) After giving effect to the Transactions, Borrower and
                                          its subsidiaries shall have outstanding no indebtedness
                                          or preferred stock (or direct or indirect guarantees or
                                          other credit support in respect thereof) other than (i)
                                          the Loans, (ii) the existing senior subordinated notes
                                          due 2008 and 2010 of Borrower, (iii) to the extent none
                                          of the Existing Target Subsidiary Bonds are refinanced
                                          with proceeds of the Second Priority Facility or the
                                          Second Term Loan B Draw or otherwise in a manner
                                          acceptable to the Lead Arrangers, the Existing Target
                                          Subsidiary Bonds, (iv) approximately $800,000 of bank
                                          debt at Target's casino hotel and entertainment

                                                 11
<PAGE>

                                          complex in Tunica County, Mississippi, (v) approximately
                                          $17.6 million of personal property subject to capital
                                          leases at Target to the extent not refinanced as part of
                                          the Transactions and (vi) such other limited debt as is
                                          reasonably acceptable to the Lead Arrangers, including not
                                          more than 15% in principal amount of the Non-Callable
                                          Notes. Any required or requested modifications to any debt
                                          instruments of Target or any of its subsidiaries shall
                                          have been obtained on a basis reasonably acceptable to the
                                          Lead Arrangers.

                                      (H) All accrued fees and expenses (including the reasonable
                                          fees and expenses of counsel to the Lead Arrangers) of
                                          the Lead Arrangers in connection with the Credit
                                          Documents shall have been paid (which may be paid out
                                          of the funds advanced on the Closing Date).

                                      (I) The Lead Arrangers shall have received (i) satisfactory
                                          title insurance policies (including such endorsements
                                          as the Lead Arrangers may require), current certified
                                          surveys, evidence of zoning and other legal compliance,
                                          certificates of occupancy, legal opinions and other
                                          customary documentation required by the Lead Arrangers
                                          with respect to all real property subject to mortgages;
                                          (ii) appraisals, satisfactory in form and substance to
                                          the Lead Arrangers, from an appraiser satisfactory to
                                          the Lead Arrangers, of the personal property and other
                                          assets to be agreed upon of Borrower and its
                                          subsidiaries after giving effect to the Transactions;
                                          and (iii) FIRREA appraisals to the extent required by
                                          applicable law or regulation.

                                      (J) To the extent that a change of control offer has been
                                          made and an Alternate Target Subsidiary Bond Offer has
                                          been requested, Borrower shall have used its best
                                          efforts to undertake it on a timely basis.

                                      (K) The Lenders shall have received such other customary
                                          legal opinions, corporate documents and other
                                          instruments and/or certificates as they may reasonably
                                          request.

                                                   12
<PAGE>

Conditions to Second Term             In addition to the conditions referred to above and in the
  Loan B Draw and Second              Commitment Letter, the drawing of the Second Term Loan B Draw and
  Priority Facility Borrowings:       the making of the Second Priority Facility Loans will be subject to
                                      the conditions that (A) Existing Target Subsidiary Bonds shall have
                                      been duly and validly tendered pursuant to the terms of the "Change
                                      of Control Offers" made pursuant to and in compliance with Section
                                      4.16 of the indenture governing the Existing Target Subsidiary
                                      Bonds and (B) the proceeds from the Second Term Loan B Draw and the
                                      Second Priority Facility Borrowings shall be used to consummate
                                      such Change of Control Offer in accordance with its terms;
                                      PROVIDED, HOWEVER, that all amounts under the Second Term Loan B
                                      Draw shall have been drawn prior to funding of the Second Priority
                                      Facility.

Conditions to All                     Each extension of credit under the Credit Facilities will be
  Extensions of Credit:               subject to customary conditions, including the (i) absence of any
                                      Default or Event of Default (to be defined) and (ii) continued
                                      accuracy of representations and warranties in all material respects
                                      (which materiality exception will not apply to representations and
                                      warranties qualified by materiality standards).

Representations and                   Customary for facilities similar to the Credit Facilities and
  Warranties:                         such additional representations and warranties as may reasonably be
                                      required by the Lead Arrangers.

Affirmative Covenants:                Customary for facilities similar to the Credit Facilities and such
                                      affirmative covenants as may reasonably be required by the Lead
                                      Arrangers.

Negative Covenants:                   Customary for facilities similar to the Credit Facilities and such
                                      others as may reasonably be required by the Lead Arrangers (all
                                      such covenants to be subject to customary baskets and exceptions
                                      and such others to be agreed upon), including, but not limited to,
                                      limitation on indebtedness; limitation on liens and further
                                      negative pledges; limitation on investments; limitation on
                                      contingent obligations; limitation on dividends, redemptions and
                                      repurchases of equity interests; limitation on mergers,
                                      acquisitions and asset sales; limitation on capital expenditures;
                                      limitation on sale-leaseback transactions; limitation on
                                      transactions with affiliates; limitation on dividend and other
                                      payment restrictions affecting subsidiaries; limitation on changes
                                      in business conducted; limitation

                                                   13
<PAGE>

                                      on amendment of documents relating to other material indebtedness
                                      and other material documents; limitation on creation of
                                      subsidiaries; and limitation on prepayment or repurchase of other
                                      indebtedness.

Financial Covenants:                  The Credit Facilities will contain financial covenants appropriate
                                      in the context of the proposed transaction based upon the financial
                                      information provided to the Lead Arrangers, including, but not
                                      limited to (definitions and numerical calculations to be set forth
                                      in the Credit Agreement):  minimum Interest Coverage Ratio (to be
                                      defined); maximum Senior Leverage Ratio (to be defined as the ratio
                                      of total senior debt to EBITDA (to include approximately $7.0
                                      million of add-backs arising from expected synergies)); minimum
                                      Fixed Charge Coverage Ratio (to be defined); and Total Leverage
                                      Ratio (to be defined as maximum ratio of total debt (including
                                      amounts related to any off-balance sheet receivables financings or
                                      other permitted securitizations, whether or not they would
                                      constitute debt) to trailing four quarter EBITDA).  The financial
                                      covenants contemplated above will be tested on a quarterly basis
                                      and will apply to Borrower and its subsidiaries on a consolidated
                                      basis commencing with the first quarter after the Closing Date.

Interest Rate Management:             An amount designated by the Lead Arrangers of the projected
                                      outstandings under the Credit Facilities must be hedged on terms
                                      and for a period of time satisfactory to the Lead Arrangers with a
                                      counterparty acceptable to the Lead Arrangers.

Events of Default:                    Customary for facilities similar to the Credit Facilities and
                                      others as may reasonably be required by the Lead Arrangers.

Taxes, Yield Protection and           Usual for facilities and transactions of this type.
  Increased Costs:

Assignments and                       Each assignment (unless to another Lender or its affiliates)
  Participations:                     shall be in a minimum amount of $1.0 million (unless Borrower and
                                      the Lead Arrangers otherwise consent or unless the assigning
                                      Lender's exposure is thereby reduced to $ 0). Assignments (which
                                      may be non-PRO RATA among loans and commitments) shall be permitted
                                      with Borrower's and the Lead Arrangers' consent (such consent not
                                      to be unreasonably withheld, delayed or conditioned), except that
                                      no such

                                                   14
<PAGE>

                                      consent of Borrower need be obtained to effect an assignment to any
                                      Lender (or its affiliates) or if any default has occurred and is
                                      continuing or if determined by the Lead Arrangers, in consultation
                                      with Borrower, to be necessary to achieve a successful syndication.
                                      Participations shall be permitted without restriction. Voting
                                      rights of participants will be subject to customary limitations.

Required Lenders:                     Lenders having a majority of the outstanding credit exposure (the
                                      "REQUIRED LENDERS"), subject to amendments of certain provisions of
                                      the Credit Documents requiring the consent of Lenders having a
                                      greater share (or all) of the outstanding credit exposure or
                                      requiring the consent of a specified affected Credit Facility.

Expenses and Indemnification:         In addition to those out-of-pocket expenses reimbursable under the
                                      Commitment Letter, all reasonable out-of-pocket expenses of the
                                      Lead Arrangers and the Administrative Agent (and the Lenders for
                                      enforcement costs and documentary taxes) associated with the
                                      preparation, execution and delivery of any waiver or modification
                                      (whether or not effective) of, and the enforcement of, any Credit
                                      Document (including the reasonable fees, disbursements and other
                                      charges of counsel for the Lead Arrangers) are to be paid by the
                                      Credit Parties.

                                      The Credit Parties will indemnify each of the Lead Arrangers, the
                                      Administrative Agent and the other Lenders and hold them harmless
                                      from and against all costs, expenses (including fees, disbursements
                                      and other charges of counsel) and liabilities arising out of or
                                      relating to any litigation or other proceeding (regardless of
                                      whether the Lead Arrangers, the Administrative Agent or any such
                                      other Lender is a party thereto) that relate to the Transactions or
                                      any transactions related thereto, except to the extent arising
                                      primarily from such person's bad faith, gross negligence or willful
                                      misconduct.

Governing Law and Forum:              New York.

Waiver of Jury Trial:                 All parties to the Credit Documents waive the right to trial by
                                      jury.

Special Counsel for Lead              Cahill Gordon & Reindel (and one or more local counsel and
  Arrangers:                          regulatory counsel as selected by the Lead Arrangers).
</TABLE>

                                                   15
<PAGE>

                                                                         ANNEX I

<TABLE>
<S>                                   <C>
Interest Rates and Fees:              Borrower will be entitled to make borrowings based on the ABR plus
                                      the Applicable Margin or LIBOR plus the Applicable Margin. The
                                      "APPLICABLE MARGIN" shall be (A) with respect to LIBOR Loans under
                                      the (i) Revolving Facility, 2.50% PER ANNUM; (ii) Term Loan A
                                      Facility 2.50% PER ANNUM; (iii) Term Loan B Facility, 2.75% PER
                                      ANNUM; and (iv) Second Priority Facility, 4.25% PER ANNUM; and (B)
                                      with respect to ABR Loans under the (i) Revolving Facility, 1.50%
                                      PER ANNUM; (ii) Term Loan A Facility, 1.50% PER ANNUM; (iii) Term
                                      Loan B Facility, 1.75% PER ANNUM; and (iv) Second Priority
                                      Facility, 3.25% PER ANNUM.

                                      Unless consented to by the Lead Arrangers in their sole discretion,
                                      no LIBOR Loans may be elected on the Closing Date or prior to the
                                      date 30 days thereafter (unless the completion of the primary
                                      syndication of the Credit Facilities as determined by the Lead
                                      Arrangers shall have occurred), except that, from and after the
                                      fifth business day after the Closing Date, LIBOR periods of 14 days
                                      may be elected until the thirtieth day after the Closing Date.

                                      Notwithstanding the foregoing, on and after the date (the "TRIGGER
                                      DATE") that is the later of (A) if the Second Priority Facility is
                                      drawn down, the date following the expiration of the "Change of
                                      Control Offers" upon which none of the Second Priority Facility is
                                      outstanding, and (B) the first date after the Closing Date on which
                                      Borrower delivers financial statements and a computation of the
                                      Total Leverage Ratio for the first fiscal quarter ended at least
                                      six months after the Closing Date in accordance with the Credit
                                      Agreement, the Applicable Margins for the Revolving Facility and
                                      Term Loan A Facility shall be subject to a grid based on the most
                                      recent Total Leverage Ratio to be negotiated.

                                      "ABR" means the higher of (i) the corporate base rate of interest
                                      announced by the Administrative Agent from time to time, changing
                                      effective on the date of announcement of said corporate base rate
                                      changes, and (ii) the Federal Funds Rate plus 0.50% PER ANNUM. The
                                      corporate base rate is not necessarily the lowest rate charged by
                                      the Administrative Agent to its customers.

<PAGE>

                                      "LIBOR" means the rate determined by the Administrative Agent to be
                                      available to the Lenders in the London interbank market for
                                      deposits in US Dollars in the amount of, and for a maturity
                                      corresponding to, the amount of the applicable LIBOR Loan, as
                                      adjusted for maximum statutory reserves.

                                      Borrower may select interest periods of one, two, three or six
                                      months for LIBOR borrowings. Interest will be payable in arrears
                                      (i) in the case of ABR Loans, at the end of each quarter and (ii)
                                      in the case of LIBOR Loans, at the end of each interest period and,
                                      in the case of any interest period longer than three months, no
                                      less frequently than every three months; PROVIDED, HOWEVER, that if
                                      the Second Priority Facility and the Second Term Loan B Draw are
                                      drawn down, interest shall be paid not less frequently than
                                      interest is paid on the Second Priority Facility and the Second
                                      Term Loan B Draw. Interest on all borrowings shall be calculated on
                                      the basis of the actual number of days elapsed over (x) in the case
                                      of LIBOR Loans, a 360-day year, and (y) in the case of ABR Loans, a
                                      365- or 366-day year, as the case may be.

                                      Commitment fees accrue on the undrawn amount of the Credit
                                      Facilities, commencing on the date of the execution and delivery of
                                      the Credit Documents. The commitment fee in respect of the Credit
                                      Facilities will accrue as set forth in the table below:

                                        TOTAL LEVERAGE              COMMITMENT FEE
                                        --------------              --------------
                                       (greater than) 5.0x               .750%
                                       (less than)    5.0x               .625%
                                       (less than)    4.5x               .500%
                                       (less than)    3.5x               .375%

                                      All commitment fees will be payable in arrears at the end of each
                                      quarter and upon any termination of any commitment, in each case
                                      for the actual number of days elapsed over a 365- or 366-day year.
</TABLE>

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EXHIBIT 10.317    
  

	 
	 	 

	CONFIDENTIAL	 	REDACTED VERSION

[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN

OMITTED AND FILED SEPARATELY WITH THE COMMISSION.

CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH

RESPECT TO THE OMITTED PORTIONS.  

 
 

Association Agreement Regarding the Sale and Servicing
  of Blood Screening Products    
  

This
Association Agreement Regarding the Sale and Servicing of Blood Screening Products (this "Association Agreement") is made effective as of May 1, 2002, between America's Blood Centers
("ABC"), a charitable and non-profit corporation, having its principal office at 725 15th Street, N.W. Suite
700, Washington, D.C. 20005, and Chiron Corporation, a Delaware corporation ("Chiron") having its offices at 4560 Horton Street, Emeryville, California 94608-2916. 

Background  

	A.
	ABC
is an association of non-profit community-based centers (each such blood center, a "Member").

	B.
	Chiron
distributes, markets and sells certain Blood Screening Assays and Blood Screening Systems for use to conduct nucleic acid amplification tests to detect the presence of certain
viruses in blood donation samples.

	C.
	ABC
wishes to make available such amplified nucleic acid tests of blood donation samples by its Members using the Blood Screening Assays and Blood Screening Systems.

	D.
	Chiron
and ABC desire to enter into an agreement on the following terms and conditions by which (i) Members may purchase Blood Screening Assays from Chiron; (ii) Members
may obtain possession of and will use Blood Screening Systems that Chiron or a Third Party lessor will make available to ABC through sale or lease; and (iii) Members may obtain from Chiron
installation, training, and instrument service related to the use of Blood Screening Systems. 

NOW, THEREFORE, in consideration of the foregoing premises and of the mutual covenants of the parties hereinafter contained, the parties hereto hereby
agree as follows: 

ARTICLE 1—DEFINITIONS  

Capitalized
terms not defined herein shall have the meanings set forth in Schedule A hereto. 

ARTICLE 2—PURCHASE OF BLOOD SCREENING ASSAYS  

Chiron
agrees to sell, and Participating Members agree to buy, Blood Screening Assays in accordance with the terms and conditions set forth in Schedule B  hereto. 

ARTICLE 3—PROVISION OF BLOOD SCREENING SYSTEMS; SOFTWARE  

Chiron
agrees to sell, or a Third Party designated by it and identified in Schedule C hereto (a "Third Party Lessor") will agree to lease, to
Participating Members during the term hereof, Blood Screening Systems in accordance with the terms and conditions set forth in Schedule C hereto,
and to license or sublicense the Software necessary for operation of the Blood Screening Assays on the 

1

 

Blood Screening Systems also in accordance with the terms and conditions set forth in Schedule C hereto; provided that, if Blood Screening
Systems are leased to ABC by a Third Party Lessor, the effectiveness of the applicable Member Supplement shall be subject to the Participating Member and the Third Party Lessor executing and
delivering a separate agreement that provides for Third Party Lessor to lease Blood Screening Systems to the Participating Member pursuant to such terms and conditions (the "Third Party Systems
Agreement"). 

ARTICLE 4—SERVICES  

Installation,
training and servicing of Blood Screening Systems (collectively, "Services"), shall be provided to each Participating Member by Chiron in accordance with the terms and conditions set
forth in Schedule D hereto. 

ARTICLE 5—PRICES, PAYMENTS  

	5.1
	Prices. Each Participating Member agrees to pay to Chiron the prices set forth in Schedule E  hereto (as revised from time
to time by mutual agreement of Chiron, ABC and the Participating Members) for the Products purchased hereunder, as determined by their respective
testing volume, existing instrument base and financing selection. If a Third Party Lessor is provided for in Schedule C hereto, the prices to be
paid by a Participating Member thereto will be as set forth in the Third Party Systems Agreement, as the case may be.

	5.2
	[**]

	5.3
	Payments. All payments shall be made on a monthly basis by each Participating Member as set forth in  Schedule E. All payments due to Chiron hereunder shall be paid in full by each Participating Member in U.S. Dollars within thirty
(30) days of the applicable due date. In the event of late payment, interest shall be charged at the rate of [**] from
the date such payment was due until the date of actual payment, such interest to accrue daily and both before and after judgment. Invoices for amounts due from a Participating Member to a Third Party
Lessor pursuant to the terms of Third Party Systems Agreement shall be payable as provided therein.

	5.4
	Books & Records; Audit. Each Participating Member shall keep reasonably detailed and accurate records and books of account,
including without limitation retaining all Data on donations tested, to enable a determination of the amounts payable to Chiron hereunder. Upon thirty (30) days written notice by Chiron, not
more frequently than once per calendar year, Chiron, at its cost (except as otherwise provided below in this Section 5.4) may have the records and books of account of a Participating Member
examined during reasonable business hours by an independent certified public accountant selected by Chiron for the purpose of verifying the amounts due hereunder. A copy of any final written report
provided by the independent accountant to Chiron shall be given concurrently to the Participating Member. Such examination shall not be permitted unless  [**] to which the books and records pertain.
Where such examination results in a finding that a Participating Member underpaid
Chiron [**], the Participating Member shall reimburse Chiron for its reasonable costs and expenses in conducting such
examination. The Participating Member and Chiron shall promptly rectify any overpayments or underpayments by repaying such amounts together with interest thereon at the rate set forth in
Section 5.3 of this Association Agreement. The parties shall endeavor to resolve any dispute between a Participating Member and Chiron as to amounts owing hereunder arising out of an audit
pursuant to this Section 5.4 pursuant to Article 11 of this Association Agreement.

	5.5
	Taxes. Each Participating Member is a non-profit, charitable corporation, exempt from the payment of sales and use taxes
and shall have no tax liability on Products unless specifically legislated by a particular state. Chiron is responsible for requesting and obtaining all tax exemption numbers as required.
Notwithstanding the above, if any federal, state, provincial, county or municipal sales or 

2

 

use
tax, excise or similar charge, or other tax assessment (other than that assessed against income), is assessed or charged on the sale of the Blood Screening Assays and Blood Screening Systems sold
by Chiron pursuant to this Agreement, it shall be paid by the applicable Participating Member. 

ARTICLE 6—CERTAIN AGREEMENTS  

	6.1
	Facilities. Each Participating Member agrees to grant Chiron reasonable access during normal business hours to inspect the facilities
used for the conduct of nucleic acid amplification testing of blood donation samples. Participating Members shall perform such testing in accordance with all applicable laws and regulations and the
instructions received from Chiron.

	6.2
	Regulatory Approvals. Chiron will use commercially reasonable efforts, at Chiron's sole expense, to obtain and maintain any applicable
regulatory approval for use of the Blood Screening Assays for testing of blood donations in the Territory. Chiron will be solely responsible for compliance with all regulatory requirements imposed on
it in connection with the maintenance of such approvals, including all regulatory reporting requirements. ABC and the Participating Members will cooperate with Chiron to support its efforts pursuant
to this Section 6.2. For clarity of understanding, Chiron has no obligation or responsibility with respect to regulatory approval or compliance relating to blood donor, blood product or blood
recipient management.

	6.3
	Regulatory Compliance.

	(a)
	The
Participating Members shall be solely responsible for compliance with all reporting and other regulatory requirements imposed on them. Upon reasonable request of Chiron or any
Participating Member, any Participating Member or Chiron shall provide to the requesting party copies of regulatory reports relating to the use of the Blood Screening Assays or the Blood Screening
Systems.

	(b)
	Chiron
shall be solely responsible for compliance with all reporting and other regulatory requirements imposed on it.

	(c)
	Any
party hereunder agrees to make available to the requesting party (with authority to provide to its Affiliates or any governmental regulatory agency) such records as may be
reasonably required for the requesting party to satisfy its regulatory requirements.

	(d)
	Each
party agrees to provide access to their facilities and documents pertaining to this Agreement without any prior or written notice, to the FDA should it require access in
accordance with any FDA policy, communication, or regulation. 

	6.4
	Data. Each Participating Member shall provide to Chiron data generated in connection with the use of the Blood Screening Assays or
Blood Screening Systems sufficient to monitor the performance of the Products for quality assurance, to determine amounts due from the Participating Members hereunder, and to perform their respective
regulatory obligations in the Territory (collectively the "Data"). The Data shall be deemed confidential information of the providing Participating Members, and shall be subject to Section 6.5,
except that the limitations of Section 6.5 shall not apply to the uses of Data specifically authorized under Section 6.4(b) of this Association Agreement.

	(a)
	Chiron
and to its Affiliates shall have the right to use the Data in connection with other regulatory applications, submissions and notifications, in any country, with respect to
Blood Screening Assays, Blood Screening Systems or related products. ABC and the Participating Members agree to cooperate in providing to Chiron such information as either may reasonably believe
appropriate or necessary and in applying for any such government approvals. At ABC's or any Participating Member's request, Chiron agrees to seek from such governmental 

3

 

regulatory
agencies confidential treatment of the Data, to the extent such confidential treatment is available. 

	(b)
	Chiron
agrees that the Data will be available for publication by ABC and/or the Participating Members only. Any such publication shall appropriately acknowledge the contributions of
Chiron, ABC and the applicable Participating Members.

	(c)
	The
parties acknowledge and agree that nothing in this Agreement or otherwise will require ABC or any Participating Members to disclose to Chiron patient-specific, or donor or
recipient identifying information (including information that could identify a group of donors, recipients or their geographical location), unless and to the extent that such information is required
by any applicable law, regulation or court order. In such event, (i) Chiron must provide notice to ABC and the applicable Participating Member in writing immediately on becoming aware of such a
requirement so that ABC and the applicable Participating Member have an opportunity to seek a protective order or other remedy; and (ii) ABC and the applicable Participating Members shall
provide the required identifying information to the extent it has such information, subject to the terms of such protective order or other remedy. 

	6.5
	Confidentiality. During the term of this Agreement and [**],
absent the consent of the other party, (i) ABC and the Participating Members agree to keep in confidence and not to disclose to any Third Party other than their Affiliates, agents or
contractors who need to know in connection with ABC and Participating Members activities under this Agreement, or use for any purpose, except pursuant to, and in order to carry out, the terms and
objectives of this Agreement, any Confidential Information of Chiron, including Confidential Information of Gen-Probe which is disclosed to ABC or Participating Members by or through
Chiron; and (ii) Chiron agrees to keep in confidence and not to disclose to any Third Party other than Gen-Probe and their respective Affiliates, agents or contractors who need to
know in connection with Chiron activities under this Agreement, or use for any purpose, except pursuant to, and in order to carry out, the terms and objectives of this Agreement, any Confidential
Information of ABC and Participating Members. Disclosures of Confidential Information to Third
Parties authorized hereunder shall be permitted only if the Third Party is bound by confidentiality obligations not less restrictive than those set forth herein. Subject to this Section 6.5 and
except as required by a court order issued by a court having appropriate jurisdiction, ABC and all Members agree not to disclose to any Third Party any financial terms of this Agreement, or any terms
of this Agreement relating to the Blood Screening Assays and Blood Screening Systems provided hereunder, without the prior written consent of Chiron. Chiron agrees to not disclose to any Third Party
any financial terms of this Agreement, or any terms of this Agreement relating to the Blood Screening Assays and Blood Screening Systems, except and only to the extent necessary to facilitate the
enforcement of applicable most favored nations provisions. Notwithstanding the above, Chiron acknowledges that any disclosure by a Participating Member in violation of this Section 6.5 shall
not be deemed a breach of this Agreement by ABC.

	6.6
	Intellectual Property; Inventions. The provision by Chiron to the Participating Members of the Blood Screening Assays and Blood
Screening Systems hereunder includes the implied license or sublicense under Chiron and Gen-Probe intellectual property to use the Blood Screening Assays and Blood Screening Systems in the
Territory as provided herein. Except for such implied license, and except as specifically set forth herein, nothing in this Agreement conveys to any party any rights or licenses under any intellectual
property of any other party. The parties do not anticipate that use of the Blood Screening Systems and Blood Screening Assays as provided herein will result in new inventions by Participating Members.
However, in the event that any such new invention is made solely by a Participating Member or persons obligated to assign inventions to a Participating Member, arising from the use of the Blood
Screening Systems and Blood Screening Assays, the Participating Member will own such invention. If such invention is an improvement to a Blood 

4

 

Screening
Assay or a component within a Blood Screening System, the Participating Member will provide written notice to Chiron of such invention, and the parties will commence exclusive negotiations,  [**], for
Chiron to obtain a worldwide license to such invention on commercially reasonable terms. If the parties fail to reach
agreement on licensing terms, the Participating Member will be free to license the invention to any Third Party. If an invention is made jointly by a Participating Member or persons obligated to
assign inventions to it, and Chiron or persons obligated to assign inventions to it, such invention will be owned jointly by the parties. All inventions made solely by Chiron or persons obligated to
assign inventions to it will be owned by Chiron. 

	6.7
	Product Changes. In the event that any manufacturer of Blood Screening Assays or Blood Screening Systems makes a change which is
required by applicable law or regulation, Chiron will provide ABC and the Participating Members with notice of such change promptly on receiving such notice from the manufacturer, and, if reasonably
practicable, at least three months prior to implementation of such change. If any manufacturer makes an improvement to any Blood Screening Assays or Blood Screening Systems which is not mandated by
applicable law or regulation, and if Chiron elects to make such improvement available in the Territory, Chiron will provide notice to ABC and the Participating Members of the availability of such
improvement. Each Participating Member may, in its discretion, elect to implement such improvement, provided, however, that Chiron reserves the right to discontinue the sale, support and servicing of
Blood Screening Assays or Blood Screening Systems that have been superceded by improved versions thereof, [**]. Each
Participating Member shall be responsible, at its expense, for validation of its own procedures and satisfaction of all regulatory requirements applicable to the use of any improvements to the Blood
Screening Assays or Blood Screening Systems which such Participating Member chooses to utilize. The parties acknowledge that the automated instrument system for single unit testing currently under
development is not to be deemed an improvement for the
purposes hereof. When commercially available, such automated system will be subject to separate terms and conditions to be negotiated at such time.

	6.8
	Disaster Planning. Chiron shall work with ABC and the Participating Members to develop a mutually agreeable disaster preparedness
and/or loss control plan to ensure continued supply of the Products in the event of a natural or man-made disaster which seriously affects or compromises production capabilities at the
Product manufacturing or distribution facilities. In this connection, Chiron shall disclose to ABC and the Participating Members its backup supply capability, how it will keep the Participating
Members supplied in the event of a loss or other disaster, how it segregates its own exposures, and its full fire and other loss protection measures for supply.

	6.9
	Association Fee. Chiron agrees to pay ABC for management and service duties performed during the term of the Association Agreement in  [**]. This amount shall be paid by Chiron to ABC quarterly within sixty (60) days of the close of each quarter. 

ARTICLE 7—REPRESENTATIONS & WARRANTIES; WARRANTY DISCLAIMER; INDEMNIFICATION; LIMITATION OF LIABILITY; INSURANCE  

	7.1
	Chiron Representations & Warranties. Chiron hereby represents and warrants that: (a) it is duly organized, validly
existing and in good standing under the laws of the jurisdiction in which it was organized; (b) this Agreement, when executed and delivered by it, will be the legal, valid and binding
obligation of Chiron, enforceable against Chiron in accordance with its terms; (c) the execution, delivery and performance of this Agreement by Chiron do not and will not (i) conflict
with, or constitute a breach or default under, its charter documents or any material agreement, contract, commitment, or instrument to which Chiron is a party or (ii) require the consent,
approval or authorization of, or notice, declaration, filing or registration with, any Third Party or 

5

 

any
governmental or regulatory authority; (d) Chiron has not previously granted and will not grant any rights to any Third Party which are, nor contract with any Third Party in any manner
which is, inconsistent with the rights granted herein. 

	7.2
	ABC Representations & Warranties. ABC hereby represents and warrants that: (a) it is duly organized, validly existing and
in good standing under the laws of the jurisdiction in which it was organized; (b) this Agreement, when executed and delivered by it, will be the legal, valid and binding obligation of ABC,
enforceable against ABC in accordance with its terms; (c) the execution, delivery and performance of this Agreement by ABC do not and will not (i) conflict with, or constitute a breach
or default under, its charter documents or any material agreement, contract, commitment, or instrument to which ABC is a party or (ii) require the consent, approval or authorization of, or
notice, declaration, filing or registration with, any Third Party or any governmental or regulatory authority; (d) ABC has not
previously granted and will not grant any rights to any Third Party which are, nor contract with any Third Party in any manner which is, inconsistent with the rights granted herein.

	7.3
	Participating Member Representations & Warranties. Each Participating Member, by executing a Member Supplement, represents and
warrants that: (a) it is duly organized, validly existing and in good standing under the laws of the jurisdiction in which it was organized; (b) the Member Supplement, when executed and
delivered by it, will be the legal, valid and binding obligation of it, enforceable in accordance with its terms; (c) all Products shall be used in accordance with the applicable manuals and
instructions provided by Chiron and with all applicable laws and regulations; (d) it has all authority and permits required under applicable law and regulation to operate as a blood center and
use the Products; (e) it is not, and it will not use in providing Chiron with any manner of service or work relating to this Agreement, a debarred person or entity under the Generic Drug
Enforcement Act, or otherwise prohibited from providing such services or work, nor shall it use any investigator who has been disqualified by the FDA.

	7.4
	Disclaimer of Warranty. EXCEPT AS SET FORTH IN SECTION 7.1 OF THIS ASSOCIATION AGREEMENT OR EXPRESSLY PROVIDED IN SCHEDULES B, C, AND D
HEREOF, CHIRON MAKES NO WARRANTIES OF ANY KIND, EXPRESS OR IMPLIED, WRITTEN OR ORAL, INCLUDING WITHOUT LIMITATION ANY IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE.

	7.5
	Pass-Through of Warranty. Chiron agrees to pass through to each Participating Member the benefit of the manufacturer's
warranties with respect to the Blood Screening Systems sold by Chiron after the effective date of the applicable Member Supplement, to the extent it is legally permitted to do so.

	7.6
	Participating Member Responsibility for Certain Damages. In no event shall Chiron (or any Affiliate thereof) be responsible for any
Damages suffered by ABC or a Participating Member arising out of a Participating Member's own negligence or willful acts or failure to act in connection with the storage, handling, or use of the
Products after transfer to the Participating Member of risk of loss or damage thereto.

	7.7
	Indemnity by Chiron. Chiron hereby indemnifies ABC and each Participating Member, their respective officers, directors, agents, and
employees (the "ABC Indemnitees") and agrees to hold them harmless from and against all Direct Damages and against all Third Party Damages arising out of bodily injury claims of Third Parties, when
such Damages arise from Chiron's breach of this Agreement or from the negligence of Chiron, its officers, directors, agents, employees or affiliates in the performance of Chiron's obligations under
this Agreement, except to the extent arising from negligence or willful misconduct of any of the ABC Indemnitees. 

6

 
	7.8
	Indemnity by ABC. ABC hereby indemnifies Chiron and its respective officers, directors, agents and employees (the "Chiron Indemnitees")
and agrees to hold them harmless from and against all Direct Damages and against all Third Party Damages arising out of bodily injury claims of Third Parties, when such Damages arise from ABC's breach
of this Agreement or from the negligence of ABC, its officers, directors, agents or employees in the performance of its obligations under this Agreement, except to the extent arising from negligence
or willful misconduct of any of the Chiron Indemnitees.

	7.9
	Indemnity by Participating Members. Each Participating Member, by executing a Member Supplement, agrees to indemnify Chiron and its
respective officers, directors, agents and employees (the "Chiron Indemnitees") and agrees to hold them harmless from and against all Direct Damages and against all Third Party Damages arising out of
bodily injury claims of Third Parties, when such Damages arise from the Participating Member's breach of this Agreement or from the negligence of the Participating Member, its officers, directors,
agents or employees in the performance of its obligations under this Agreement, except to the extent arising from negligence or willful misconduct of any of the Chiron Indemnitees.

	7.10
	IP Infringement Indemnity. Chiron shall defend, at its expense, any legal action brought against ABC or a Participating Member by a
Third Party to the extent that it is based on any claim that the use by a Participating Member of any Products supplied by Chiron and sold pursuant to this Agreement constitute an infringement of any
patent or intellectual property rights claimed by such Third Party in the Territory. Chiron will pay all Damages finally awarded against ABC or a Participating Member in such action that are
attributable to such claim. Notwithstanding the foregoing, Chiron shall have no liability hereunder to the extent that the infringement (or allegation of infringement) arises from or is attributable
to (i) the use of the Products in combination with other products or materials not supplied by Chiron hereunder; (ii) part (or all) of the Products being used for a purpose other than
that indicated by this Agreement; or (iii) use of the Products other than in accordance with the documentation provided by Chiron. Chiron's obligation to indemnify shall be subject to ABC or a
Participating Member promptly notifying Chiron in writing of such claim and providing reasonable cooperation to Chiron in the defense of such claim or proceeding.

	7.11
	Indemnification Procedures. Any party claiming indemnification under Section 7.7, 7.8 or 7.9 of this Association Agreement (the
"Indemnitee") shall notify the party from which indemnification is claimed (the "Indemnifying Party") in writing promptly upon becoming aware of any claim to which such indemnification may apply.
Failure to provide such notice shall constitute a waiver of the Indemnifying Party's indemnity obligations hereunder if, and only to the extent that, the Indemnifying Party is materially damaged
thereby. The Indemnifying Party shall have the right to assume and control the defense of the claim at its own expense. If the right to assume and have sole control of the defense is exercised, the
Indemnitee shall have the right to participate in, but not to control, such defense at its own expense. If the Indemnifying Party does not assume the defense of the claim, the Indemnitee may defend
the claim at the Indemnifying Party's expense. The Indemnitee will not settle or compromise the claim without the prior written consent of the Indemnifying Party, and the Indemnifying Party will not
settle or compromise the claim in any manner which would have an adverse effect on the Indemnitee without the consent of Indemnitee, which consent, in each case, will not be unreasonably withheld. The
Indemnitee shall reasonably cooperate with the Indemnifying Party and will make available to the Indemnifying Party all pertinent information under the control of the Indemnitee.

	7.12
	Exclusion of Consequential Damages. Excepting any obligation to indemnify against Third Party Damages as provided in this Agreement,
no party to this Agreement shall be liable to any other party to this Agreement with respect to the subject matter of this Agreement under breach of contract, negligence, strict liability or any other
cause of action for any Consequential Damages. 

7

 
	7.13
	Insurance. Chiron and the Participating Members agree to insure their potential liabilities resulting from this Agreement as follows:

	(a)
	Participating
Members shall obtain and maintain, at their sole cost, a policy or policies of insurance with the coverages set forth in the applicable Member Supplement.

	(b)
	Chiron
shall obtain and maintain at its sole cost, a policy or policies of insurance with the following coverages, which shall be in full force and effect for the term of this
Agreement and thereafter through two years following the termination of the Agreement: a) a Commercial General Liability policy including Products and Completed Operations Liability in an
amount of not less than [**] combined single limit for each occurrence; and b) Workers' Compensation coverage with
statutory limits for each jurisdiction where the work required of such party under this Agreement is performed and an employers' liability policy with at least the following limits,  [**] per accident,
[**] per disease (policy limit), and  [**] disease (each employee).

	(c)
	Each
party shall provide the other with certificates of insurance evidencing the coverage required herein upon execution of this Agreement, and renewal certificates on request from
the other party. Each party must notify the other within a reasonable time if there is a material change to any of the insurance policies referred to in this Section 7.13. Such certificates
shall provide for thirty (30) days prior written notice to the certificate holder in the event of non-renewal of the policies, cancellation or material change in the coverage
provided. 

ARTICLE 8—TERM AND TERMINATION  

	8.1
	Term. This Association Agreement shall enter into force as of the Effective Date and shall continue to the  [**]. Six months
before the expiration of this Association Agreement, the parties shall meet to negotiate in good faith whether
or not this Association Agreement shall be extended and/or revised and/or discontinued with effect from the termination date of such initial period. Each Member
Supplement will become effective and terminate on its own terms; provided, however, that all Member Supplements shall terminate immediately upon the termination or expiration of this Association
Agreement. Any termination of a Member Supplement shall have no impact on the continuing effectiveness of any other Member Supplement or this Association Agreement.

	8.2
	Termination. This Association Agreement may be terminated by written notice to the other party at any time during the term of this
Association Agreement, which termination shall be effective when such termination notice is received in accordance with Section 12.6 of this Association Agreement, as follows:

	(a)
	by
either ABC or Chiron if the other party fails to observe, perform or otherwise breaches any of its material covenants, agreements or obligations under this Association Agreement,
provided such failure continues for a period of thirty (30) days after receipt by the other party of an initial written notice thereof specifying such failure and provided further Chiron shall
not have invoked its rights under Section 8.4 of this Association Agreement; or

	(b)
	by
either ABC or Chiron if the other party files a petition in bankruptcy, becomes bankrupt or insolvent or subject to the reorganization of its business for the benefit of creditors
under any law or regulation relating to bankruptcy, or a receiver is appointed for all or substantially all of its property or assets, or upon the making by such other party of a composition with its
creditors, or upon the taking by such other party of any act for the winding up of its business, or upon any governmental authority exercising any power or authority resulting in the expropriation or
confiscation of all or substantially all of its business and assets; or

	(c)
	by
mutual agreement of the parties at any time without penalty. 

8

 

	8.3
	[**].

	8.4
	[**]. 

ARTICLE 9—CONSEQUENCES OF THE TERMINATION OF THE AGREEMENT  

	9.1
	Payment Obligations Unaffected. The termination of this Association Agreement for any reason whatsoever shall not affect any party's
obligations to pay any amount actually invoiced and due to Chiron prior to such termination. In the event that termination occurs at a time prior to a Participating Member having made full payment
that is due and owing for any Products, the parties agree that Chiron shall have all applicable ownership rights to such Products until such payment has been made in full to Chiron.

	9.2
	Survival of Certain Provisions. In addition, notwithstanding anything herein to the contrary, the following provisions of this
Association Agreement shall survive termination of this Association Agreement: Sections 6.5, 6.6 and 7.4 through 7.12, and Articles 9, 10, 11 and 12.

	9.3
	Return of Confidential Information. Upon termination of this Agreement for any reason whatsoever, unless required to retain such
information for regulatory purposes, the parties shall immediately return to the other all confidential information in documentary or printed form and any copies or extracts thereof and shall
thereafter cease to use such information but without prejudice to the then surviving confidentiality obligations provided for in Section 6.5 of this Association Agreement.

	9.4
	No Other Payment. No indemnity or compensation in any form whatsoever shall be paid by either the party to the other in connection with
a termination in accordance with the terms hereof (subject to any liability that may exist in respect of any material breach prior to such termination). 

ARTICLE 10—APPLICABLE LAW  

This
Agreement shall be governed by and construed in accordance with the laws of the State of California, without giving effect to any conflict of law rules and regulations. 

ARTICLE 11—DISPUTES  

	11.1
	To
the extent that there are disputes with respect to performance under this Agreement, such disputes (other than non-payment) are not cause for Chiron to stop
performance under this Agreement, but will be resolved in due course to the extent possible in accordance with this Article.

	11.2
	The
parties to this Agreement will attempt to resolve any problem or dispute arising out of, or related to, this Agreement through good faith consultation in the ordinary course of
business. In the event that any problem or dispute is not so resolved, either party may upon written notice to the other request that the matter be referred to senior management officers within each
respective organization with express authority to resolve the problem or issue and who are not immediately responsible for the matters contemplated by this Agreement. Such senior management officers
will meet or confer at least once in good faith to negotiate a resolution.

	11.3
	If
the senior management officers are unable to resolve the problem or dispute within thirty (30) days, either party may pursue the matter as set forth in Sections 11.4
through 11.6 below. No party may institute a court proceeding until the procedure has been completed unless, and to the extent that, doing so is necessary to avoid irreparable harm.

	11.4
	If
any problem or dispute arising out of or related to this Agreement is not resolved by the parties in the manner set forth in Sections 11.2 and 11.3 above, at the request of either
party, the matter will be submitted to mediation, or to such other form of dispute resolution as the parties may then agree to. A neutral person acceptable to both parties will conduct the mediation,
and unless other 

9

 

procedures
are agreed to, it will be conducted in accordance with the Center for Public Resources Model Procedure for Mediation of Business Disputes. 

	11.5
	Any
controversy, claim or dispute arising out of or relating to this Agreement, or the breach thereof, which is not resolved through the procedures described in Sections 11.2 through
11.4 above shall be resolved by binding arbitration. If arbitration is necessary pursuant to this paragraph, the parties shall agree upon a single arbitrator. If the parties are unable to agree on an
arbitrator, then they will obtain nominations of three (3) potential arbitrators who are retired federal or state judges and each party will have the right to strike one candidate's name from
the list.

	11.6
	The
prevailing party shall be entitled to recover all costs and expenses, including reasonable attorney's fees, incurred because of any legal action arising in relation to this
Agreement. 

ARTICLE 12—MISCELLANEOUS  

	12.1
	Force Majeure. Each party shall be excused from any delay in performance or from failure to perform in accordance with the terms of
this Agreement, to the extent that such delay or failure to perform results from a Force Majeure Event. The provisions of this paragraph shall apply only if such party shall have used its reasonable
efforts to avoid such Force Majeure Event. Such party shall give
notice to the other promptly in writing upon learning of the Force Majeure Event. The affected party's time for performance shall be extended for the period of the delay or inability to perform due to
such Force Majeure Event and notwithstanding any provision herein to the contrary, the affected party shall not be liable for any Damages arising out of such Force Majeure Event.

	12.2
	Exclusion of Convention of Vienna for the International Sale of Goods. The parties hereby expressly exclude the application to this
Agreement of the terms of the Convention of Vienna for the International Sale of Goods.

	12.3
	Equal Employment Opportunity. None of the parties will discriminate, in terms and conditions of employment, against employees or
applicants because of age, race, color, religion, sex, national origin, qualified disability or any other basis protected by applicable state or local law. The parties agree to abide by all federal,
state and local employment and labor law notice posting requirements.

	12.4
	Assignment. This Agreement shall not be directly or indirectly assigned or otherwise transferred by ABC or, as to a Member Supplement,
by any Participating Member, nor, except as expressly provided hereunder, may any right or obligations of ABC or any Participating Member hereunder be assigned or transferred (whether voluntarily, by
operation of law or otherwise) without the consent of Chiron. Chiron may assign and transfer to an Affiliate (provided Chiron remains a guarantor of such Affiliate's obligations hereunder), or to a
Third Party possessing sufficient capitalization to satisfy its obligations under the Agreement that is acquiring all or substantially all of the business of Chiron, the rights and obligations of
Chiron hereunder without further action by ABC or any Participating Member. This Agreement shall inure to the benefit of and be binding upon the parties hereto and their respective successors and
permitted assigns.

	12.5
	Subcontracting. Chiron's obligations under this contract may not be subcontracted without the prior written consent of the effected
Participating Members. Any attempt to subcontract without such consent will be null and void and of no effect. Chiron must require that all subcontractors approved by the affected Participating
Members be bound by the terms of this Agreement and to assume toward Chiron all obligations and responsibilities which Chiron assumes toward the affected Participating Members. Chiron must make
available to each approved subcontractor, prior to the execution of any subcontract agreement, a copy of this Agreement to which the 

10

 

subcontractor
will be bound. For purposes of any subcontracts entered into pursuant to this Section 12.5, the term "Chiron" as used in this Agreement, will include any and all subcontractors. 

	12.6
	Notices. Any Notice or request required or permitted to be given in connection with this Agreement shall be deemed to have been
sufficiently given if sent by pre-paid registered or certified mail, by courier or by facsimile at the address set forth below or to such other address as may have been notified in
writing. 

	 
	 	 
	 	 

	 	 	If to Chiron:	 	Chiron Corporation

Attention: President, Blood Testing

4560 Horton Street

Emeryville, CA 94608

Telephone: (510) 923-2416

Fax: (510) 655-8556

cc: General Counsel
	

 	
 	

If to ABC:	
 	

America's Blood Centers

Attention: Jim MacPherson, Chief Executive Officer

725 15th Street, N.W., Suite 700

Washington, DC 20005

Telephone: (202) 393-5725

Fax: (202) 393-1282

A
notice, consent, approval or other communication takes effect from the time it is received unless a later time is specified in it, and receipt shall be deemed to occur as follows: 

	(a)
	if
it is sent by mail, seven (7) calendar days after posting;

	(b)
	if
it is sent by courier, on the date and at the time shown on the courier's standard written confirmation of receipt;

	(c)
	if
it is sent by facsimile, on the date and at the time shown on a successful transmission report by the machine from which the facsimile was sent. 

	12.7
	Entire Agreement. This Agreement constitutes the entire agreement between the parties in respect of the subject matter hereof. This
Agreement cancels and supersedes any and all pre-existing agreements, either oral or in writing between the parties, including without limitation the Agreement, dated as of
April 15, 2000 by and among Chiron, ABC and Gen-Probe, as amended. There are not and shall not be any oral statements, representations, warranties, undertakings or agreements
between the
parties other than as provided by this Agreement and any mutually accepted written amendments hereto.

	12.8
	No Waiver. The failure on the part of either party hereto to exercise or enforce any right conferred upon it by this Agreement shall
not be a waiver of any such right nor shall any single or partial exercise of any right or power hereunder or further exercise thereof operate so as to bar the later exercise or enforcement thereof.

	12.9
	Nature of Relationship. Nothing herein contained shall be deemed to be or construed as constituting either party the agent or partner
of the other party. The relationship between Chiron and each Participating Member shall be that of an independent contractor. No party shall have the right, title or authority to enter into any
contract, agreement or commitment on behalf of the other or to bind the other party in any manner whatsoever. In no event shall ABC have any responsibility for the financial obligations of any
Participating Member, nor shall any Participating Member have any responsibility for the financial obligations of any other Participating Member. 

11

 

	 
	 

	12.10	Conflict Between Terms and Conditions. In the event of any conflict between the terms and conditions of this Association Agreement and any terms and conditions that may be set forth in a Member
Supplement or on any invoice or purchase order or other similar document, the terms and conditions of this Association Agreement govern.
	

12.11	
Compliance with Applicable Law. In performing this Agreement, the parties shall comply with all applicable laws. Nothing in this Agreement shall be construed so as to require the violation
of law, and wherever there is any conflict between any provision of this Agreement and any rule of mandatory law, the latter shall prevail, but in such event, the affected provision of this Agreement shall be ineffective only to the extent necessary
to comply with the applicable law, and the parties hereto undertake to replace the invalid and/or unenforceable provision by a valid and/or enforceable provision, the nature and scope of which will come as close as possible to the contractual
provision to be replaced.
	

12.12	
Counterparts. This Association Agreement and any Member Supplement may be executed in two or more counterparts, each of which shall be deemed to be an original and each of which shall
constitute one and the same Agreement.
	

12.13	
Severability. In the event that any provision of this Agreement is found to be invalid or in conflict with any applicable law or regulation, the affected provision of this Agreement shall be
limited or eliminated only to the extent necessary to comply with such law or regulation, and the remainder of this Agreement shall remain in full force and effect, provided that the remainder of this Agreement is consistent with the economic
intentions of the parties as evidenced by this Agreement as a whole.

IN
WITNESS WHEREOF, the parties hereto, through their authorized representatives, have set their hands as of the date first above written, whereby they evidence their intent to be legally bound. 

	CHIRON CORPORATION	 	AMERICA'S BLOOD CENTERS
	

By:	
 	

/s/  WILLIAM G. GREEN      
	
 	

By:	
 	

/s/  JIM MACPHERSON      

	

Name:	
 	

William G. Green	
 	

Name:	
 	

Jim MacPherson
	

Title:	
 	

President of Blood Testing	
 	

Title:	
 	

CEO

12

  

	 
	 	 

	CONFIDENTIAL	 	REDACTED VERSION

 
 

SCHEDULE A
  
    Definitions    
  

Capitalized
terms used and not otherwise defined in this Agreement shall have the following meanings: 

	1.1
	"Affiliate" shall mean (i) any corporation or business entity of which securities or other ownership interests representing
fifty percent (50%) or more of the equity or fifty percent (50%) or more of the ordinary voting power or fifty percent (50%) or more of the general partnership interests are, at the time such
determination is being made, owned, Controlled (as hereinafter defined) or held, directly or indirectly, by such corporation or business entity, or (ii) any other corporation or business entity
which, at the time such determination is being made, is Controlling, Controlled by or under common Control with, such corporation or business entity. For purposes of this definition, "Control",
whether used as a noun or verb, refers to the possession, direct or indirect, of the power to direct, or cause the direction of, the management or policies of any corporation or business entity,
whether through the ownership of voting securities, by contract or otherwise.

	1.2
	"Agreement" shall mean collectively this Association Agreement, including the Schedules hereto, and all Member Supplements, including
the Exhibits thereto.

	1.3
	"Blood Screening Assays" shall mean the TMA Assays purchased by Chiron from Gen-Probe from time to time and available for
sale hereunder, as more specifically described in one or more schedules, labeled B-1, B-2, etc.

	1.4
	"Blood Screening Field" shall mean the testing of human blood, plasma, platelets or other blood products intended for transfusion or
further processing for other administration to humans, including autologous donors, as limited by the Intended Use for each Blood Screening Assay, as set forth in the applicable Package Insert, as
amended from time to time.

	1.5
	"Blood Screening Systems" shall mean the instrument(s) and related Software for DNA/RNA amplified assay processing that Chiron has
available for sale or lease hereunder, as more specifically described in Schedule C, as it may be amended from time to time.

	1.6
	"Confidential Information" means any and all technical, business and other information and materials disclosed by or on behalf of such
party to the other party pursuant to this Agreement or during discussions leading to this Agreement, except to the extent that the receiving party can provide evidence that such information:

	(a)
	is
known to the receiving party prior to its disclosure by the disclosing party; or

	(b)
	is
obtained by the receiving party from a source other than the disclosing party which source (i) did not require the receiving party to hold such information in confidence; or
(ii) did not limit or restrict the receiving party's use thereof, or

	(c)
	has
become public knowledge otherwise than through the fault of the receiving party; or

	(d)
	has
been developed by the receiving party independently of the information received from the disclosing party as shown by the receiving party's written records; or

	(e)
	is
required to be disclosed by the receiving party by law or for the purpose of complying with governmental regulations and/or the obligations of the receiving party to a licensing or
regulatory authority in connection with this Agreement. 

13

 

	1.7
	"Consequential Damages" means consequential damages as defined by California law, including loss of profit or loss of business
opportunity, and all Third Party Damages.

	1.8
	"Damages" means Direct Damages and Third Party Damages, collectively.

	1.9
	"Direct Damages" means costs or expenses incurred by a party that are not Consequential Damages, including without limitation, the
incremental additional costs of substitute products and costs or expenses of product recall.

	1.10
	"Documentation" shall mean text material that describes the design, functions, operation, or use of the Software and that is delivered
by Chiron to Participating Members. Documentation for the Software shall be the same that is provided to licensees of such Software generally.

	1.11
	"Effective Date" means the date set forth on the first page of this Agreement.

	1.12
	"FDA" shall mean the United States Food and Drug Administration, or the successor thereto.

	1.13
	"Force Majeure Event" shall mean a cause beyond the reasonable control of a party, including without limitation, fires, floods,
epidemics, quarantine restrictions, strikes, war, earthquake, acts of God, labor difficulties, riot, failure of public utilities, freight embargoes, unusually severe weather conditions, delays in
delivery of goods or services by suppliers or subcontractors to such party, loss of goods in transit, and governmental or court action.

	1.14
	"Gen-Probe" shall mean Gen-Probe Incorporated, a Delaware corporation.

	1.15
	"HCV" means the Hepatitis C virus.

	1.16
	"HIV-1" means Human Immunodeficiency virus type 1.

	1.17
	"Member" shall have the meaning set forth in the Recitals.

	1.18
	"Member Supplement" shall mean the agreement executed after the Effective Date of this Association Agreement by and among Chiron and a
Member and incorporating by reference the terms and conditions of this Association Agreement.

	1.19
	"Package Insert" shall mean the package insert approved by the FDA for the applicable Blood Screening Assay, as the same may be
amended from time to time.

	1.20
	"Participating Member" shall mean a Member electing to utilize the Blood Screening Assays and Blood Screening Systems that
memorializes its election by execution of a Member Supplement.

	1.21
	"Person" shall mean an individual, corporation, partnership, limited liability company, trust, business trust, association, joint
stock company, joint venture, pool, syndicate, sole proprietorship, unincorporated organization, governmental authority or any other form of entity not specifically listed herein.

	1.22
	"Pooled Testing" means the conduct of testing on pools of samples from blood donations as follows. For the purposes of this Agreement,
Pooled Testing consists of: 

[**]

[**]

[**]

	1.23
	"Primary Operators" means the employees of Participating Members trained by Chiron at Chiron's facility.

	1.24
	[**].

	1.25
	"Products" shall mean Blood Screening Assays, Blood Screening Systems and Software. 

14

 
	1.26
	"Reagent Utilization Factor" means, with respect to a specified time period, the quantity of Blood Screening Assay tests consumed by
an applicable Participating Member during such period divided by the number of Reportable Results obtained by such Participating Member during such period.

	1.27
	"Reportable Result" means a result obtained through the use of a Blood Screening Assay and Blood Screening System in Pooled Testing or
Single Unit Testing from which it is determined to release for use or hold and not use (a) a blood donation intended for transfusion or for further processing for other administration to humans
or (b) a product derived from such donation.

	1.28
	"Secondary Operator" means the employees of Participating Members trained at the facility of a Participating Member by either a
Primary Operator or Chiron.

	1.29
	"Single Unit Testing" means testing of blood donations consisting of (i) testing a sample from each individual blood donation
using a Blood Screening Assay, and (ii) follow up discriminatory testing of positive results for HIV-1 or HCV.

	1.30
	"Software" means the following software programs: 

CPT-16
Pooling Software, Version 2.0.0.2

ProcleixTM Assay Software, Version 2.0.0.76

ProcleixTM Assay Software LHP, Version 2.1

ProcleixTM System Software, Version 3.0.3.4

ProcleixTM Protocol, Version 2.1.0.0

ProcleixTM Worklist Editor, Version 3.0.3.2 

	1.31
	"Specifications" shall mean, in respect of each Product, the specifications, tests, procedures, process description, and other
information relating to such Product and packaging thereof prepared by Chiron or its Affiliates provided to Participating Members by Chiron under separate cover, which may be amended from time to time
by Chiron in writing; provided, however, that the foregoing information shall be consistent with the product registration in the Territory from time to time. As to Blood Screening Assays,
"Specifications" shall mean the information set forth in the current Package Insert.

	1.32
	"Tecan Instrument" means a Tecan Genesis 150/8 Instrument, sold by Chiron or leased by a Third Party Lessor hereunder for use in the
performance of the assays using the Blood Screening Assays.

	1.33
	"Territory" means the United States of America, including Puerto Rico, Guam and all other protectorates.

	1.34
	"Testing Centers" mean the locations identified on Exhibit 2 to the Member Supplements.

	1.35
	"Third Party" shall mean any Person other than ABC, its Members, Gen-Probe, Chiron and their respective Affiliates.

	1.36
	"Third Party Damages" means any liability arising out of a Third Party's claim (whether arising out of fault, strict liability or
otherwise) in the form of an obligation, loss, fine, judgment for damages, arbitration award, settlement amount, penalty or claim, and all reasonable costs and expenses related thereto (including
reasonable costs of investigation, fees and expenses payable to outside counsel, independent accountants and similar professional advisors or consultants, but not including any corporate allocation
for use, of similar in-house services or facilities).

	1.37
	"TMA Assay" shall mean an in vitro diagnostic assay based on or utilizing transcription-mediated amplification. 

15

 

	 
	 	 

	CONFIDENTIAL	 	REDACTED VERSION

 
 

SCHEDULE B-1
  
    TERMS AND CONDITIONS FOR PURCHASE OF PROCLEIXTM HIV-1/HCV
  BLOOD SCREENING ASSAY    
  

Chiron
will supply the ProcleixTM HIV-1/HCV Blood Screening Assay to the Participating Members on the following terms and conditions: 

	1.
	Description of Blood Screening Assays. The ProcleixTM HIV-1/HCV Blood Screening Assays that will be supplied by
Chiron to the Participating Members hereunder are described in the current Package Insert, included as Attachment B-1 to this Schedule B-1 and include the following
components: 

ProcleixTM
HIV-1/HCV Assay 

1000
Test Kit P/N 301031

5000 Test Kit P/N 301030 

Internal
Control Reagent

Target Capture Reagent

Amplification Reagent

Enzyme Reagent

Probe Reagent

Selection Reagent

ProcleixTM Negative Calibrator

ProcleixTM HIV-1 Positive Calibrator

ProcleixTM HCV Positive Calibrator 

	2.
	Supply Obligation. During the term of this Agreement Chiron agrees to supply to each Participating Member, at the prices specified in  Schedule E, all Blood Screening Assays necessary to permit each Participating Member to conduct screening of blood donations for the presence of
HIV-1 and /or HCV in the Territory. Each Participating Member agrees to store and handle all Blood Screening Assays in accordance with the Package Insert. Any Blood Screening Assays lost
or damaged due to failure to comply with such storage and handling instructions will be replaced at the affected Participating Member's sole expense, which expense reflects the Reagent Utilization
Factor premium specified in Schedule E.

	3.
	Purchase Obligation. During the term of this Agreement, each Participating Member agrees to acquire 100% of its requirements of Blood
Screening Assays necessary to conduct screening by nucleic acid testing of blood donations for the presence of HIV-1 and/or HCV. However, nothing in this Agreement
will restrict the right of a Participating Member to evaluate new technologies or to perform, in its discretion, any confirmatory and supplementary nucleic acid testing.

	4.
	Other Supplies. All supplies necessary for the conduct of tests using the Blood Screening Assays, other than Blood Screening Assays,
Blood Screening Systems and such disposables and calibrators included with each Blood Screening Assay Kit, shall be purchased separately by each Participating Member and the price of such supplies is
not included in the fees established by this Agreement. Certain of such supplies and the associated prices thereof as of the date of execution of this Agreement are identified in  Schedule E. Such
prices of supplies shall increase from time to time in the event of, and in the amount of, any price increases by the
manufacturers of such supplies.

	5.
	Packing and Delivery of Blood Screening Assays. All Blood Screening Assays will be suitably packed and transported to ensure safe
transport to the Participating Members in accordance with the 

16

 

manufacturer's
instructions and delivered Carriage and Insurance paid to the Participating Member's designated Testing Centers, and each delivery will be accompanied by a packing slip indicating the
quantity delivered. Blood Screening Assays will be delivered during normal business hours and accompanied by storage instructions and arrive at the temperatures specified by the manufacturer and set
out in the Package Insert. The Blood Screening Assays will be delivered in kit form, with appropriate distribution between screening tests, discriminatory tests and related calibrators. 

	6.
	Shipping. Except as set forth below, all shipping and handling charges for the Blood Screening Systems and the regular monthly shipments
of Blood Screening Assays will be borne entirely by Chiron on shipments to the Testing Centers. All shipping and handling charges for shipping requests other than to a Testing Center, and all
incremental shipping and handling charges for Modified Orders and Changed Orders, will be borne by the requesting Participating Member.

	7.
	Forecasts and Orders.

	7.1
	Each
Participating Member will provide Chiron with a written twelve month forecast of its requirements of Blood Screening Assays (each a "Product Requirements Forecast") on an annual
basis, including requested delivery dates, which forecast shall constitute such Participating Member's standing firm purchase order for each month contained therein. Not less than ninety
(90) days prior to each anniversary of the effective date of the applicable Member Supplement, each Participating Member will provide such a Product Requirements Forecast. Participating Members
shall deliver any modifications to the standing firm purchase order for Blood Screening Assays for delivery during the next following month on or prior to the first day of the immediately preceding
calendar month (for example, a Participating Member will provide requested modifications to the February standing firm purchase order—for deliveries to be made during the month of
February—prior to January 1). All purchase order modification requests must be received at least 30 days prior to a requested delivery date. Except as otherwise agreed,
Chiron agrees to accept modifications to standing firm purchase orders which do not differ by more than [**] from the quantities
forecast for delivery in the applicable month in the current
Product Requirements Forecast. Participating Members may adjust their Product Requirements Forecast from time to time with the consent of Chiron, such consent to not be unreasonably withheld.

	7.2
	If
the variance between the modification requested and the current Product Requirements Forecast exceeds the  [**] referenced in Section 7.1 of this Schedule B-1,
Chiron will notify the requesting Participating Member within five (5) business days after receipt of the modification request as to whether it accepts such modification request. If a
modification request is accepted, Chiron agrees to deliver such amounts of Blood Screening Assays on the delivery date(s) stated. If a modification request is not accepted, the parties will use all
reasonable endeavors to agree on further modifications to the order and/or delivery date (a "Modified Order"), subject to Chiron's manufacturer's accommodating Chiron's requests for changes in
forecasted amounts.

	8.
	Changes to Orders. If a Participating Member requests any modifications to quantities of Blood Screening Assays ordered or the delivery
schedule or locations reflected in such order within 30 days of a delivery date (a "Changed Order"), Chiron will use reasonable commercial efforts to comply with such request.

	9.
	IQA Procedures. Prior to the initial delivery of Blood Screening Assays, Chiron, ABC and the Participating Members shall mutually agree
upon procedures for quality assurance testing of Blood Screening Assays received by Participating Members ("IQA Procedures"). Chiron agrees to replace Blood Screening Assays which fail to conform to
the Specifications as set forth in the Package Insert. The IQA Procedures shall include procedures for notice to Chiron and for implementing the return of Blood Screening Assays for replacement. If
testing by Chiron or its supplier confirms the non-conformity of the Blood Screening Assays, Chiron will bear the shipping costs associated 

17

 

with
replacement. If Chiron's testing provides reasonably acceptable evidence to the applicable Participating Member that the Blood Screening Assays do conform to the specifications in question, the
shipping costs will be borne by the applicable Participating Member. 

	10.
	Technical Support. Chiron will provide Participating Members with technical support to facilitate the operation by Participating
Members of the Blood Screening Assays on the Blood Screening Systems.

	11.
	Nature of Testing. Each Participating Member agrees that Blood Screening Assays supplied by Chiron hereunder shall be used by the
Participating Member solely to conduct Pooled Testing with a pool size of 16. If a Participating Member desires to change its testing from Pooled Testing using a pool size of 16 to Single Unit Testing
or any other pool size, the Participating Member and Chiron shall enter into an addendum to the applicable Member Supplement reflecting any additional Blood Testing Systems, changes to the fees or
prices payable under Schedule E of this Agreement or any other amendments that may be applicable by reason of such change in the nature of the
Participating Member's testing of blood donations.

	12.
	Warranty; Limitation of Liability.

	12.1
	All
Blood Screening Assays supplied by Chiron shall be manufactured in accordance with, and shall conform with, the Specifications, provided that ABC uses the Blood Screening Assays
in accordance with the instructions provided by Chiron. Any Blood Screening Assays failing to meet such Specifications shall be replaced by Chiron at Chiron's cost unless the defect was caused by an
act or omission of a Participating Member.

	12.2
	Chiron
disclaims all other warranties and further limits its liability in accordance with Sections 7.4 and 7.12 of this Association Agreement, respectively. 

18

 
 

ATTACHMENT B-1
  
    Package Insert    
  

 

ProcleixTM HIV-1/HCV Assay 

For In Vitro Diagnostic Use

1000 Test Kit, 5000 Test Kit  

	 
	 	 

	TABLE OF CONTENTS	 	 
	 	INTENDED USE	 	1
	 	SUMMARY AND EXPLANATION OF THE TEST	 	2
	 	PRINCIPLES OF THE PROCEDURE	 	2
	 	MATERIALS PROVIDED	 	4
	 	MATERIALS REQUIRED, SOLD SEPARATELY	 	5
	 	MATERIALS REQUIRED BUT NOT PROVIDED	 	6
	 	REAGENTS	 	7
	 	STORAGE INSTRUCTIONS	 	8
	 	PRECAUTIONS	 	9
	 	REAGENT PREPARATION	 	11
	 	SPECIMEN COLLECTION, STORAGE, AND HANDLING	 	12
	 	PROCEDURAL NOTES	 	13
	 	INSTRUCTIONS FOR USE	 	16
	 	 	Target Capture	 	16
	 	 	Amplification	 	18
	 	 	Hybridization Protection Assay (HPA)	 	19
	 	 	Procleix HIV-1 and HCV

    Discriminatory Assays	 	20
	 	QUALITY CONTROL PROCEDURES	 	21
	 	 	Acceptance Criteria for the Procleix

    HIV-1/HCV Assay and Procleix

    HIV-1 and HCV Discriminatory Assays	 	21
	 	 	 	Acceptance Criteria for the Calibration and Calculation of Cutoff	 	22
	 	INTERPRETATION OF RESULTS	 	28
	 	PERFORMANCE CHARACTERISTICS	 	30
	 	PERFORMANCE OF POOLED SAMPLE TESTING	 	32
	 	PERFORMANCE OF INDIVIDUAL DONATION TESTING	 	46
	 	LIMITATIONS OF THE PROCEDURE	 	48
	 	CONCLUSIONS	 	49
	 	BIBLIOGRAPHY	 	49

INTENDED USE  

The
ProcleixTM HIV-1/HCV Assay* is a qualitative in vitro nucleic acid assay system for the detection of human immunodeficiency
virus type 1 and/or hepatitis C virus RNA in human plasma from donations of whole blood and blood components for transfusion. The assay is intended for use in screening individual donor samples or
pools of human plasma comprised of equal aliquots of not more than 16 individual donations. This assay is intended to be used in conjunction with licensed tests for detecting antibodies to
HIV-1 and HCV. 

This
assay may be used as an alternative to licensed HIV-1 p24 antigen tests for screening human plasma from donations of whole blood and blood components. 

This
assay is not intended for use as an aid in diagnosis. 

*Developed
and manufactured by Gen-Probe Incorporated; distributed by Chiron® Corporation. 

IN0076 Rev. F

1

 

SUMMARY AND EXPLANATION OF THE TEST  

        Epidemiological studies identified human immunodeficiency virus type 1 (HIV-1) as the etiological agent of acquired immunodeficiency syndrome
(AIDS)1-7 and hepatitis C virus (HCV)8-13 as the etiological agent for most blood-borne non-A, non-B hepatitis (NANBH). Both viruses are
transmitted primarily by
exposure to infected blood or blood products, certain body fluids or tissues, and from mother to fetus or child. 

        Current
detection of HIV-1 infection in the blood bank setting is based on serologic screening for anti-viral antibodies by enzyme immunoassay (EIA) with
confirmation by supplemental antibody tests such as Western blot or immunofluorescence assays. Although sensitivity of HIV-1 antibody detection has increased in the last few years and
sensitive tests for p24 antigen (p24Ag) have been developed and implemented, a window period between infection and detectable serological markers still exists14,16-17. The screening of
blood with current EIA tests results, on average, in a 22-day seronegative window17. Although addition of the p24Ag test allows earlier detection of HIV-1
infection, implementation of the p24Ag test in the U.S. yielded a very modest number of Ab(-)/Ag(+) donors with no significant reduction in the risk of infection. Several studies suggest that addition
of nucleic acid-based amplification tests would reduce the window period of detection to 6-11 days, preventing more than half of the HIV-1 infections by
blood transfusion14. 

        Nucleic
Acid Testing (NAT) of whole blood donations has been in place in the United States since early 1999. Stramer et al., have reported the results of testing small pools of 16, 24
and 128 plasma samples15,30 under IND (Investigational New Drug Application) clearances from the FDA. As of November 2001, the major programs (pooled and individual donation
testing) in the U.S. have tested a total of 24.9 million donations for HCV RNA and HIV-1 RNA. A total of 89 donations (1:280,000 screened units) were confirmed to be positive for
HCV RNA and negative in serological testing. Similarly, nine HIV-1 RNA positive, serologically negative donations (1:2,767,000) were identified. During this testing period, two specimens
were reactive for HIV-1 RNA and p24 Ag but nonreactive by HIV antibody testing. 

        Detection
of HCV is based on serologic screening for anti-viral antibodies with enzyme-linked immunosorbent assays (ELISA) or enzyme immunoassays (EIA) and confirmation with
a Strip Immunoblot Assay (e.g., RIBA® SIA). Even though the development of these tests has significantly reduced the incidence of post transfusion HCV infection in the U.S., risk of
contracting HCV through transfusion still exists14,16-17. Recent studies indicate that nucleic acid-based amplification tests for HCV RNA will allow detection of HCV
infection approximately 59 days earlier than the current antibody-based tests17. 

        The
Procleix HIV-1/HCV Assay utilizes target amplification nucleic acid probe technology for the detection of HIV-1 and HCV RNA in voluntary blood
donors18. The assay contains reagents which may be used for simultaneous detection of both viruses or individual viruses, HIV-1 and HCV. All three assays incorporate an
Internal Control for monitoring assay performance in each individual specimen. 

PRINCIPLES OF THE PROCEDURE  

        The Procleix HIV-1/HCV Assay involves three main steps which take place in a single tube: sample preparation; HIV-1 and HCV RNA target
amplification by Transcription-Mediated Amplification
(TMA)19; and detection of the amplification products (amplicon) by the Hybridization Protection Assay (HPA)20. 

        During
sample preparation, RNA is isolated from plasma specimens via the use of target capture. Plasma is treated with a detergent to solubilize the viral envelope, denature proteins and
release viral genomic RNA. Oligonucleotides ("capture oligonucleotides") that are homologous to highly conserved 

IN0076 Rev. F

2

 

regions of HIV-1 and HCV, are hybridized to the HIV-1 or HCV RNA target, if present, in the test specimen. The hybridized target is then captured onto magnetic microparticles
that are separated from plasma in a magnetic field. Wash steps are utilized to remove extraneous plasma components from the reaction tube. Magnetic separation and wash steps are performed with the
Procleix TCS. 

        Target
amplification occurs via TMA, which is a transcription-based nucleic acid amplification method that utilizes two enzymes, MMLV reverse transcriptase and T7 RNA polymerase. The
reverse transcriptase is used to generate a DNA copy (containing a promoter sequence for T7 RNA polymerase) of the target RNA sequence. T7 RNA polymerase produces multiple copies of RNA amplicon from
the DNA copy template. The Procleix HIV-1/HCV Assay utilizes the TMA method to amplify regions of HIV-1 RNA and of HCV RNA. 

        Detection
is achieved by HPA using single-stranded nucleic acid probes with chemiluminescent labels that are complementary to the amplicon. The labeled nucleic acid probes hybridize
specifically to the amplicon. The Selection Reagent differentiates between hybridized and unhybridized probes by inactivating the label on unhybridized probes. During the detection step, the
chemiluminescent signal produced by the hybridized probe is measured in a luminometer and is reported as Relative Light Units (RLU). 

        Internal
Control is added to each test specimen, external quality control, or assay calibrator tube via the Target Capture Reagent that contains the Internal Control. The Internal
Control in this reagent controls for specimen processing, amplification and detection steps. Internal Control signal in each tube or assay reaction is discriminated from the HIV-1/HCV
signal by the differential kinetics of light emission from probes with different labels21. Internal Control specific amplicon is detected using a probe with rapid emission of light
(termed flasher signal). Amplicon specific to HIV-1/HCV is detected using probes with relatively slower kinetics of light emission (termed glower signal). The Dual Kinetic Assay (DKA) is a
method used to differentiate between the signals from flasher and glower labels21. When used for the simultaneous detection of HIV-1 and HCV, the Procleix
HIV-1/HCV Assay differentiates between Internal Control and combined HIV-1/HCV signals but does not discriminate between individual HIV-1 and HCV signals. 

        Specimens
found to be reactive in the Procleix HIV-1/HCV Assay must be run in individual HIV-1 and HCV Discriminatory Assays to determine if they are reactive for
HIV-1, HCV or both. 

        The
Procleix HIV-1 and HCV Discriminatory Assays utilize the same three main steps as the Procleix HIV-1/HCV Assay (target capture, TMA and HPA); the same assay
procedure is followed with one difference: HIV-1-specific or HCV-specific probe reagents are used in place of the Procleix HIV-1/HCV Assay Probe
Reagent. 

IN0076 Rev. F

3

 

MATERIALS PROVIDED  

	Procleix HIV-1/HCV Assay	 	 
	 	 	1000 Test Kit P/N 301031

5000 Test Kit P/N 301030
	 	Internal Control Reagent	 	 
	 	Target Capture Reagent	 	 
	 	Amplification Reagent	 	 
	 	Enzyme Reagent	 	 
	 	Probe Reagent	 	 
	 	Selection Reagent	 	 
	 	Procleix Negative Calibrator	 	 
	 	Procleix HIV-1 Positive Calibrator	 	 
	 	Procleix HCV Positive Calibrator	 	 

IN0076 Rev. F

4

 

MATERIALS REQUIRED, SOLD SEPARATELY  

	 
	 	 

	Procleix HIV-1 and HCV

Discriminatory Probe Reagents	 	P/N 301026
	 	

HIV-1 Discriminatory Probe Reagent	
 	

 
	 	HCV Discriminatory Probe Reagent	 	 
	
Procleix Assay Fluids	
 	
P/N 301027
	 	Wash Solution	 	 
	 	Oil	 	 
	 	Buffer for Deactivation Fluid	 	 
	
 Procleix Auto Detect Reagents	
 	
P/N 301038
	 	Auto Detect 1	 	 
	 	Auto Detect 2	 	 
	
 Disposables	
 	

 
	(Disposables are single use only, do not reuse.

Use of other disposables is not recommended.)	 	 
	 	Ten-Tube Units (TTUs)	 	P/N TU0022
	 	Ten Tip Cassettes	 	P/N 104578
	 	Sealing Cards	 	P/N 102085
	
 Procleix HIV-1/HCV

Proficiency Panel	
 	
P/N 301034
	 	HIV-1 Positive Panel Members	 	 
	 	HCV Positive Panel Members	 	 
	 	HIV-1 and HCV Positive Panel Member	 	 
	 	Negative Panel Members	 	 
	
 Procleix HIV-1 and HCV

External Quality Controls	
 	
P/N 301035
	 	HIV-1 Positive External Quality Control	 	 
	 	HCV Positive External Quality Control	 	 
	 	Negative External Quality Control	 	 
	
 Procleix HIV-1/HCV

Assay Calibrators	
 	
P/N 301036
	 	HIV-1 Positive Calibrator	 	 
	 	HCV Positive Calibrator	 	 
	 	Negative Calibrator	 	 
	
Chiron CPT (Correlated Pipetting Transfer)

Pooling Software (Only required for pooling)	
 	

P/N 10001970

        The
Chiron CPT Pooling Software, used in combination with the TECAN GENESIS RSP, performs sample scanning and pooling operations that combine aliquots from 16 individual samples into a
single Master Pool Tube, which may be used for further testing. 

IN0076 Rev. F

5

 

Equipment

        All
equipment is available from Chiron Corporation unless otherwise noted. 

	 
	 	 

	Procleix System	 	P/N 104955 (nominal 115V)

P/N 104954 (nominal 230V)

        Dedicated
fixed or adjustable repeat pipettor capable of delivering 400 μL of Target Capture Reagent with a ± 5% accuracy and a
precision of < 5% CV. (Only required for manual sample pipetting method.) 

        Dedicated
single channel pipettor capable of delivering 500 μl of specimen with a ± 5% accuracy and a precision of
< 5% CV. (only required for manual sample pipetting method.) 

MATERIALS REQUIRED BUT NOT PROVIDED  

Eppendorf
COMBITIPS repeat pipettor tips (12.5 mL, 5.0 mL, 1.25 mL) or equivalent 

Disposable
1000 μL filter tips in rack 

Bleach

For
use in final concentration of 5% sodium hypochlorite and 0.5% sodium hypochlorite 

Sterile,
polypropylene conical tubes with sealing caps 

Freestanding
tubes are recommended in two different sizes (5 mL to 10 mL tube and > 30 mL tube). The tubes must be able to accommodate the diameter of an Eppendorf Repeat
pipettor tip 

TECAN
GENESIS disposable 1000 μL conductive filter tips 

TECAN
100 mL reagent troughs 

IN0076 Rev. F

6

 

REAGENTS  

Procleix HIV-1/HCV Assay Kit:  

P/N 301031 - 1000 Test Kit  

P/N 301030 - 5000 Test Kit  

	CONTENTS
 
	 	Number of vials/

Volume per vial

	Reagent Name
 
	 	1000

Test Kit
	 	5000

Test Kit

	Internal Control Reagent
 A HEPES buffered solution containing detergent and an RNA transcript.	 	2 X 5

mL	 	10 X 5

mL
	Store unopened reagent at –15° to –35°C.	 	 	 	 
	
Target Capture Reagent
 A HEPES buffered solution containing detergent, capture oligonucleotides and magnetic microparticles.	
 	
2 X 280

mL	
 	

10 X 280

mL
	Store at 2° to 8°C. (Do not freeze)
 Internal Control Reagent must be added to Target Capture Reagent before use in the assay.	 	 	 	 
	
Amplification Reagent
 Primers, dNTPs, NTPs and co-factors in TRIS buffered solution containing PROCLIN 300 as preservative.	
 	
3 X 32

mL	
 	

15 X 32

mL
	Store unopened reagent at –15° to –35°C.	 	 	 	 
	
Enzyme Reagent
 MMLV Reverse Transcriptase and T7 RNA Polymerase in HEPES/TRIS buffered solution containing 0.05% sodium azide as preservative.	
 	
2 X 18

mL	
 	

10 X 18

mL
	Store unopened reagent at –15° to –35°C.	 	 	 	 
	
Probe Reagent
 Chemiluminescent oligonucleotide probes in succinate buffered solution containing detergent.	
 	
2 X 75

mL	
 	

10 X 75

mL
	Store unopened reagent at –15° to –35°C.	 	 	 	 
	
Selection Reagent
 Borate buffered solution containing surfactant.	
 	
2 X 180

mL	
 	

10 X 180

mL
	Store at 15° to 30°C.	 	 	 	 
	
Procleix Negative Calibrator
 Defibrinated normal human plasma, nonreactive for hepatitis B surface antigen (HBsAg),

HIV-1 p24Ag, antibodies to human immunodeficiency virus type 1 (anti-HIV-1) and type 2 (anti-HIV-2), and antibodies to human hepatitis C virus (anti-HCV) when tested by FDA-licensed assays, containing gentamicin and 0.2% sodium azide as
preservatives.

Store at –15° to –35°C.	
 	
30 X 2

mL	
 	

90 X 2

mL

 
        

IN0076 Rev. F

7

 

	
Procleix HIV-1 Positive Calibrator
 Inactivated HIV-1 positive plasma in defibrinated normal human plasma, nonreactive for hepatitis B surface antigen (HBsAg), and antibodies to
human hepatitis C virus (anti-HCV) when tested by FDA-licensed assays, containing gentamicin and 0.2% sodium azide as preservatives.

Store at –15° to –35°C.	
 	
30 X 2

mL	
 	

90 X 2

mL

 
        
	
Procleix HCV Positive Calibrator
 Inactivated HCV positive plasma in defibrinated normal human plasma, nonreactive for hepatitis B surface antigen (HBsAg), and antibodies to
human immunodeficiency virus type 1 (anti-HIV-1) and type 2 (anti-HIV-2), when tested by FDA-licensed assays, containing gentamicin and 0.2% sodium azide as preservatives.

Store at –15° to –35°C.	
 	
30 X 2

mL	
 	

90 X 2

mL

 
        

STORAGE INSTRUCTIONS  

	A.
	Room
temperature is defined as 15° to 30°C.

	B.
	

  The
Procleix HIV-1/HCV Assay Probe Reagent and the Discriminatory Probe Reagents are light sensitive. Protect these reagents from light during storage and preparation for use. 

	C.
	Target
Capture Reagent (TCR) is stable when stored unopened at 2° to 8°C until the expiration date. Do not use after expiration date. If a precipitate forms in
the Target Capture Reagent during storage, see instructions under REAGENT PREPARATION. DO NOT VORTEX. DO NOT FREEZE Target Capture Reagent. 

NOTE:
If after removing the TCR from storage at 2° to 8°C, the precipitate is allowed to settle to the bottom of the container, the likelihood of the formation of a gelatinous
precipitate is increased substantially. 

	D.
	Selection
Reagent is stable when stored unopened at room temperature until the expiration date. Do not use after expiration date. Mix thoroughly prior to use.

	E.
	The
following reagents are stable when stored unopened at room temperature until the expiration date. 

	Wash Solution

Oil

Auto Detect 1

Auto Detect 2

Buffer for Deactivation Fluid

Do
not use after expiration date. 

	F.
	Once
opened, Wash Solution, Oil, Selection Reagent, Buffer for Deactivation Fluid, Auto Detect 1 and Auto Detect 2 are stable for 30 days when stored at room temperature. 

IN0076 Rev. F

8

 
	G.
	The
following reagents are stable when stored unopened at -15° to -35°C until the expiration date. 

	Internal Control Reagent

Amplification Reagent

Enzyme Reagent

Probe Reagent

Procleix Negative Calibrator

Procleix HIV-1 Positive Calibrator

Procleix HCV Positive Calibrator

Procleix HIV-1 Discriminatory Probe Reagent

Procleix HCV Discriminatory Probe Reagent

        Do not use after expiration date. 

	H.
	After
thawing, the Amplification Reagent, Enzyme Reagent, Probe Reagent, HIV-1 Discriminatory Probe Reagent and HCV Discriminatory Probe Reagent are stable when stored at
2° to 8°C for 30 days. Once completely thawed, these reagents may be kept at room temperature up to 8 hours per 24 hour period while in use, not to exceed
80 hours at room temperature. Do not refreeze Amplification, Enzyme, Probe, HIV-1 and HCV Discriminatory Probe Reagents after the initial thaw.

	I.
	After
thawing, Negative, HIV-1 and HCV Positive Calibrators may be kept at room temperature up to 4 hours. These are single use vials and must be discarded after
use.

	J.
	After
addition of Internal Control Reagent, the working Target Capture Reagent is stable when stored at 2° to 8°C for 30 days and may be kept at room
temperature up to 8 hours per 24 hour period while in use, not to exceed 80 hours at room temperature.

	K.
	If
precipitate forms in the Wash Solution, Amplification Reagent, Probe Reagent, or HIV-1 and HCV Discriminatory Probe Reagents, warm to 15°to 30°C
and mix thoroughly prior to use. See instructions under REAGENT PREPARATION.

	L.
	If
precipitate forms in the Selection Reagent during storage, see instructions under REAGENT PREPARATION.

	M.
	Changes
in the physical appearance of the reagent supplied may indicate instability or deterioration of these materials. If changes in the physical appearance of the reagents are
observed (e.g., obvious changes in reagent color or cloudiness apparent with microbial contamination), they should not be used. 

PRECAUTIONS  

For In Vitro Diagnostic Use.  

	A.
	Specimens
may be infectious. Use Universal Precautions22,26 when performing the assay. Proper handling and disposal methods should be established according to local,
state and federal regulations.23-25 Only personnel qualified as proficient in the use of the Procleix HIV-1/HCV Assay, the use of the TECAN GENESIS RSP and/or manual
sample/TCR pipetting, and trained in handling infectious materials should perform this type of diagnostic procedure.

	B.
	CAUTION: Some components of this kit contain human blood products. The HIV-1 Positive Calibrator in this kit contains human plasma that is
HIV-1 positive and has been heat-treated to inactivate the virus. The HCV Positive Calibrator contains human plasma that is HCV positive and has been heat-treated
to inactivate the virus. The Negative Calibrator has been assayed by FDA licensed tests and found non-reactive for the presence of hepatitis B surface antigen (HBsAg), HIV-1
p24Ag and antibodies to HIV-1/2 and HCV. No known test method can offer  

IN0076 Rev. F

9

 

 complete assurance that products derived from human blood will not transmit infectious agents. All human blood sourced materials should be considered potentially infectious and should be handled with
Universal Precautions.22,26 If spillage occurs, immediately disinfect, then wipe up with a 0.5% (final concentration) sodium hypochlorite solution (diluted bleach) or follow appropriate
site procedures.

	C.
	Use
routine laboratory precautions. Do not pipette by mouth. Do not eat, drink or smoke in designated work areas. Wear disposable gloves and laboratory coats when handling specimens
and kit reagents. Wash hands thoroughly after handling specimens and kit reagents.

	D.
	This
product contains sodium azide as a preservative. Do not use metal tubing for reagent transfer. If solutions containing azide compounds are disposed of in a plumbing system, they
should be diluted and flushed with generous amounts of running water. These precautions are recommended to avoid accumulation of deposits in metal piping in which explosive conditions could develop.

	E.
	Avoid
contact of Auto Detect Reagents 1 and 2 with skin, eyes and mucous membranes. Wash with water if contact with these reagents occurs. If spills of these reagents occur, dilute
with water before wiping dry and follow appropriate site procedures.

	F.
	Dispose
of all materials that have come in contact with specimens and reagents according to local, state and federal regulations.23,24 Thoroughly clean and disinfect all
work surfaces.

	G.
	Use
only supplied or specified required disposables.

	H.
	Do
not use this kit after its expiration date. DO NOT interchange, mix, or combine reagents from kits with different master lot numbers.

	I.
	Avoid
microbial and ribonuclease contamination of reagents.

	J.
	Store
all assay reagents at specified temperatures. The performance of the assay may be affected by use of improperly stored assay reagents. See STORAGE
INSTRUCTIONS and REAGENT PREPARATION.

	K.
	Do
not combine any assay reagents or fluids without specific instruction.

	L.
	Some
reagents of this kit are labeled with risk and safety symbols according to the European Directive 1999/45/EC and should be handled accordingly. 

Material
Safety Data Sheets are available upon request. 

IN0076 Rev. F

10

 

The
following reagents contain 0.2% sodium azide as a preservative: 

	Procleix Negative Calibrator

Procleix HIV-1 Positive Calibrator

Procleix HCV Positive Calibrator

	Xn. Harmful	 	

 

 R22/R32/S2

S13/S36/S46

	R22	 	Harmful if swallowed
	R32	 	Contact with acid liberates very toxic gas
	S2	 	Keep out of reach of children
	S13	 	Keep away from food, drink, and animal feeding stuffs
	S36	 	Wear suitable protective clothing
	S46	 	If swallowed, seek medical advice immediately and show this container or label

	M.
	Refer
to PRECAUTIONS in other Procleix Assay package inserts and Procleix System Operator's Manuals. 

REAGENT PREPARATION  

        This step should be performed prior to beginning Target Capture in an area that is free of template and amplicon.

	1.
	Warm all reagents to room temperature and mix thoroughly prior to use. A dedicated waterbath at room temperature may be used to aid this process.    
Ensure that precipitates are dissolved. Do not use a reagent if precipitate or cloudiness is present. See step 6 for Target Capture Reagent preparation.

	2.
	DO NOT heat Probe Reagent, HIV-1 Discriminatory Probe Reagent or HCV Discriminatory Probe Reagent above 30oC.

	3.
	Thaw
reagents upright.

	4.
	If
necessary, thaw Amplification, Probe and Enzyme Reagents at room temperature or at 2° to 8°C. Internal Control, Amplification and Probe Reagents may be mixed
by vortexing. Enzyme Reagent should be mixed thoroughly by gentle inversion taking care to avoid excessive foaming. Once completely thawed, these reagents may be kept at room temperature up to
8 hours per 24 hour period while in use. These reagents are stable for 30 days when stored at 2° to 8°C. Record date of thaw (THAW DATE) for Amplification,
Probe and Enzyme Reagents in the space provided on the label.

	5.
	Precipitate
will form in the Probe Reagent when stored at 2° to 8°C. Probe Reagent may be warmed in a water bath to facilitate dissolution of precipitate, but
temperature in the bath should not exceed 30°C. The Probe Reagent may take up to 4 hours with periodic mixing to allow complete dissolution of precipitate if thawing is conducted on
the lab bench. Ensure that precipitates in the Probe Reagent are dissolved. Do not use if precipitate or cloudiness is present.

	6.
	Selection
Reagent is stored at room temperature. If Selection Reagent has been inadvertently stored at 2° to 8°C or the temperature of the laboratory falls
below 15°C, precipitate may form. If precipitate forms in the Selection Reagent during storage, heat at 60° ± 1° C for no 

IN0076 Rev. F

11

 

more
than 45 minutes, shaking the bottle frequently (every 5 to 10 minutes). Once all precipitate has gone back into solution, place the bottle in a room temperature water bath and allow the bottle
to equilibrate for at least 1 hour. Do not use the Selection Reagent until it has equilibrated. The Selection Reagent must be at room temperature before use. Do not use if precipitate or
cloudiness is present. 

	7.
	Prepare
working Target Capture Reagent: thaw one vial of Internal Control Reagent at room temperature or 2° to 8°C. Mix the Internal Control Reagent thoroughly
by inversion. Remove Target Capture Reagent (TCR) from 2° to 8°C storage. IMMEDIATELY upon removing from storage, mix vigorously (at least 10 inversions). DO NOT VORTEX. After
mixing, place the TCR bottle at 22° to 30°C. Approximately every 10 minutes shake the bottle until all precipitate has disappeared. TCR precipitate should normally dissolve in
about 30 minutes. If a gel is observed after performing this procedure, a new bottle must be used according to the handling recommendations above. Return the bottle with gel back to 2° to
8°C storage for subsequent use. When the Internal Control Reagent and TCR have reached room temperature, mix TCR thoroughly by inversion. Pour the entire vial of Internal Control Reagent
into the TCR bottle. The total time for each of these reagents at room temperature must not exceed 8 hours, in the first 24-hour period. This is now the working Target Capture
Reagent. Mix thoroughly. Use the space indicated on the TCR bottle to record the date Internal Control Reagent was added and lot number used (IC LOT). Record the expiration date of the working TCR in
the space provided on the label.

	8.
	Thaw
calibrators at room temperature. These are single use vials and must be thawed prior to each run. Once thawed, use calibrators within four hours. Mix thoroughly by inversion.

	9.
	Wash
Solution is shipped at ambient temperature and stored at room temperature. Precipitates may form in the Wash Solution during shipment or during storage when temperatures fall
below 15°C. Wash Solution may be incubated in a warm water bath to facilitate dissolution of precipitate. Temperature in the bath should not exceed 30°C. Ensure that
precipitates in the Wash Solution are dissolved prior to use. Do not use if precipitate or cloudiness is present.

	10.
	Once
opened, Wash Solution, Oil, Selection Reagent, Buffer for Deactivation Fluid, Auto Detect 1 and Auto Detect 2 are stable for 30 days when stored at room temperature.
Record the date the reagent was first opened (OPEN DATE) in the space provided on the label.

	11.
	To
prepare Deactivation Fluid, mix one part Buffer for Deactivation Fluid with one part 5% sodium hypochlorite. Deactivation Fluid is stable for 30 days when stored at
room temperature. 

SPECIMEN COLLECTION, STORAGE AND HANDLING  

NOTE: Handle all specimens as if they are potentially infectious agents.  

Take
care to avoid cross-contamination during the sample handling steps. For example, discard used material without passing over open tubes. 

	A.
	Plasma
collected in K2EDTA, K3EDTA or in Becton Dickinson EDTA Plasma Preparation Tubes (PPT) may be used. Follow sample tube manufacturer's instructions.
Specimen stability is affected by elevated temperature. Whole blood or plasma from pooled or individual donor specimens may be stored for up to 72 hours from time of draw at
< 25°C; temperatures not to exceed 30°C are acceptable for no more than 24 hours. Specimens may be stored an additional five days
at 2° to 8°C following centrifugation. Plasma separated from the cells may be stored for longer periods of time at
<-20°C before testing. 

IN0076 Rev. F

12

 

Do
not freeze whole blood. 

 Temperature

(°C)  

	

 

*The
2-30°C and 2-25°C periods indicated above may occur at any time. 

	B.
	Additional
specimens taken from blood or plasma units collected in ACD or sodium citrate according to the collection container manufacturer's instructions may be used. ACD or sodium
citrate whole blood or plasma may be stored as in A. above.

	C.
	Additional
specimens may be taken from whole blood or plasma units containing CPD, CP2D, or CPDA-1 anticoagulants collected according to the collection container
manufacturer's instructions. Whole blood (not plasma units) collected in these anticoagulants may be stored for up to 13 days at 2° to 8°C prior to centrifugation. At
any time within this 13 day period, the whole blood unit may have been stored for up to one day at 30°C and up to two days at 25°C. Following centrifugation, the plasma
may be stored for an additional five days at 2° to 8°C before testing. Plasma separated from the cells may be stored for longer periods of time at
<-20°C before testing.

	D.
	No
adverse effect on assay performance was observed when plasma was subjected to three freeze-thaw cycles.

	E.
	Mix
thawed plasma thoroughly and centrifuge for 10 minutes at 1000 to 3000 X g before testing. Centrifugation times and speeds for thawed PPT tubes must be validated by
the user.

	F.
	Other
collection and storage conditions should be validated by the user. If specimens are to be shipped, they should be packaged and labeled in compliance with applicable federal and
international regulations covering the transport of clinical specimens and etiologic agents.25

	G.
	False
positive results may occur if cross contamination of specimens is not adequately controlled during specimen handling and processing.

	H.
	Specimen
Pooling 

The
Chiron CPT Pooling Software, used in combination with the TECAN GENESIS RSP, performs sample scanning and pooling operations that combine aliquots from 16 individual samples into a single Master
Pool Tube, which may be used for further testing. 

PROCEDURAL NOTES  

	A.
	RUN
SIZE 

IN0076 Rev. F

13

 

When
the average run size is 55 tests or more, P/N 301030 should yield 5000 tests per kit. P/N 301031 should yield 1000 tests per kit. Smaller run sizes will result in a lower yield. Each run of up to
100 tests must contain 3 replicates each of the Negative Calibrator, the HIV-1 Positive Calibrator and the HCV Positive Calibrator. 

	B.
	EQUIPMENT
PREPARATION 
	1.
	Three
dedicated circulating water baths must be used: one for target capture and pre-amplification (60° ± 1°C),
one for amplification (41.5°
± 1°C) and one for hybridization and selection (60° ± 1°C). An additional water bath is required
to be maintained at 23° ± 4°C for the step preceding detection.

	2.
	Equilibrate
circulating water baths to 60° ± 1°C for target capture and 41.5°
± 1°C for amplification incubations.

	3.
	Prepare
the TECAN GENESIS RSP for use according to instructions in the Operator's Manual.

	4.
	Prepare
the Procleix TCS for use according to instructions in the Operator's Manual.

	5.
	Wipe
work surfaces and pipettors daily with diluted bleach (0.5% sodium hypochlorite in water). Allow bleach to contact surfaces and pipettors for at least 15 minutes and then follow
with a water rinse. DO NOT USE DEACTIVATION FLUID ON SURFACES.

	6.
	Equilibrate
a circulating water bath to 60° ± 1°C for hybridization and selection incubations. Prepare an additional container
of water at 23° ± 4°C for cool down prior to detection.

	7.
	Setup
procedures for the Procleix HC+ Luminometer are given in the Operator's Manual. 

	C.
	REAGENTS

	1.
	Add
all reagents using an Eppendorf repeat pipettor (or equivalent) capable of delivering specified volume with ± 5% accuracy and a precision
of < 5% CV. Check pipettor functionality monthly and calibrate regularly.

	2.
	To
minimize waste of Amplification, Oil, Enzyme, Probe, and Selection Reagents, aliquot each reagent for a given run size. Aliquoting must be performed after reagent preparation using
sterile, polypropylene conical tubes with sealing caps in an area that is template and amplicon free. The aliquoting area must be wiped down with diluted bleach (0.5% sodium hypochlorite in water)
before and after the aliquoting process. The aliquoted reagents must be used the same day the aliquoting was performed. DO NOT store reagents in the aliquot conical tubes. 

	D.
	WORK
FLOW

	1.
	To
minimize the possibility of laboratory areas from becoming contaminated with amplicon, the laboratory area should be arranged with a uni-directional workflow. Proceed
from reagent preparation to sample preparation to amplification and then to detection areas. Samples, equipment and reagents should not be returned to the area where a previous step was performed.
Also, personnel may not move from the dedicated HPA area back into previous work areas without proper anti-contamination safeguards.

	2.
	Perform
reagent preparation in a template free area.

	3.
	Perform
Target Capture and Pre-Amplification steps in an amplicon-free area.

	4.
	Perform
Hybridization Protection Assay in an area separate from the reagent preparation and amplification areas. 

	E.
	TEMPERATURE 

IN0076 Rev. F

14

 

	1.
	The
Target Capture, Amplification, Hybridization and Selection reactions are temperature dependent. Therefore, it is imperative that the water baths are maintained within the specified
temperature range. Use a calibrated thermometer.

	2.
	Room
temperature is defined as 15° to 30°C.

	3.
	Detection
is sensitive to temperature. The laboratory temperature in the detection area must be 21° to
27°C. 

	F.
	TIME

	1.
	The
Target Capture, Amplification, and Hybridization Protection Assay steps are all time dependent. Adhere to specific times outlined in INSTRUCTIONS FOR USE. Use a calibrated timer. 

	G.
	VORTEXING

	1.
	Proper
vortexing is important to the successful performance of the Procleix HIV-1/HCV Assay. Vortex equipment speed settings may vary. Start the vortexor at low speed and
then adjust upward to allow reaction mixture to reach and maintain a height within the upper half of all tubes. The reaction mixture should never touch the sealing cards. It is
critical to have a homogeneous mixture after the additions of the Probe Reagent and Selection Reagent.

	H.
	PIPETTING

	1.
	All
pipettors used in the Amplification and HPA steps must be dedicated. All pipettors used for manual pipetting in the Target Capture steps must be dedicated.

	2.
	Take
care to deliver reagents, excluding working TCR, to each tube without inserting pipette tip into the tube or touching the rim of the tube to minimize the chance of carryover from
one tube to another. 

	I.
	MANUAL
SPECIMEN PIPETTING

	1.
	When
using the manual sample/TCR pipetting method, improper pipetting technique will affect the results of the assay. See PROCEDURAL
NOTES, Section H. In order to avoid the loss of Positive ID Tracking, verification of correct sample ID by a second individual is recommended.

	2.
	Ensure
that the TTU is oriented in the rack with the pointed end on the left side and the rounded end on the right side of the rack. Pipette the first calibrator into the first tube
next to the pointed end of the TTU. Samples are pipetted from left to right.

	3.
	Use
a new pipette tip for each sample and dispose of the tip in a biological waste container after use. Take care to avoid cross-contamination by pipetting the specimens and discarding
the used pipette tips without passing over open tubes or touching laboratory surfaces or other pieces of equipment.

	4.
	To
avoid the risk of contamination, clean and decontaminate manual sample pipettors between assay runs.

	5.
	Ensure
proper sample placement into the correct TTU position as indicated on the manual work list record. 

	J.
	DECONTAMINATION

	1.
	The
extremely sensitive nature of the test makes it imperative to take all possible precautions to avoid contamination. Laboratory bench surfaces, and pipettes must be decontaminated
daily with diluted bleach (0.5% sodium hypochlorite in water). Allow bleach to contact surfaces for 

IN0076 Rev. F

15

 

at
least 15 minutes and then follow with a water rinse. Chlorine solutions may pit equipment and metal. Thoroughly rinse bleached equipment to avoid pitting. 

	2.
	Reactions
must be decontaminated with Deactivation Fluid as described in the detection procedure. 

	K.
	SEALING
CARDS

	1.
	When
applying sealing cards, cover the TTUs with the sealing card and press gently to ensure complete contact with all of the tubes. Always use a new sealing card. DO NOT
re-use sealing cards.

	2.
	When
removing sealing cards, carefully lift and peel in one continuous motion to avoid aerosols and cross contamination. Immediately dispose of card in appropriate waste container. 

INSTRUCTIONS FOR USE:  

PROCLEIX HIV-1/HCV ASSAY ON INDIVIDUAL DONOR PLASMA SAMPLES OR ON POOLED PLASMA SAMPLES  

All specimens (individual donations or pooled samples) should be run in singlet in the initial Procleix HIV-1/HCV Assay.

Per CLIA requirements (42 CFR 493), the Procleix HIV-1 and HCV External Quality Controls or equivalent must be run every time a Procleix assay is performed.
Procleix HIV-1/HCV Assay Calibrators and Discriminatory Probe Reagents are to be used with the corresponding master lot of the Procleix HIV-1/HCV Assays. The operator must
check to ensure that the Procleix HIV-1/HCV Assay Calibrators and Discriminatory Probe Reagents are used with the corresponding master lot of kit reagents as indicated on the master lot
sheet enclosed with each shipment of Procleix HIV-1/HCV Assay Calibrators and Discriminatory Probe Reagents.

To
run the Procleix HIV-1/HCV Assay for the detection of HIV-1 and HCV RNA, follow the steps below for Target Capture, Amplification and Hybridization Protection Assay. To run
the Procleix HIV-1/HCV Assay for discrimination between HIV-1 and HCV RNA, see Section D, below, prior to proceeding. 

Note:
Continuous Process Flow: 

All
process steps described below are intended to be completed in a continuous flow with a minimal, if any, delay between steps. 

	A.
	TARGET
CAPTURE 

The Procleix HIV-1/HCV Assay has been validated using the TECAN GENESIS RSP 150/8. The use of manual pipetting requires additional operator training and
demonstration of proficiency. Repeat pipettors used in this step must be dedicated for use only in the TARGET CAPTURE steps.

IF
USING THE TECAN GENESIS RSP 150/8 PIPETTOR: 

	1.
	Start
the Procleix Assay Software. Refer to the Procleix Assay Software Operator's Manual for software operating instructions.

	2.
	Place
TTU Carriers on the TECAN GENESIS RSP deck according to the deck layout indicated on the screen. Load sufficient Ten Tube Units (TTUs) for the run
into TTU Carriers.

	3.
	Mix
working Target Capture Reagent thoroughly to resuspend microparticles. This is important before putting into the TECAN GENESIS RSP reagent trough.
Put sufficient 

IN0076 Rev. F

16

 

working
Target Capture Reagent into the reagent trough and place on the TECAN GENESIS RSP deck as indicated on the deck layout screen. If pipetting can not be completed within 2 hours, remix
prior to use. 

	4.
	Place
Calibrators and samples into TECAN 16-Tube Strip Racks. Place TECAN 16-Tube Strip Racks on the TECAN GENESIS RSP deck
according to the deck layout indicated on the screen.

	5.
	Reference
the Procleix Assay Software Operator's Manual for instructions on pipetting. The TECAN GENESIS RSP will read bar codes of all carriers, TTUs,
Calibrators, and samples. The TECAN GENESIS RSP will pipette 400 μL of working TCR into each reaction tube and then pipette 500 μL each of calibrators
and test samples into assigned reaction tubes. An electronic work list will be created.

	6.
	When
all samples have been pipetted, transfer the TTUs to a TTU rack. Cover the TTUs with sealing cards. See PROCEDURAL
NOTES.

	7.
	Vortex
the rack of TTUs a minimum of 20 seconds and until magnetic microparticles are resuspended. See PROCEDURAL
NOTES.

	8.
	Rack
may remain at room temperature up to 75 minutes prior to proceeding to the 60°C ± 1°C
incubation.

	9.
	Incubate
the tubes in a water bath at 60° ± 1°C for 20 minutes
± 1 minute.

	10.
	Remove
the rack of TTUs and transfer to target capture area.

	11.
	Incubate
the rack of TTUs on the lab bench at room temperature for 14 minutes to 20 minutes.

	12.
	Transfer
the rack of TTUs to the Procleix TCS separation bay for 9 to 20 minutes.

	13.
	Carefully
remove and dispose of the sealing cards. See PROCEDURAL NOTES.

	14.
	Aspirate
the solution from each tube according to the Procleix TCS Operator's Manual.

	15.
	Add
1 mL of Wash Solution to each tube. Cover the TTUs with sealing cards. See PROCEDURAL NOTES. Remove
the rack of TTUs from the Procleix TCS separation bay and vortex to resuspend the microparticle pellets. See PROCEDURAL NOTES.

	16.
	Place
the rack of TTUs on the Procleix TCS separation bay for 4 to 10 minutes.

	17.
	Carefully
remove and dispose of the sealing cards. See PROCEDURAL NOTES.

	18.
	Aspirate
the solution from each tube according to the Procleix TCS Operator's Manual.

	19.
	Add
1 mL of Wash Solution to each tube. Cover the TTUs with sealing cards. Remove the rack of TTUs from the Target Capture System separation bay and
vortex to resuspend the microparticle pellets. See PROCEDURAL NOTES.

	20.
	Place
the rack of TTUs on the Procleix TCS separation bay for 4 to 10 minutes.

	21.
	Carefully
remove and dispose of the sealing cards. See PROCEDURAL NOTES.

	22.
	Completely
aspirate the solution from each tube according to the Procleix TCS Operator's Manual. Cover the TTUs with a sealing card.

	23.
	Remove
the rack of TTUs from the Procleix TCS separation bay and proceed directly to Amplification. 

IN0076 Rev. F

17

 

IF
USING THE MANUAL SAMPLE PIPETTING METHOD: 

The assay results within the run report will be marked "M" indicating that the specimens were manually pipetted.

	1.
	For
sample tracking, an electronic worklist must be created using the Procleix Worklist Editor software. Refer to the Worklist Editor Operator's Manual for instructions. Verification
of correct sample ID on the worklist with the specimen tubes and with the detailed assay run report by a second individual is recommended.

	2.
	Load
sufficient Ten Tube Units (TTUs) for the run into a TTU rack.

	3.
	Thoroughly
mix working TCR immediately before use to resuspend microparticles.

	4.
	Refer
to the worklist and carefully pipette 400 μL of working TCR to each reaction tube that will contain a specimen. To dispense,
insert the tip approximately one quarter of the way into the tube at an angle and pipette working TCR down the side of the tube. Always pipette the working TCR first, followed by the
specimen.

	5.
	Pipette
specimens.

	a.
	Refer
to the worklist to identify the TTU number with the corresponding calibrator and test specimen identification numbers.

	b.
	Aspirate
500 μL of each calibrator, external quality control or test sample from its collection tube using a single channel pipettor with corresponding
filtered disposable tip. Insert only the end of the pipette tip into the specimen. Do not disturb the sediment, if any.

	c.
	To
dispense, insert the pipette tip halfway into the tube taking care not to touch the sides of the upper half of the tube with the pipette tip. At an angle, pipette the specimen down
the side of the bottom half of the tube. Hold down the plunger of the pipettor while removing it from the tube. Take care to avoid touching the rim or the side of the tube with the pipette tip when
removing it from the tube. 

	6.
	Replace
pipette tip with a new tip and repeat Step 5 until all specimens have been pipetted.

	7.
	Visually
inspect tubes to ensure proper specimen volume and working TCR volume have been dispensed.

	8.
	Cover
the TTUs with sealing cards. See PROCEDURAL NOTES. Proceed to Step 7 of section titled "If Using the TECAN GENESIS RSP 150/8
Pipettor", above. 

	B.
	AMPLIFICATION

The repeat pipettors used in this step must be dedicated for use only in AMPLIFICATION steps.

	1.
	Carefully
remove and dispose of the sealing cards. See PROCEDURAL NOTES.

	2.
	Deliver
75 μL of Amplification Reagent to the bottom of each tube using the dedicated repeat pipettor. Take care to deliver the reagent to the bottom of each
tube without inserting the pipette tip into the tube or touching the rim of the tube.

	3.
	Add
200 μL of Oil to each reaction tube using the dedicated repeat pipettor. Angle the pipette tip toward the sides of the tubes, not straight to the bottom,
to avoid splashback.

	4.
	Cover
the TTUs with sealing cards. See PROCEDURAL NOTES. 

IN0076 Rev. F

18

 

	5.
	Vortex
the rack of TTUs a minimum of 20 seconds and until all microparticles are resuspended. Ensure that magnetic particles are no longer adhering to the walls of the tube, and are
evenly dispersed in the aqueous phase.

	6.
	Incubate
the TTUs in a water bath at 60° ± 1°C for 10 minutes ± 1 minute, then at
41.5° ± 1°C for 9 to 20 minutes.

	7.
	Leaving
the rack of TTUs at 41.5° ± 1°C, carefully remove and dispose of the sealing cards. See PROCEDURAL NOTES. Proceed
immediately to enzyme addition. Add 25 μL of the Enzyme Reagent into each tube using the dedicated repeat pipettor. Take care to deliver the reagent to the bottom of each tube
without inserting the pipette tip into the tube or touching the rim of the tube. Place new sealing cards over the TTUs. See PROCEDURAL NOTES. Remove the rack of TTUs from the water bath and shake to
mix. DO NOT VORTEX. Minimize the time the tubes are out of the water bath.

	8.
	Incubate
the rack of TTUs in the water bath at 41.5° ± 1°C for 60 minutes ± 5 minutes.

	9.
	Remove
the rack of TTUs from the water bath and transfer it to the Hybridization Protection Assay area. Rack may remain at room temperature for up to 30 minutes prior to the addition
of Probe Reagent. 

	C.
	HYBRIDIZATION
PROTECTION ASSAY (HPA) 

The repeat pipettor used in this step must be dedicated for use only in HYBRIDIZATION PROTECTION ASSAY.

A
separate, dedicated location for the Hybridization Protection Assay (HPA) step is recommended to minimize amplicon contamination in the assay. This dedicated area should be on a separate bench in a
separate area from the reagent and sample preparation and amplification areas. 

	1.
	Hybridization

	a.
	Carefully
remove and dispose of the sealing cards. See PROCEDURAL NOTES.

	b.
	Add
100 μL of Probe Reagent into each tube using the dedicated repeat pipettor. Take care to deliver the reagent to the bottom of each
tube without inserting the pipette tip into the tube or touching the rim of the tube. Angle the pipette tip toward the sides of the tubes, not straight to the bottom, to avoid
splashback.

	c.
	Cover
the TTUs with sealing cards. See PROCEDURAL NOTES.

	d.
	Vortex
the rack of TTUs a minimum of 20 seconds and until a homogeneous solution is achieved. To avoid possible contamination, do not allow reaction mixture to come in contact with the
sealing card. See PROCEDURAL NOTES.

	e.
	Incubate
the rack of TTUs in a dedicated water bath at 60° ± 1°C for 15
minutes ± 1 minute. 

	2.
	Selection

	a.
	Remove
the rack of TTUs from the 60° ± 1°C water bath. Carefully remove and dispose of the sealing cards. See  PROCEDURAL NOTES.

	b.
	Add
250 μL of Selection Reagent to each tube using a repeat pipettor. Take care to deliver the reagent to the bottom of each tube without inserting the pipette
tip into the tube or touching the rim of the tube. Angle the pipette tip toward the sides of the tubes, not straight to the bottom, to avoid splashback. 

IN0076 Rev. F

19

 

	c.
	Cover
the TTUs with sealing cards. See PROCEDURAL NOTES. Vortex the rack of TTUs a minimum of 20 seconds and until a homogeneous
solution is achieved. To avoid possible contamination, do not allow reaction mixture to come in contact with the sealing card. See PROCEDURAL NOTES.

	d.
	Return
the rack of TTUs to the 60° ± 1°C water bath for 10 minutes ± 1 minute.

	e.
	Remove
the rack of TTUs from the 60° ± 1°C water bath.

	f.
	Cool
the rack of TTUs in a 23° ±
4°C container of water for a minimum of 10 minutes while preparing for Detection (step 3a).

	g.
	Remove
the rack of TTUs from the 23° ±
4°C container of water onto absorbent material. 

	3.
	Detection

	a.
	Prepare
the Procleix HC+ Luminometer for operation as indicated in the Operator's Manual. Ensure that there are sufficient volumes of Auto Detect 1 and Auto Detect 2 to complete the
tests.

	b.
	Select
the "HIV-HCV" assay protocol from the Procleix System Software menu.

	c.
	Carefully
remove and dispose of the sealing cards. See PROCEDURAL NOTES.

	d.
	Before
transferring TTUs to the luminometer, wipe the outside of the tubes using an absorbent tissue dampened with deionized water. This will ensure that no residue is present on the
outside of the tubes and will help reduce static electricity that may affect luminometer readings.

	e.
	Transfer
TTUs to the luminometer according to the software instructions. Note: Tube reading should be completed within 75 minutes after completing the selection reaction (step 2e in
Selection procedure).

	f.
	When
the analysis is complete, remove the TTUs from the luminometer.

	g.
	After
removing the TTUs from the luminometer, add at least 1 mL Deactivation Fluid to each tube. Allow to sit at room temperature for at least 30 minutes before disposing the contents
of the tubes. This will help to prevent contamination of the laboratory environment with amplicon.

	h.
	TTU
racks should be decontaminated by complete immersion in diluted bleach (0.5% sodium hypochlorite in water) for a minimum of 15 minutes. The bleach should then be rinsed off with
water and the rack may be allowed to air dry or may be wiped dry. 

	D.
	PROCLEIX
HIV-1 AND HCV DISCRIMINATORY ASSAYS

	1.
	All
reactive individual specimens should be run in singlet in the HIV-1 and/or HCV Discriminatory Assays.

	2.
	To
perform the discriminatory assays, make the following modifications to the procedure above:

	a.
	Perform
all TARGET CAPTURE and AMPLIFICATION steps exactly as they are outlined above. Set up separate runs for HIV-1 and HCV Discriminatory Assays. Both Discriminatory
Assays use the same Calibrators that are used in the Procleix HIV-1/HCV Assay. 

IN0076 Rev. F

20

 

	b.
	Substitute
HIV-1 or HCV Discriminatory Probe Reagent for Probe Reagent, in step C.1.b, when performing HYBRIDIZATION PROTECTION ASSAY.

	c.
	Choose
the appropriate Procleix System Software protocol: "dHIV-1" for HIV-1 DISCRIMINATORY ASSAY or "dHCV" for HCV DISCRIMINATORY ASSAY, in step C.3.b, when
performing the HYBRIDIZATION PROTECTION ASSAY. 

QUALITY CONTROL PROCEDURES:  

PROCLEIX HIV-1/HCV ASSAY ON INDIVIDUAL DONOR PLASMA SAMPLES OR ON POOLED PLASMA SAMPLES  

	I.
	ACCEPTANCE CRITERIA FOR THE PROCLEIX HIV-1/HCV ASSAY AND PROCLEIX HIV-1 AND HCV DISCRIMINATORY ASSAYS  

Run Validity Criteria  

	A.
	A
run is valid if the minimum number of calibrators is valid and calibrators meet acceptance criteria (see II.A. below). In a run, no more than 2 of the 9 calibrators may be invalid.
The Procleix System Software will invalidate a run if more than 2 calibrators are invalid in a run. Cutoff values will be calculated for Internal Control (flasher) and Analyte (glower) in valid runs
(see II.A. below). For Positive Calibrators or samples which are reactive for Analyte (glower signal), an Internal Control signal below the cutoff is not used to invalidate the result. All specimens
in an invalid run are to be retested, except as noted in step I.B. below.

	B.
	Procleix HIV-1/HCV Assay. If more than 10% of calibrators plus specimen results (overall interpretation) are invalid in the
Procleix HIV-1/HCV Assay, then the run is invalidated by the Procleix System Software and the run must be repeated. An assay run or an individual sample may also be invalidated by an
operator if specific technical/ operator/ instrument difficulties were observed and documented. If individual samples are invalidated by an operator, then the 10% run validity criterion for the
Procleix HIV-1/HCV Assay must be manually recalculated. 

Potential
reactive specimens in an invalid run due to the 10% run validity criterion must be identified by the user. Any reactive result serves as the test of record and the sample should be resolved
according to the resolution algorithm for reactive specimens, as explained below in the INTERPRETATION OF RESULTS section, step 4 or 5. 

Nonreactive
specimens in an invalid run due to the 10% run validity criterion are to be re-tested, as explained below in the INTERPRETATION OF RESULTS  section, step 1. 

	C.
	Procleix HIV-1 and HCV Discriminatory Assays. For the Procleix HIV-1 and HCV Discriminatory Assays, the Procleix
System Software will only invalidate a Procleix HIV-1 or HCV Discriminatory Assay run based on calibrator invalidity criteria described in (A) above. Specimen results are not used
to invalidate the Procleix HIV-1 and HCV Discriminatory Assays. An assay run or an individual sample may be invalidated by an operator if specific technical/ operator/ instrument
difficulties were observed and documented.

	D.
	When
using the TECAN GENESIS RSP, specimens that are invalid due to insufficient sample or TCR are not included in the calculation of the 10% criterion.

	II.
	ACCEPTANCE CRITERIA FOR THE CALIBRATION AND CALCULATION OF CUTOFF

	A.
	Procleix HIV-1/HCV Assay

Negative Calibrator Acceptance Criteria

IN0076 Rev. F

21

 

Each
individual Negative Calibrator (NC) must have an Internal Control (IC) value greater than or equal to 75,000 RLU and less than or equal to 300,000 RLU. Each individual Negative Calibrator must
also have an Analyte value less than or equal to 40,000 RLU and greater than or equal to 0 RLU. If one of the Negative Calibrator values is invalid due to an IC value or an Analyte value outside of
these limits, the Negative Calibrator mean (NCx) will be recalculated based upon the two acceptable values. The run is invalid and must be repeated if two or more of the three Negative
Calibrator values have IC values or Analyte values that are outside of these limits. 

Determination
of the mean of the Negative Calibrator values (NCx) for Internal Control [NCx (Internal Control)]. 

Example:

	

Negative Calibrator

	
 	

Internal Control

Relative Light Units

	1	 	124,000
	2	 	126,000
	3	 	125,000
	 	 	

	Total Internal Control RLU =	 	375,000

NCx
(Internal Control) = Total Internal Control RLU = 125,000

            3 

Determination
of the mean of the Negative Calibrator values (NCx) for Analyte [NCx (Analyte)]. 

Example:

	

Negative Calibrator

	
 	

Analyte

Relative Light Units

	1	 	14,000
	2	 	16,000
	3	 	15,000
	 	 	

	Total Analyte RLU =	 	45,000

NCx
(Analyte) = Total Analyte RLU = 15,000

    3 

HIV-1 Positive Calibrator Acceptance Criteria  

Individual
HIV-1 Positive Calibrator (PC) Analyte values must be less than or equal to 1,800,000 RLU and greater than or equal to 300,000 RLU. If one of the HIV-1 Positive
Calibrator values is outside these limits, the HIV-1 Positive Calibrator mean (HIV-1 PCx) will be recalculated based upon the two acceptable HIV-1
Positive Calibrator values. The run is invalid and must be repeated if two or more of the three HIV-1 Positive Calibrator Analyte values are outside of these limits. IC values may not
exceed 475,000 RLU. 

Determination
of the mean of the HIV-1 Positive Calibrator (HIV-1 PCx) values for Analyte [HIV-1 PCx(Analyte)]. 

IN0076 Rev. F

22

 

Example:

	

HIV-1 Positive Calibrator

	
 	

Analyte

Relative Light Units

	1	 	690,000
	2	 	700,000
	3	 	710,000
	 	 	

	Total Analyte RLU =	 	2,100,000

HIV-1
PCx (Analyte) = Total Analyte RLU = 700,000

            3 

HCV Positive Calibrator Acceptance Criteria  

        Individual HCV Positive Calibrator Analyte values must be less than or equal to 900,000 RLU and greater than or equal to 200,000 RLU. If one of the HCV Positive
Calibrator values is outside these limits, the HCV Positive Calibrator mean (HCV PCx) will be recalculated based upon the two acceptable HCV Positive Calibrator values. The run is invalid
and must be repeated if two or more of the three HCV Positive Calibrator Analyte values are outside these limits. IC values may not exceed 475,000 RLU. 

Determination
of the mean of the HCV Positive Calibrator (HCV PCx) values for Analyte [HCV PCx) (Analyte)]. 

Example:

	HCV Positive Calibrator
 
	 	Analyte

Relative Light Units
 

	1	 	350,000
	2	 	360,000
	3	 	340,000
	 	 	

	Total Analyte RLU =	 	1,050,000

HCV
PCx (Analyte) = Total Analyte RLU = 350,000

        3 

Calculation of the Internal Control Cutoff Value  

Internal
Control Cutoff Value = 0.5 X [NCx (Internal Control)] 

Using
values given in the Negative Calibrator example above: 

Internal
Control Cutoff Value = 0.5 X (125,000) 

Internal
Control Cutoff Value = 62,500 RLU 

Calculation of the HIV-1/HCV Analyte Cutoff Value  

Analyte
Cutoff Value = NCx (Analyte) + [0.02 X HIV-1 PCx

(Analyte)]+ [0.04 X HCV PCx (Analyte)] 

Using
values given in the Negative Calibrator and Positive Calibrator examples above: 

Analyte
Cutoff Value = 15,000 + (0.02 X 700,000) + (0.04 X 350,000) 

Analyte
Cutoff Value = 43,000 RLU 

IN0076 Rev. F

23

 

Summary of Acceptance Criteria for Procleix HIV-1/ HCV Assay  

	Acceptance Criteria:	 	 
	
Negative Calibrator	
 	

 
	Analyte	 	> 0 and < 40,000 RLU
	Internal Control	 	> 75,000 and < 300,000 RLU
	HIV-1 Positive Calibrator	 	 
	Analyte	 	> 300,000 and < 1,800,000 RLU
	Internal Control	 	< 475,000 RLU
	
HCV Positive Calibrator	
 	

 
	Analyte	 	> 200,000 and < 900,000 RLU
	Internal Control	 	< 475,000 RLU

Summary of Cutoff Calculations for Procleix HIV-1/HCV Assay  

	Analyte Cutoff =	 	NC Analyte Mean RLU
	 	 	+ 0.02 X (HIV-1 PC Analyte Mean RLU)
	 	 	+ 0.04 X (HCV PC Analyte Mean RLU)
	                Internal Control Cutoff = 0.5 X (Negative Calibrator IC Mean RLU)

	B.
	Procleix HIV-1 Discriminatory Assay  

Negative Calibrator Acceptance Criteria

Each
individual Negative Calibrator (NC) must have an Internal Control (IC) value greater than or equal to 75,000 RLU and less than or equal to 300,000 RLU. Each individual Negative Calibrator must
also have an Analyte value less than or equal to 40,000 RLU and greater than or equal to 0 RLU. If one of the Negative Calibrator values is invalid due to an IC value or Analyte value that is outside
of these limits, the Negative Calibrator mean (NCx) will be recalculated based upon the two acceptable values. The run is invalid and must be repeated if two or more of the three Negative
Calibrator values have IC values or Analyte values that are outside of these limits. 

Determination
of the mean of the Negative Calibrator (NCx) values for Internal Control [NCx (Internal Control)]. 

Example:

	Negative Calibrator
 
	 	Internal Control Relative Light Units

	1	 	124,000
	2	 	126,000
	3	 	125,000
	 	 	

	Total Internal Control RLU =	 	375,000

NCx
(Internal Control) = Total Internal Control RLU = 125,000

3 

Determination
of the mean of the Negative Calibrator values (NCx) for Analyte [NCx (Analyte)]. 

IN0076 Rev. F

24

 

Example:

	Negative Calibrator
 
	 	Analyte

Relative Light Units

	1	 	12,000
	2	 	11,000
	3	 	13,000
	 	 	

	Total Analyte RLU =	 	36,000

NCx
(Analyte) = Total Analyte RLU = 12,000

    3 

HIV-1 Positive Calibrator Acceptance Criteria

Individual
HIV-1 Positive Calibrator (PC) Analyte values must be less than or equal to 1,800,000 RLU and greater than or equal to 300,000 RLU. If one of the HIV-1 Positive
Calibrator values is outside these limits, the HIV-1 Positive Calibrator mean (HIV-1 PCx) will be recalculated based upon the two acceptable HIV-1
Positive Calibrator values. The run is invalid and must be repeated if two or more of the three HIV-1 Positive Calibrator Analyte values are outside these limits. IC values may not exceed
475,000 RLU. 

Determination
of the mean of the HIV-1 Positive Calibrator (HIV-1 PCx) values for Analyte [HIV-1 PCx (Analyte)]. 

Example:

	HIV-1 Positive Calibrator	 	Analyte

Relative Light Units
	1	 	690,000
	2	 	700,000
	3	 	710,000
	 	 	

	Total Analyte RLU =	 	2,100,000

(HIV-1
PCx) (Analyte) = Total Analyte RLU = 700,000

3 

HCV Positive Calibrator Acceptance Criteria

In
the HIV-1 Discriminatory Assay, each individual HCV Positive Calibrator must have Analyte values less than or equal to 40,000 RLU and greater than or equal to 0 RLU. Each HCV Positive
Calibrator must also have IC values greater than or equal to 75,000 RLU and less than or equal to 300,000 RLU. The run is invalid and must be repeated if two or more of the three calibrator values
have IC values or Analyte values that are outside these limits. 

Calculation of the Internal Control Cutoff Value

Internal
Control Cutoff Value = 0.5 X [NCx (Internal Control)] 

Using
values given in the Negative Calibrator example above: 

Internal
Control Cutoff Value = 0.5 X (125,000) 

Internal
Control Cutoff Value = 62,500 RLU 

Calculation of the Analyte Cutoff Value

Analyte
Cutoff Value = NCx (Analyte) + [0.04 X HIV-1 PCx (Analyte)] 

IN0076 Rev. F

25

 

Using
values given in the Negative Calibrator and HIV-1 Positive Calibrator examples above: 

Analyte
Cutoff Value = 12,000 + (0.04 X 700,000) 

Analyte
Cutoff Value = 40,000 RLU 

Summary of Acceptance Criteria for the Procleix HIV-1 Discriminatory Assay  

	Acceptance Criteria:	 	 
	
Negative Calibrator	
 	

 
	Analyte	 	> 0 and < 40,000 RLU
	Internal Control	 	> 75,000 and < 300,000 RLU
	
HIV-1 Positive Calibrator	
 	

 
	Analyte	 	> 300,000 and < 1,800,000 RLU
	Internal Control	 	< 475,000 RLU
	
HCV Positive Calibrator*	
 	

 
	Analyte	 	> 0 and < 40,000 RLU
	Internal Control	 	< 75,000 and < 300,000 RLU

	*
	Note that the HCV Positive Calibrator performs similarly to the Negative Calibrator in the HIV-1 Discriminatory Assay.

Summary of Cutoff Calculations for the Procleix HIV-1 Discriminatory Assay  

	Analyte Cutoff =	NC Analyte Mean RLU + 0.04 X (HIV-1 PC Analyte Mean RLU)
	                Internal Control Cutoff = 0.5 X (Negative Calibrator IC Mean RLU)

	C.
	Procleix HCV Discriminatory Assay  

Negative Calibrator Acceptance Criteria  

Each
individual Negative Calibrator must have an Internal Control (IC) value greater than or equal to 75,000 RLU and less than or equal to 300,000 RLU. Each individual Negative Calibrator must also
have an Analyte value less than or equal to 40,000 RLU and greater than or equal to 0 RLU. If one of the Negative Calibrator values is invalid or an IC or Analyte value is outside of these limits, the
Negative Calibrator mean (NCx) will be recalculated based upon the two acceptable values. The run is invalid and must be repeated if two or more of the three Negative Calibrator values
have IC values or Analyte values that are outside of these limits. 

Determination
of the mean of the Negative Calibrator values (NCx) for Internal Control [NCx (Internal Control)]. 

Example:

	

Negative Calibrator

	
 	

Internal Control

Relative Light Units

	1	 	124,000
	2	 	126,000
	3	 	125,000
	 	 	

	Total Analyte RLU =	 	375,000

NCx
(Internal Control) = Total Internal Control RLU = 125,000

3 

IN0076 Rev. F

26

 

Determination
of the Analyte mean of the Negative Calibrator values (NCx) for Analyte [NCx(Analyte)]. 

Example:

	
 Negative Calibrator
 
	
 	

Analyte

Relative Light Units
 

	1	 	20,000
	2	 	22,000
	3	 	18,000
	 	 	

	Total Analyte RLU =	 	60,000

NCx
(Analyte) = Total Analyte RLU = 20,000

3 

HIV-1 Positive Calibrator Acceptance Criteria  

In the HCV Discriminatory Assay, each individual HIV-1 Positive Calibrator must have Analyte values less than or equal to 40,000 RLU and greater than or equal to 0
RLU. Each HIV-1 Positive Calibrator must also have IC values greater than or equal to 75,000 RLU and less than or equal to 300,000 RLU. The run is invalid and must be repeated if two or
more of the three calibrator values have IC values or Analyte values that are outside of these limits. 

HCV Positive Calibrator Acceptance Criteria  

Individual HCV Positive Calibrator value must be less than or equal to 2,700,000 RLU and greater than or equal to 400,000 RLU. If one of the HCV Positive Calibrator values is
outside these limits, the HCV Positive Calibrator mean (HCV PCx) will be recalculated based upon the two acceptable HCV Positive Calibrator values. The run is invalid and must be repeated
if two or more of the three HCV Positive Calibrator values are outside these limits. IC values may not exceed 475,000 RLU. 

Determination
of the mean of the HCV Positive Calibrator (HCV PCx) values for Analyte [HCV PCx (Analyte)]. 

Example:

	HCV Positive Calibrator
 
	 	Analyte

Relative Light Units
 

	1	 	900,000
	2	 	1,000,000
	3	 	1,100,000
	 	 	

	Total Analyte RLU =	 	3,000,000

HCV
PCx (Analyte) = Total Analyte RLU = 1,000,000

3 

Calculation of the Internal Control Cutoff Value  

Internal Control Cutoff Value = 0.5 X [NCx (Internal Control)] 

Using
values given in the Negative Calibrator example above: 

Internal
Control Cutoff Value = 0.5 X (125,000) 

Internal
Control Cutoff Value = 62,500 

Calculation of the Analyte Cutoff Value  

IN0076 Rev. F

27

 

Analyte Cutoff Value = NCx(Analyte) + [0.04 X HCV PCx(Analyte)] 

Using
values given in the Negative Calibrator and HCV Positive Calibrator examples above: 

Analyte
Cutoff Value = 20,000 + (0.04 X 1,000,000) 

Analyte
Cutoff Value = 60,000 RLU 

Summary of Acceptance Criteria for the Procleix HCV Discriminatory Assay  

	Acceptance Criteria:	 	 
	
Negative Calibrator	
 	

 
	Analyte	 	> 0 and < 40,000 RLU
	Internal Control	 	> 75,000 and < 300,000 RLU
	
HIV-1 Positive Calibrator*	
 	

 
	Analyte	 	> 0 and < 40,000 RLU
	Internal Control	 	> 75,000 and < 300,000 RLU
	
HCV Positive Calibrator	
 	

 
	Analyte	 	> 400,000 and < 2,700,000 RLU
	Internal Control	 	< 475,000 RLU

	*
	Note that the HIV-1 Positive Calibrator performs similarly to the Negative Calibrator in the HCV Discriminatory Assay.

Summary of Cutoff Calculations for the Procleix HCV Discriminatory Assay  

	Analyte Cutoff =	 	NC Analyte Mean RLU
	 	 	+ 0.04 X (HCV PC Analyte Mean RLU)
	Internal Control Cutoff =	 	0.5 X (Negative Calibrator IC Mean RLU)

INTERPRETATION OF RESULTS

All calculations described above are performed by the Procleix System Software. Two cutoffs are determined for each assay: one for the Analyte signal
(glower signal) termed the Analyte Cutoff and one for the Internal Control signal (flasher signal) termed the Internal Control Cutoff. The calculation of these cutoffs is shown above. For each sample,
an Analyte signal RLU value and Internal Control signal RLU value is determined. Analyte signal RLU divided by the Analyte Cutoff is abbreviated as the Analyte Signal/Cutoff (S/CO) on the report. 

For
a sample with Analyte signal less than the Analyte Cutoff (i.e., Analyte S/CO < 1), the Internal Control (IC) signal must be greater than or equal to the Internal Control Cutoff (IC
Cutoff) for the result to be valid. In this case the Internal Control result will be reported as Valid and the sample is reported as  NonReactive. For a
sample with the Analyte signal less than the Analyte Cutoff (i.e., Analyte S/CO < 1) and the Internal Control
signal less than the Internal Control Cutoff, the Internal Control Result will be reported as Invalid and the sample result is reported as  Invalid. For all
samples, the Internal Control signal may not exceed 475,000 RLU. The sample will automatically be reported as  Invalid with the Procleix System Software.
 

IN0076 Rev. F

28

 

Summary of Sample Validity:  

	

Sample

Interpretation
	
 	

Internal Control

Result
	
 	

 

	Nonreactive	 	Valid	 	Analyte S/CO < 1 and IC

> IC Cutoff and IC <

475,000 RLU
	Reactive	 	(Not used)	 	Analyte S/CO > 1and IC

< 475,000 RLU

	1.
	Any
specimen with an invalid Procleix HIV-1/HCV Assay, Procleix HIV-1 Discriminatory Assay or Procleix HCV Discriminatory Assay result must be retested in the
same assay in singlet, except as noted in step 6 below.

	2.
	If
at any point in the testing algorithm there is insufficient volume to complete the testing then an alternate specimen from the index donation (e.g., plasma unit or serology tube)
may be used as long as the storage criteria in the package insert are met.

	3.
	Specimens
with a valid internal control and with an S/CO less than 1.00 in the HIV-1/HCV Assay are considered Nonreactive for HIV-1 and HCV RNA. If the
Nonreactive specimen is a pool of 16, each of the 16 individual specimens comprising the pool is considered Nonreactive and no further testing is required.

	4.
	Specimens
with S/CO greater than or equal to 1.00 are considered Reactive. 

IF
THE REACTIVE SPECIMEN IS A POOL, then each of the individual specimens comprising the pool is tested with the HIV-1/HCV Assay. 

	a.
	If
an individual specimen tests Nonreactive with the HIV-1/HCV Assay, then the specimen is considered Nonreactive for HIV-1 and HCV RNA and no further testing
is required.

	b.
	If
an individual specimen tests Reactive with the HIV-1/HCV Assay, then the specimen must be tested with the HIV-1 Discriminatory and HCV Discriminatory Assays.

	(1)
	If
an individual specimen then tests Reactive with one or both Discriminatory tests, then the specimen is considered Reactive-Discriminated and may be confirmed as described in
(7) below.

	(2)
	If
an individual specimen then tests Nonreactive with both Discriminatory tests, then the specimen is considered Non-Discriminated. Further clarification of
Non-Discriminated specimens may be obtained by testing an alternate specimen from the index donation with the Procleix Assays and/or by follow-up testing. 

	5.
	IF
THE REACTIVE SPECIMEN IS FROM AN INDIVIDUAL DONATION, then the specimen must be tested with the HIV-1 Discriminatory and HCV Discriminatory Assays.

	a.
	If
an individual specimen then tests Reactive with one or both Discriminatory tests, then the specimen is considered Reactive-Discriminated and may be confirmed as described in
(7) below.

	b.
	If
an individual specimen then tests Nonreactive with both Discriminatory tests, then the specimen is considered Non-Discriminated. The Non-Discriminated
specimen may be retested in the HIV-1/HCV Assay if sufficient sample is available. 

IN0076 Rev. F

29

 

	(1)
	If
the individual specimen tests Nonreactive in the repeated HIV-1/HCV Assay, then the specimen is considered Nonreactive for HIV-1 and HCV RNA and no further
testing is required.

	(2)
	If
the individual specimen tests Reactive in the repeated HIV-1/HCV Assay, then the specimen is considered Repeatedly Reactive, Non-Discriminated for
HIV-1 and HCV RNA. Further clarification of these specimens may be obtained by testing an alternate specimen from the index donation with the Procleix Assays and/or by
follow-up testing. 

	6.
	Potential
reactive specimens in an invalid run due to the 10% run validity criterion must be identified by the user, by viewing the run report, and become the test of record. Any
reactive result (analyte signal/cutoff > 1) serves as the test of record and the sample should be resolved according to the resolution algorithm for reactive
specimens, as explained in the INTERPRETATION OF RESULTS section, step 4 or 5. 

Nonreactive
specimens in an invalid run due to the 10% run validity criterion are to be retested in the same assay in singlet. 

	7.
	HIV
seroreactive specimens found to be Reactive-HIV-1 Discriminated in the Procleix tests may be considered positive for HIV-1 nucleic acid. HCV
seroreactive specimens found to be Reactive-HCV Discriminated in the Procleix tests may be considered positive for HCV nucleic acid. The interpretation of Reactive-Discriminated specimen
results on specimens that are Nonreactive by serology is unclear. Further clarification may be obtained by testing an alternate specimen from the index donation with the Procleix Assays (to eliminate
false positives due to possible specimen contamination) and/or by follow-up testing to determine if the NAT reactivity of the index donation represents early pre-seroconversion
infection. 

PERFORMANCE CHARACTERISTICS

REPRODUCIBILITY  

Procleix
HIV-1/HCV Assay reproducibility was determined at three blood testing laboratories. The reproducibility study evaluated both automated pipetting using TECAN GENESIS RSP, and
manual pipetting of the specimen and Target Capture Reagent (TCR) into the reaction tube. The reproducibility of the HIV-1/HCV Assay was assessed with a seven member reproducibility panel;
16 individual specimens were pipetted with the Chiron CPT Pooling Software to create each of the seven panel members (each panel member is a 16 member pool). Each pool contained from zero to three
HIV-1 and/or HCV RNA positive specimens with the remaining specimens in the pool being HIV-1 and HCV RNA negative (Table I). 

For
determination of the reproducibility of the Procleix HIV-1 Discriminatory Assay and the Procleix HCV Discriminatory Assay, nine panel members were tested as individual specimens and
not in a pool. Eight of these panel members were HIV-1 and/or HCV RNA positive, and one was HIV-1 and HCV RNA negative (Tables IIa, IIb). 

The
reproducibility panels were tested by a total of six operators (two at each site) with three different Clinical Lots over at least 18 nonconsecutive days. Inter- and intra-assay variability and
inter-lot variability were determined. Mean S/CO, standard deviation (SD) and coefficient of variation (%CV) results are shown for panel members and for the Negative, HIV-1
Positive and HCV Positive Calibrators. Since no significant difference in assay reproducibility was observed between automated
pipetting and manual pipetting, results for the two methods are combined in the Tables below (Tables I, IIa, IIb). Also, since HCV RNA positive and HIV-1 RNA positive samples containing 90
copies/mL or greater gave high (saturated) signals in all three assays, results on multiple panel members are combined. 

IN0076 Rev. F

30

 

Table I. Reproducibility of the Procleix HIV-1/HCV Assay  

	 
	 	 
	 	 
	 	 
	 	 
	 	 
	 	Intra-Assay
	 	Inter-Assay
	 	Inter-Lot

	Specimen
 
	 	 
	 	Concentration

Copies/mL
	 	Number of

replicates
	 	%

Agreement
	 	Mean

S/CO

	 	N
	 	SD
	 	%CV
	 	SD
	 	%CV
	 	SD
	 	%CV

	Nonreactive	 	1	 	0	 	320	 	100.00	 	0.23	 	0.054	 	23.5	 	0.034	 	14.7	 	0.041	 	17.7
	HIV-1	 	3	 	190, 620, 720	 	965	 	99.90	 	18.75	 	1.864	 	9.9	 	1.191	 	6.4	 	2.351	 	12.5
	HIV-1/HCV	 	2	 	620,720/90	 	641	 	100.00	 	27.42	 	2.374	 	8.7	 	1.840	 	6.7	 	2.743	 	10.0
	HCV	 	1	 	190	 	321	 	100.00	 	8.70	 	1.074	 	12.3	 	0.615	 	7.1	 	0.743	 	8.5

	 
	 	 
	 	 
	 	 
	 	Intra-Assay
	 	Inter-Assay
	 	Inter-Lot

	Specimen
 
	 	Number of

replicates
	 	%

Agreement
	 	Mean

RLU

	 	SD
	 	%CV
	 	SD
	 	%CV
	 	SD
	 	%CV

	Negative Calibrator	 	323	 	N/A	 	10363	 	2023	 	19.5	 	1740	 	16.8	 	1606	 	15.5
	HIV-1 Positive Calibrator	 	324	 	N/A	 	858644	 	34660	 	4.0	 	55020	 	6.4	 	141285	 	16.5
	HCV Positive Calibrator	 	316	 	N/A	 	398939	 	17511	 	4.4	 	15926	 	4.0	 	41127	 	10.3

N
= Number of panel members combined for this analysis. 

Table IIa. Reproducibility of the Procleix HIV-1 Discriminatory Assay (excludes 10 false positive results)  

	 
	 	 
	 	 
	 	 
	 	 
	 	 
	 	Intra-Assay
	 	Inter-Assay
	 	Inter-Lot

	Specimen
 
	 	 
	 	Concentration

Copies/mL
	 	Number of

replicates
	 	% Agreement
	 	Mean

S/CO

	 	N
	 	SD
	 	%CV
	 	SD
	 	%CV
	 	SD
	 	%CV

	Nonreactive	 	1	 	0	 	322	 	100.00	 	0.19	 	0.050	 	26.3	 	0.029	 	15.3	 	0.024	 	12.3
	HIV-1	 	4	 	150, 500,	 	1289	 	100.00	 	19.69	 	2.391	 	12.1	 	1.114	 	5.7	 	0.883	 	4.5
	 	 	 	 	1500, 10000	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	HIV-1/HCV	 	1	 	500/500	 	318	 	100.00	 	19.44	 	1.225	 	6.3	 	1.373	 	7.1	 	1.045	 	5.4
	HCV	 	3	 	150, 500, 1500	 	955	 	100.00	 	0.18	 	0.054	 	29.7	 	0.038	 	20.9	 	0.029	 	16.1

	 
	 	 
	 	 
	 	 
	 	Intra-Assay
	 	Inter-Assay
	 	Inter-Lot

	Specimen
 
	 	Number of

replicates
	 	% Agreement
	 	Mean

RLU

	 	SD
	 	%CV
	 	SD
	 	%CV
	 	SD
	 	%CV

	Negative Calibrator	 	323	 	N/A	 	8900	 	2121	 	23.8	 	1824	 	20.5	 	1470	 	16.5
	HIV-1 Positive Calibrator	 	320	 	N/A	 	894464	 	57091	 	6.4	 	63756	 	7.1	 	30695	 	3.4
	HCV Positive Calibrator	 	322	 	N/A	 	8686	 	2381	 	27.4	 	1572	 	18.1	 	783	 	9.0

N
= Number of panel members combined for this analysis. 

IN0076 Rev. F

31

 

Table IIb. Reproducibility of the Procleix HCV Discriminatory Assay (excludes 3 false positive results)  

	 
	 	 
	 	 
	 	 
	 	 
	 	 
	 	Intra-Assay
	 	Inter-Assay
	 	Inter-Lot

	Specimen
 
	 	 
	 	Concentration

Copies/mL
	 	Number of

replicates
	 	% Agreement
	 	Mean

S/CO

	 	N
	 	SD
	 	%CV
	 	SD
	 	%CV
	 	SD
	 	%CV

	Nonreactive	 	1	 	0	 	323	 	100.00	 	0.13	 	0.051	 	39.0	 	0.031	 	24.1	 	0.010	 	8.0
	HIV-1	 	4	 	150, 500,	 	1288	 	100.00	 	0.13	 	0.073	 	55.0	 	0.042	 	31.5	 	0.018	 	13.3
	 	 	 	 	1500, 10000	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	HIV-1/HCV	 	1	 	500/500	 	323	 	100.00	 	21.32	 	1.965	 	9.2	 	1.000	 	4.7	 	0.510	 	2.4
	HCV	 	3	 	150, 500, 1500	 	966	 	99.90	 	21.48	 	1.884	 	8.8	 	1.211	 	5.6	 	0.479	 	2.2

	 
	 	 
	 	 
	 	 
	 	Intra-Assay
	 	Inter-Assay
	 	Inter-Lot

	Specimen
 
	 	Number of

replicates
	 	%

Agreement
	 	Mean

RLU

	 	SD
	 	%CV
	 	SD
	 	%CV
	 	SD
	 	%CV

	Negative Calibrator	 	320	 	N/A	 	8132	 	2861	 	35.2	 	1893	 	23.3	 	81	 	1.0
	HIV-1 Positive Calibrator	 	321	 	N/A	 	7937	 	3089	 	38.9	 	2240	 	28.2	 	929	 	11.7
	HCV Positive Calibrator	 	323	 	N/A	 	1243692	 	57818	 	4.6	 	92720	 	7.5	 	36728	 	3.0

N
= Number of panel members combined for this analysis. 

PERFORMANCE OF POOLED SAMPLE TESTING

Specificity of the Procleix HIV-1/HCV Assay  

The
HIV-1/HCV Assay was used to screen plasma pools comprised of 16 donor specimens and individual donor specimens (IDS). These specimens were tested at eight volunteer blood donor sites
using three Clinical Lots of reagents. This population derived from approximately 103 geographically diverse blood donor sites in the continental US and five others which were US military blood donor
sites located in Hawaii (one), Japan (two), Germany (one), and Guam (one). Pools or individual specimens with S/CO<1.0 are considered Nonreactive (NR). Individual specimens that are
Reactive (R) by the HIV-1/HCV Assay and Reactive by either the HIV-1 or HCV Discriminatory Assay or both are termed Reactive-Discriminated. Individual specimens that are
reactive by the HIV-1/HCV Assay but Nonreactive by both the HIV-1 or HCV Discriminatory Assays are termed Reactive-Non-Discriminated. A
non-discriminated specimen which tested again as HIV-1/HCV Reactive was termed Repeatedly Reactive-Non-Discriminated. A non-discriminated
specimen which tested again as HIV-1/HCV Assay Nonreactive was considered Nonreactive for HIV-1 and HCV RNA. 

At
the time the study was performed there was no recognized standard for establishing the presence or absence of HIV-1 RNA or HCV RNA in blood. Specificity was based on testing of blood
donations from random volunteer blood donors. For the purpose of specificity calculations, specimens testing seroreactive for anti-HIV-1 and anti-HCV antibody (Ab)
or HIV p24 antigen (Ag) were eliminated from the analysis. 

In
the pooling specificity study, 11,978 pools (191,648 donor specimens) were tested (Table III and Table IV). Specificity of pool testing relative to serology testing was 99.67% (11,625/11,663).
Specificity was defined as number of pools containing all serology and Procleix HIV-1/HCV Assay nonreactive specimens (True negative, TN) divided by the sum of TN and False positive pools.
False positive pools were defined as pools Reactive by the HIV-1/HCV Assay and that contained all specimens nonreactive by serology. 

There
were 175 (1.46%) pools initially reactive by the HIV-1/HCV Assay. All 16 individual donor specimens from each reactive pool were tested. There were 33 pools containing all
Nonreactive 

IN0076 Rev. F

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individual donor specimens. One hundred and sixty-six individual donor specimens derived from the remaining 142 pools were Reactive in the HIV-1/HCV Assay. No significant
differences among sites or Clinical Lots were observed. 

Of
the 166 HIV-1/HCV Assay reactive individual donor specimens, 138 (83.1%) were Reactive in the HCV Discriminatory Assay, 13 (7.8%) were Reactive in the HIV-1 Discriminatory
Assay and 15 (9.0%) were Nonreactive in both discriminatory tests. The 15 Reactive-Non-Discriminated specimens were seronegative for HIV and HCV and were Nonreactive when
retested in the HIV-1/HCV Assay. The adjusted reactive rate after removal of reactive pools containing true positive samples was 0.31% (37/11,841). 

A
total of 49,054 specimens (total of pooled and individual donor specimens) were run in the HIV-1/HCV Assay during these specificity studies and 185 (0.38%) specimens tested as initially
invalid due to an Internal Control failure. All 185 specimens giving initially invalid results gave valid repeat testing results in the HIV-1/HCV Assay. 

Table III. Procleix HIV-1/HCV Assay Reactivity in Volunteer Blood Donors  

	 
	 	Procleix HIV-1/HCV Assay

Plasma Pool of 16

	Samples Tested*	 	11,978
	Initial Reactive	 	175
	Initial Reactive Rate	 	1.46%
	Adjusted Reactive Rate	 	0.31%
	Combined Mean S/CO on Negative Analytes	 	0.21 ± 0.10

*Combined
data across all sites and Clinical Lots. 

No
significant differences among Clinical Lots of reagents were observed for either the Negative population Analyte mean S/CO or mean Internal Control S/CO in the negative population distribution. 

Results
of deconvolution of all 16 member pools are shown in Table IV. In these pivotal specificity studies (pooled and individual donation testing), no specimen was identified as a yield specimen
based on the HIV-1/HCV Assay reactivity, HIV-1 and/or HCV Discriminatory Assay reactivity, reactivity by Alternative NAT and lack of HCV or HIV-1 antibody
reactivity. The finding of no HIV-1 or HCV RNA yield donors in 226,205 specimens is consistent with published yields15. Rates of specimens testing reactive for both HCV RNA
and HCV antibody in volunteer donors was 1 in 1,508 donors and rates of specimens testing reactive for both HIV-1 RNA and HIV-1 antibody was 1 in 14,138 donors. 

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Table IV. Deconvoluted Pooling Results  

	 
	 	N (%)
	 	Sero-RR*
	 	 
	 	 

	Total pools tested	 	11,978 (100.0	)	N/A	 	 	 	 
	HIV-1/HCV Assay Nonreactive pools	 	11,803 (98.54	)	N/A	 	 	 	 
	HIV-1/HCV Assay Reactive pools	 	175 (1.46	)	N/A	 	 	 	 
	

Pools with all HIV-1/HCV Assay Nonreactive IDS	
 	

33 (18.9	
)	

N/A	
 	

 	
 	

 
	Pools with > 1 HIV-1/HCV Assay Reactive IDS	 	142 (81.1	)	N/A	 	 	 	 
	

HIV-1/HCV Assay Reactive IDS	
 	

166 (100.0	
)	

120	
 	

 	
 	

 
	HIV-1 and HCV Discriminatory Reactive IDS	 	0 (0.0	)	0	 	 	 	 
	HIV-1 Discriminatory Reactive IDS	 	13 (7.8	)	13	 	 	 	 
	HCV Discriminatory Reactive IDS	 	138 (83.1	)	131	 	 	 	 
	HIV-1 and HCV Discriminatory Nonreactive IDS	 	15 (9.0	)	0	 	 	 	 
	

Repeat HIV-1/HCV Assay Nonreactive IDS	
 	

15 (100.0	
)	

0	
 	

 	
 	

 
	Repeat HIV-1/HCV Assay Reactive IDS	 	0 (0.0	)	0	 	 	 	 

*EIA
repeatedly reactive, supplemental serology positive or indeterminate. 

IDS
= Individual Donor Specimen. 

Specificity of the Procleix HIV-1 and HCV Discriminatory Assays  

In
the HIV-1 and HCV Discriminatory Assays specificity study, the HIV-1 Discriminatory and HCV Discriminatory assays were run only on individual donor specimens which had
previously tested as Nonreactive by the HIV-1/HCV assay. The initial reactive rates for the HIV-1 Discriminatory and HCV Discriminatory Assays were 0.24% (6/2508) and 0.29%
(7/2443), respectively. In this study initially reactive specimens were not retested. 

Comparison with Serology

Results
generated from the pooled and individual donation testing specificity studies allow comparison of the HIV-1/HCV Assay with serology reactivity (Table V). Sixteen of 17
HIV-1 seroreactive, Western blot positive specimens were also Procleix HIV-1/HCV Assay Reactive (Table V). The one discordant specimen was Nonreactive when tested as a pool by
the Procleix HIV-1/HCV Assay but was Reactive by the Procleix HIV-1/HCV Assay when tested as an individual donor specimen. All of the HIV seroreactive specimens which were
Indeterminate or negative by Western Blot (91.7% of total HIV seroreactive specimens) were Nonreactive by the Procleix HIV-1/HCV Assay. Overall agreement between the Procleix
HIV-1/HCV Assay and Western blot was 100% (226/226) if testing at an individual donor level is compared. 

77.3%
(150/194) of HCV seroreactive, Chiron RIBA HCV 3.0 (RIBA) Positive specimens were Reactive by the HIV-1/HCV Assay. 3.3% (2/60) of HCV seroreactive, RIBA Indeterminate specimens were
reactive by the Procleix HIV-1/HCV Assay. All 163 RIBA Negative specimens were also Nonreactive by the Procleix HIV-1/HCV Assay. Overall agreement between the Procleix
HIV-1/HCV Assay and RIBA was 89.0% (371/417). These data are consistent with previous reports that about 20% of HCV seropositives will have undetectable HCV RNA27 and
estimates that approximately 20% of HCV seropositive individuals may have resolved infection28. 

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Table V. Comparison of Serologic and Procleix HIV-1/HCV Assay Reactives from the Specificity Studies  

	 
	 	 
	 	Procleix HIV-1/HCV
	 
	Serology
	 	Reactive
	 	Nonreactive
	 
	HIV Ab RR	 	POS	 	16 (7.0	%)	1* (0.4	%)
	Western Blot	 	IND	 	0 (0	%)	74 (32.5	%)
	(N = 228)	 	NEG	 	0 (0	%)	135 (59.2	%)
	 	 	N/A	 	0 (0	%)	2 (0.9	%)
	HCV Ab RR	 	POS	 	150 (35.8	%)	44 (10.5	%)
	RIBA	 	IND	 	2 (0.5	%)	58 (13.8	%)
	(N = 419)	 	NEG	 	0 (0.0	%)	163 (38.9	%)
	 	 	N/A	 	1 (0.2	%)	1 (0.2	%)

*Sample
contained < 50 copies/mL of HIV-1 RNA and was Procleix HIV-1/HCV negative in pool testing but reactive in individual sample testing. 

Non-Specificity Studies

When
tested with the Procleix HIV-1/HCV Assay, no cross-reactivity or interference was observed for naturally occurring icteric, hemolyzed or lipemic specimens or plasma containing the
following substances: serum albumin (up to 225 g/L), hemoglobin (up to 5000 mg/L), billirubin (up to 200 mg/L) and lipids (up to 2,752 mg/dL). 

No
cross-reactivity or interference was observed in specimens from patients with autoimmune diseases or with liver diseases not caused by HCV infection. Autoimmune conditions included rheumatoid
arthritis (n = 10), rheumatoid factor (n = 10), antinuclear antibody (n = 10), multiple sclerosis (n = 10), lupus (n = 10) and multiple myeloma (n =
9). Also tested were flu vaccinees (n = 10), hepatitis B vaccinees (n = 10), elevated IgM (n = 6), elevated IgG (n = 11), alcoholic liver cirrhosis
(n = 10) and elevated ALT (n = 10). 

No
cross-reactivity or interference was observed in bacterially contaminated plasmas or in plasmas infected with other blood borne pathogens, including herpes simplex virus-1 (n =
10), herpes simplex virus-2 (n = 1), CMV (n = 10), EBV (n = 10), hepatitis A virus (n = 10), HTLV-I (n = 10), HTLV-II (n =
10), hepatitis B virus (n = 10), HIV-2 (n = 10), rubella (n = 10) and parvovirus B-19 (n = 10). 

CLINICAL SENSITIVITY

Testing of Whole Blood Donor Specimens

A
total of 24,764,889 donations were screened as part of pooled sample testing since early 199930. As of November 2001, eighty-eight Procleix HCV yield cases (1:281,419) and seven
HIV-1 yield cases (1:3,537,841) were identified across the ten Procleix pooled testing sites. Yield cases were confirmed to be positive for either HIV-1 or HCV RNA, but
negative in serology testing. 

Two
of the nine HIV-1 yield cases were reactive for HIV-1 RNA and p24 Ag but Nonreactive by HIV antibody testing (Table VI). 

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Table VI. Summary of Procleix Assay Yield Cases  

	Pooled Sample Testing

	Number of Donations Tested	 	24,764,889
	Procleix HCV

Yield Cases	 	88

(1:281,419)
	Procleix HIV-1	 	7
	Yield Cases	 	(1:3,537,841)

Testing of Specimens from HIV-1 and/or HCV Infected Individuals  

A
total of 2014 specimens positive by commercial HIV-1 RNA and HCV RNA assays (sensitivity >100 copies/mL) were obtained from four commercial vendors. Three
Clinical Lots were used for all testing. These specimens were classified as HIV-1 RNA positives (n = 867), HCV RNA positives (n = 967) and both HIV-1 and HCV RNA
(coinfected) positives (n = 180) based on alternate nucleic acid testing (Table VII). These specimens were also classified by disease category as described below and as shown in Table
VIII. These positive samples were tested undiluted (neat) with the Procleix HIV-1/HCV Assay, HIV-1 Discriminatory Assay and the HCV Discriminatory Assay, and tested diluted
1:16 with the Procleix HIV-1/HCV Assay. All dilutions were made with processed human serum that was negative for HIV-1 RNA and antibody/antigen, and HCV RNA and antibody. 

During
the study, specimens known to contain <100 copies/mL of viral RNA were excluded from this analysis and therefore the sensitivity presented herein is for samples with viral RNA
concentrations equal to or greater than 100 copies/mL, or of unknown viral concentration. 

The
sensitivity for the Procleix HIV-1/HCV and HIV-1 Discriminatory Assays for undiluted (neat) HIV-1 positive samples was 99.9% (95% CI: 99.4-100%) and
100% (95% CI: 99.6-100%), respectively. The sensitivity for the Procleix HIV-1/HCV Assay for diluted (1:16) HIV-1 positive samples was 99.0% (95% CI:
98.0-99.5%). 

The
sensitivity for both the Procleix HIV-1/HCV Assay and the HCV Discriminatory Assay for undiluted (neat) HCV positive samples was 99.6% (95% CI: 98.9-99.9%). The sensitivity
for the Procleix HIV-1/HCV Assay for diluted (1:16) HCV positives was 99.6% (95% CI: 98.9-99.9). 

The
sensitivity for the Procleix HIV-1/HCV Assay, HIV-1 Discriminatory Assay and HCV Discriminatory Assay for undiluted HIV-1/HCV coinfected specimens was 100% (95%
CI: 98.0-100%), 100% (95% CI: 97.9-100%) and 100% (95% CI: 92.6-100%), respectively. The sensitivity for the Procleix HIV-1/HCV Assay for
HIV-1/HCV coinfected specimens was 98.9% (95% CI: 96.0-99.9) when tested at 1:16 dilution. 

The
overall clinical sensitivity for the Procleix HIV-1/HCV Assay, which takes into account all samples (RNA concentrations > 100 copies/mL or unknown viral
concentration) tested, is 99.8% (95% CI: 99.4-99.9), that for the HIV-1 Discriminatory Assay is 100% (95% CI: 99.6-100%), and that for the HCV Discriminatory Assay
is 99.6% (95% CI: 99.0-99.9%). 

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Table VII. The Sensitivity of the Procleix HIV-1/HCV, HIV-1 and HCV Discriminatory Assays for HIV-1 and HCV Positive Specimens with RNA
Concentrations > 100 Copies/mL or Unknown

	HIV-1/HCV Assay
 
	 
	 
	 	Sensitivity for Neat Specimens
	 	Sensitivity for 1:16 Diluted Specimens
	 
	Sample
 
	 
	 	N
	 	TP
	 	%
	 	(95% C. I.)
	 	N
	 	TP
	 	%
	 	(95% C. I.)
	 
	All	 	2014	 	2009	 	99.8	 	(99.4—99.9	)	2012	 	1997	 	99.3	 	(98.8—99.6	)
	HIV Only	 	867	 	866	 	99.9	 	(99.4—100.0	)	866	 	857	 	99.0	 	(98.0—99.5	)
	HCV Only	 	967	 	963	 	99.6	 	(98.9—99.9	)	966	 	962	 	99.6	 	(98.9—99.9	)
	HIV & HCV	 	180	 	180	 	100	 	(98.0—100.0	)	180	 	178	 	98.9	 	(96.0—99.9	)

	HIV-1 Discriminatory Assay
 
	 
	 
	 	Sensitivity
	 
	Sample
 
	 
	 	N
	 	TP
	 	%
	 	(95% C. I.)
	 
	All	 	1042	 	1042	 	100	 	(99.6—100.0	)
	HIV Only	 	868	 	868	 	100	 	(99.6—100.0	)
	HIV & HCV	 	174	 	174	 	100	 	(97.9—100.0	)

	HIV Discriminatory Assay
 
	 
	 
	 	Sensitivity
	 
	Sample
 
	 
	 	N
	 	TP
	 	%
	 	(95% C. I.)
	 
	All	 	1014	 	1010	 	99.6	 	(99.0—99.9	)
	HCV Only	 	966	 	962	 	99.6	 	(98.9—99.9	)
	HIV & HCV	 	48	 	48	 	100	 	(92.6—100.0	)

C.
I. = Confidence interval. 

The
data from the above study were further analyzed according to the disease stages of the patients from whom the specimens were obtained as shown in Table VIII. A total of 296 samples were from AIDS
patients (as defined by AIDS-indicative conditions and/or a CD4 count of <200/mm3), 338 from asymptomatic patients (asymptomatic, persistent generalized
lymphadenopathy, or acute HIV infection), 168 from symptomatic but non-AIDS patients (not AIDS and not asymptomatic) and 240 from individuals with unknown HIV disease
state29. Most of these patients were on HIV anti-viral medication. The sensitivity for HIV detection with the Procleix HIV-1/HCV Assay ranged from 99.6 to 100%
for neat specimens and from 96.4 to 100% for 1:16 diluted specimens. The sensitivity for the HIV-1 Discriminatory Assay was 100%. All HIV-1 p24 Ag reactive specimens were also
reactive with the Procleix HIV-1/HCV Assay when tested as undiluted (neat) or as 1:16 diluted samples, and with HIV-1 Discriminatory Assay when tested as neat samples. This was
also true of all specimens excluded from the study due to low viral RNA concentrations (<100 copies/mL). 

Similarly,
the specimens from HCV infected patients were segregated as shown in Table IX. A total of 887 specimens were from volunteer blood donors whose donations were HCV reactive with
PCR-based NAT, 53 specimens were from patients with chronic HCV infection that was first identified by blood donation screening and 75 specimens were not categorized by the vendor other
than being HCV NAT or antibody positive. The sensitivity for HCV testing with the Procleix HIV-1/HCV Assay ranged from 99.5 to 100% (95% CI: 98.9-99.9%) with neat samples and
97.3 to 100% (95% CI: 93.3-100%) with 1:16 diluted samples. The sensitivity for HCV Discriminatory Assay ranged from 99.5 to 100% (95% CI: 95.2-100%) for neat samples. 

During
this clinical study, in which a total of 1014 HCV RNA-positive samples were tested, two of these samples were consistently reactive when tested at 1:16 dilution, but nonreactive
when tested neat. 

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In
the same study, 13 sero-positive samples with low copy numbers of HIV or HCV (or both) were non-reactive when tested at 1:16 dilution, and reactive when tested neat. 

In
summary, it appears that the disease stages for HIV-1 or HCV infected individuals did not significantly affect the sensitivity for the Procleix Assays, although some low copy number HCV
antibody positive specimens (2/967) were non-reactive when tested neat but reactive when tested at 1:16 dilution. 

The
clinical sensitivity claims of the assay are still met with the inclusion of these specimens. 

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38

   Table VIII. Sensitivity of the Procleix HIV-1/HCV and HIV-1 Discriminatory Assays for HIV-1 Positive Specimens from Individuals at Various
Disease States*  

	 
	 	Procleix HIV-1/HCV Assay
	 	HIV-1 Discriminatory
	 	HIV-1 Antibody
	 	HIV-1 p24 Ag

	 
	 	Neat
	 	1:16 Dilution
	 	Neat
	 	 
	 	 
	 	 
	 	 
	 	 
	 	 

	Disease
 
	 	N

Tested
	 	N

R
	 	%

R
	 	N

Tested
	 	N

R
	 	%

R
	 	N

Tested
	 	N

R
	 	%

R
	 	N

Tested
	 	N

R
	 	%

R
	 	N

Tested
	 	N

R
	 	%

R

	AIDS	 	295	 	295	 	100.0	 	296	 	295	 	99.7	 	296	 	296	 	100.0	 	296	 	296	 	100.0	 	226	 	44	 	19.5
	Symptomatic**	 	168	 	168	 	100.0	 	167	 	161	 	96.4	 	168	 	168	 	100.0	 	168	 	168	 	100.0	 	138	 	14	 	10.1
	Asymptomatic***	 	338	 	338	 	100.0	 	338	 	338	 	100.0	 	338	 	338	 	100.0	 	338	 	297	 	87.9	 	234	 	73	 	31.2
	Unknown	 	240	 	239	 	99.6	 	240	 	238	 	99.2	 	240	 	240	 	100.0	 	236	 	234	 	99.2	 	202	 	29	 	14.4
	 	 	
	 	
	 	
	 	
	 	
	 	
	 	
	 	
	 	
	 	
	 	
	 	
	 	
	 	
	 	

	Total	 	1041	 	1040	 	99.9	 	1041	 	1032	 	99.1	 	1042	 	1042	 	100.0	 	1038	 	995	 	95.9	 	800	 	160	 	20.0

N = Number        R = Reactive 

	*
	Samples
with confirmed viral loads < 100 copies/mL excluded.

	**
	Symptomatic
(not asymptomatic and not AIDS).

	***
	Asymptomatic
(asymptomatic, persistent generalized lymphadenopathy, or acute HIV infection). 

Table IX. Sensitivity of the Procleix HIV-1/HCV and HCV Discriminatory Assays for HCV Positive Specimens From Individuals at Various Disease States*  

	 
	 	Procleix HIV-1/HCV Assay
	 	HIV Discriminatory Assay
	 	HIV Antibody

	 
	 	Neat
	 	1:16 Dilution
	 	Neat
	 	 
	 	 
	 	 

	Disease
 
	 	N

Tested
	 	N

R
	 	%

R
	 	N

Tested
	 	N

R
	 	%

R
	 	N

Tested
	 	N

R
	 	%

R
	 	N

Tested
	 	N

R
	 	%

R

	First Time Blood	 	887	 	883	 	99.5	 	886	 	882	 	99.5	 	886	 	882	 	99.5	 	886	 	886	 	100
	Chronic HCV	 	53	 	53	 	100	 	53	 	53	 	100	 	53	 	53	 	100	 	53	 	53	 	100
	Unknown	 	75	 	75	 	100	 	75	 	73	 	97.3	 	75	 	75	 	100	 	52	 	20	 	38.5
	 	 	
	 	
	 	
	 	
	 	
	 	
	 	
	 	
	 	
	 	
	 	
	 	

	Total	 	1015	 	1011	 	99.6	 	1014	 	1008	 	99.4	 	1014	 	1010	 	99.6	 	991	 	959	 	96.8

N = Number        R = Reactive 

	*
	Samples
with confirmed viral loads < 100 copies/mL excluded. 

Sensitivity for Pooled Samples  

        The clinical sensitivity of the Procleix HIV-1/HCV Assay with pooled samples was determined by testing 102 sixteen-member pools composed of one
HIV-1 or HCV positive sample and 15 negative samples, and 102 sixteen-member pools composed of two HIV-1 and/or HCV positive samples and 14 negative samples. The viral load of
the HIV-1 positive samples used to make the pools ranged from 1060 copies/mL to 10,018,200 copies/mL with a median of 27,490 copies/mL. The viral load of the HCV positive samples used to
make the pools ranged from 1660 copies/mL to 20,200,000 copies/mL with a median of 327,000 copies/mL. All 204 (100%; 95% CI: 98.2-100%) pools containing at least one HIV-1
and/or HCV RNA positive specimen were reactive with the HIV-1/HCV Assay. 

Prospective Study of Individuals at High Risk for HIV-1 and HCV Infection  

        Specimens from 539 individuals at high risk for infection with HIV-1 and/or HCV were tested as undiluted (neat) samples with the Procleix
HIV-1/HCV, HIV-1 Discriminatory and HCV Discriminatory Assays. These samples were also tested at 1:16 dilution with the Procleix HIV-1/HCV Assay. Results 

IN0076 Rev. F

39

 

are shown in Table X. 72.5% (391/539) had IV drug use (IVDU) as one of their risk factors. Risk factors other than IVDU included having unprotected sex, men having sex with men, occupational
exposure, having sex with positive partner, and having transfusion of blood or blood products. Sensitivity was determined by comparing the Procleix Assays with an HIV-1 or HCV
PCR-based assay that has a claimed analytical sensitivity of 3100 copies viral RNA /mL. 

        Both
the Procleix HIV-1/HCV Assay and HIV-1 Discriminatory Assay detected all 23 samples, either undiluted or 1:16 diluted, that were tested reactive for
HIV-1 with the PCR NAT test. Of these 23 HIV-1 reactive specimens, 11 were also reactive with the HCV Discriminatory Assay and are considered samples from individuals
coinfected with HIV-1 and HCV. 

        There
was one confirmed HIV-1 yield case that appeared to be in the window period. This specimen was reactive with the Procleix HIV-1/HCV and HIV-1
Discriminatory Assays as an undiluted sample, and with the Procleix HIV-1/HCV Assay as a 1:16 diluted sample. The specimen was HIV antibody seronegative, HIV p24 Ag positive and was
positive with an alternate HIV-1 nucleic acid test (NAT). 

        There
were 268 HCV antibody and/or alternate HCV NAT positive specimens among the 520 high-risk specimens that were tested with Procleix HIV-1/HCV and HCV
Discriminatory Assays. When tested as undiluted (neat) samples, 266 of the 268 positive specimens (99.3%, 95% CI: 97.3-99.9%) were reactive with both the Procleix HIV-1/HCV and
HCV Discriminatory Assays. When tested as diluted samples, 254 of 259 (98.1%, 95% CI: 95.6-99.4%) were reactive with the Procleix HIV-1/HCV Assay. There were 44 HCV
seropositive specimens that were nonreactive in all Procleix Assays. Of the 44, 37 were tested
by an alternate HCV NAT and 34 were found to be NAT negative (considered Procleix TN for sensitivity calculations), two were equivocal, and one was positive (Procleix FN). This study resulted in three
confirmed HCV yield cases that were considered true positives for the Procleix assay. These specimens were HCV antibody negative; two of which were alternate HCV NAT positive and one was QNS for
alternate NAT. All three subjects later seroconverted. 

Table X. Clinical Sensitivity of the Procleix HIV-1/HCV Assay in a High Risk Population  

	 
	 	 
	 	 
	 	 
	 	 
	 	 
	 	 
	 	Sensitivity

	Disease
 
	 	 
	 	 
	 	 
	 	 
	 	 
	 	 

	 	Specimen
	 	Number
	 	TP
	 	FP
	 	TN
	 	FN
	 	%
	 	(95% C. I.)

	HIV-1*	 	Neat	 	530	 	23	 	0	 	507	 	0	 	100	 	(85.2 - 100.0)
	 	 	Diluted	 	520	 	23	 	0	 	497	 	0	 	100	 	(85.2 - 100.0)
	

HCV**	
 	

Neat	
 	

520	
 	

266	
 	

3	
 	

249	
 	

2	
 	

99.3	
 	

(97.3 - 99.9)
	 	 	Diluted	 	508	 	254	 	2	 	247	 	5	 	98.1	 	(95.6 - 99.4)

	*
	Reactive
in the HIV-1/HCV Assay and the HIV-1 Discriminatory Assay.

	**
	Reactive
in the HIV-1/HCV Assay and the HCV Discriminatory Assay. 

Analytical Sensitivity  

        To determine the analytical sensitivity of the Procleix HIV-1/HCV Assay and HIV-1 and HCV Discriminatory Assays for detection of
HIV-1 and HCV viral RNA, HIV-1 panel members were prepared by serial dilution of negative human plasma spiked with HIV-1 (type B isolate) tissue culture
supernatant. HCV panel members were made by serial dilution of a patient plasma specimen containing HCV (subtype 1a). The RNA levels in viral stocks used to make the HIV-1 panel and high
titer HCV plasma used to make the HCV panel were value assigned using an in-house quantitative HIV-1 assay calibrated to the VQA standard obtained from Dr. James Bremer
(Rush-Presbyterian 

IN0076 Rev. F

40

 

Hospital, Chicago, IL) or quantitative HCV assay compared to HCV RNA WHO standard. (1 WHO IU/mL is equivalent to 2.7 copies/mL). 

        The
panel members were tested with ten clinical lots of reagents and the test results are presented in Table XI. The Procleix HIV-1/HCV Assay and HIV-1 and HCV
Discriminatory Assays achieved 100% detection for panel members containing 300 copies/mL, and > 99% detection for those members containing 100 copies/mL of HIV-1 or HCV RNA. The lower
bound of 95% CI for both HIV-1 and HCV at 100 and 300 copies/mL for all assays exceeded 95%, which is consistent with a claimed analytical sensitivity of 100 copies RNA/mL. The Procleix
HIV-1/HCV and Discriminatory Assays were able to detect 30 copies/mL of HIV-1 or HCV RNA at a frequency greater than 90%, with the lower bound of 95% CI ranging from 90% to
97.3%. 

Table XI. Detection of HIV-1 B RNA and HCV 1a RNA in Analytical Sensitivity Panels  

	 
	 	Procleix HIV-1/HCV Assay
	 	HIV-1 Discriminatory Assay

	 
	 	 
	 	 
	 	95%

Confidence Limits
	 	 
	 	 
	 	95%

Confidence Limits

	HIV-1

Copies/mL
 
	 	Number of

reactive/

tested*
	 	%

Positive
	 	Number of

reactive/

tested*
	 	%

Positive

	 	Lower
	 	Upper
	 	Lower
	 	Upper

	300	 	716/716	 	100	 	99.5	 	100	 	715/715	 	100	 	99.5	 	100
	100	 	719/719	 	100	 	99.5	 	100	 	718/718	 	100	 	99.5	 	100
	30	 	707/720	 	98.2	 	96.9	 	99.0	 	702/713	 	98.5	 	97.3	 	99.2
	10	 	573/718	 	79.8	 	76.7	 	82.7	 	592/717	 	82.6	 	79.6	 	85.3
	3	 	297/718	 	41.4	 	37.7	 	45.1	 	305/717	 	42.5	 	38.9	 	46.3
	1	 	112/717	 	15.6	 	13.0	 	18.5	 	139/718	 	19.4	 	16.5	 	22.4

	

 
	
 	

Procleix HIV-1/HCV Assay
	
 	

HIV Discriminatory Assay

	 
	 	 
	 	 
	 	95%

Confidence Limits
	 	 
	 	 
	 	95%

Confidence Limits

	HIV 1a

Copies/mL
	 	Number of

reactive/

tested*
	 	%

Positive
	 	Number of

reactive/

tested*
	 	%

Positive

	 	Lower
	 	Upper
	 	Lower
	 	Upper

	300	 	718/718	 	100	 	99.5	 	100	 	720/720	 	100	 	99.5	 	100
	100	 	720/720	 	100	 	99.5	 	100	 	745/746	 	99.9	 	99.3	 	100
	30	 	669/718	 	93.2	 	91.1	 	94.9	 	660/716	 	92.2	 	90.0	 	94.0
	10	 	470/719	 	65.4	 	61.8	 	68.9	 	458/717	 	63.9	 	60.2	 	67.4
	3	 	231/718	 	32.2	 	28.8	 	35.7	 	258/717	 	36.0	 	32.5	 	39.6
	1	 	70/716	 	9.8	 	7.7	 	12.2	 	104/719	 	14.5	 	11.0	 	17.3

	*
	Invalid
reactions were not re-tested. 

CBER HIV-1 RNA Panel  

        Panel A (5 members) and Panel B (8 members) were tested in duplicate with 5 Clinical Lots using both the HIV-1/HCV Assay and the HIV-1
Discriminatory Assay. Results for both Panel A and B are shown in Table XII. For Panel A, testing with the HIV-1/HCV Assay showed reproducible detection of HIV-1 RNA at copy
levels ranging from 250,000 to 100 copies/mL; the panel member at 0 copies/mL was non-reactive. Results for Panel B demonstrated reproducible detection of HIV-1 RNA at copy
levels ranging from 250,000 to 50 copies/mL and non-reactive results with both negative panel members (B4 and B8). Similar results were obtained with the Discriminatory Assays. 

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CBER HCV RNA Panel  

        This panel consisted of 10 panel members with copy levels ranging from 100,000 to 0 copies/mL. This panel was tested in duplicate with 5 Clinical Lots using both
the HIV-1/HCV and HCV Discriminatory Assays. Results are shown in Table XII. Reproducible detection of HCV was obtained down to 50 copies/mL with both assays. 

Table XII. Detection of HIV-1 RNA and HCV RNA in CBER panel members  

	 
	 	Panel members tested and positivity rates
	 
	 
	 	A1
	 	A2
	 	A3
	 	A4
	 	A5
	 	B1
	 	B2
	 	B3
	 	B4
	 	B5
	 	B6
	 	B7
	 	B8
	 
	CBER HIV-1 RNA Panel (copies/mL)	 	250,00	 	25,000	 	1,000	 	100	 	0	 	2,500	 	10	 	250,000	 	0	 	100	 	50	 	25,000	 	0	 
	HIV-1/HCV Assay*	 	100	%	100	%	100	%	100	%	0	%	100	%	60	%	100	%	0	%	100	%	100	%	100	%	0	%
	HIV-1 Discriminatory Assay**	 	100	%	100	%	100	%	100	%	0	%	100	%	100	%	100	%	0	%	100	%	100	%	100	%	0	%

	

 
	
 	

Panel members tested and positivity rates
	
 
	 
	 	1
	 	2
	 	3
	 	4
	 	5
	 	6
	 	7
	 	8
	 	9
	 	10
	 
	CBER HCV RNA Panel (copies/mL)	 	1,000	 	0	 	100,000	 	10,000	 	0	 	500	 	200	 	50	 	10	 	5	 
	HIV-1/HCV Assay*	 	100	%	0	%	100	%	100	%	0	%	100	%	100	%	100	%	90	%	30	%
	HCV Discriminatory Assay**	 	100	%	0	%	100	%	100	%	0	%	100	%	100	%	100	%	100	%	50	%

* n=10; ** n=6 

WHO International Standard for HIV-1  

        The WHO International Standard for HIV-1 RNA (NIBSC code 97/656) with a concentration of 100,000 IU/mL was serially diluted and tested with the
HIV-1/HCV Assay and the HIV-1 Discriminatory Assay. The results obtained are shown in Table XIII. 

WHO International Standard for HCV  

        The WHO International Standard for HCV RNA (96/790) with a concentration of 100,000 international units (IU)/mL was serially diluted and tested with the
HIV-1/HCV Assay and the HCV Discriminatory Assay. The results obtained are shown in Table XIII. 

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Table XIII. Testing of International Standards for HIV-1 RNA (NIBSC code 97/656) and HCV RNA (NIBSC 96/790)  

	 
	 	Concentrations tested and positivity rates

	WHO HIV-1 (97/656)	 	300

IU/mL	 	100

IU/mL	 	33.3

IU/mL	 	11.1

IU/mL	 	3.7

IU/mL	 	1.23

IU/mL	 	0

IU/mL
	HIV-1/HCV Assay*	 	100%	 	100%	 	100%	 	77.5%	 	50%	 	32.5%	 	0%
	HIV-1 Discriminatory Assay**	 	100%	 	100%	 	100%	 	80%	 	27.6%	 	26.6%	 	0%

	

 
	
 	

Concentrations tested and positivity rates

	WHO HCV (96/790)	 	110

IU/mL	 	37

IU/mL	 	11

IU/mL	 	3.7

IU/mL	 	1.1

IU/mL	 	0.37

IU/mL	 	0.11

IU/mL	 	0.04

IU/mL	 	0.00

IU/mL
	HIV-1/HCV Assay*	 	100%	 	100%	 	100%	 	100%	 	50%	 	25%	 	0%	 	0%	 	0%
	HCV Discriminatory Assay**	 	100%	 	100%	 	100%	 	95%	 	60%	 	25%	 	0%	 	0%	 	0%

*
n=40; ** n=30 

Reactivity in Seroconverting Donors  

        Commercially available seroconversion panels collected from plasmapheresis donors were tested with the Procleix HIV-1/HCV Assay (neat and 1:16
diluted), HIV-1 Discriminatory (neat only) and HCV Discriminatory (neat only) Assays. Ten seroconversion panels for HIV-1 and ten panels for HCV were tested with one Clinical
Lot. The test results were compared with those of the Ortho HCV 3.0 ELISA test or the Abbott Anti-HCV 2.0 test for HCV seroconversion panels, or with those of Abbott
HIV-1/-2 antibody and Abbott or Coulter HIV-1 p24 antigen test for HIV-1 seroconversion panels. The Procleix HIV-1/HCV Assay was able to
detect the infection with median values of 12 and 7 days earlier than the Abbott HIV-1/-2 antibody and HIV-1 p24 Ag assays, respectively, when specimens were
tested neat (Table XIV). The Procleix HIV-1/HCV Assay was able to detect the infection with median values of 10 and 3 days earlier than the Abbott HIV-1/-2
antibody and HIV-1 p24 Ag tests, respectively, when specimens were tested at a 1:16 dilution. The HIV-1 Discriminatory Assay was able to detect infection with median values of
12 and 6 days earlier than the Abbott HIV-1/-2 antibody and HIV-1 p24 Ag tests, respectively, when specimens were tested neat. Reduction of the window period
was observed in 9 of 10 panels when the Procleix HIV-1/HCV and HIV-1 Discriminatory Assays were used as compared to the use of the Abbott HIV Ab test alone. When compared to
the HIV-1 p24 Ag assay, the Procleix HIV-1/HCV Assay detected the infection earlier in 8 of 10 panels and at the same time as HIV-1 p24 Ag in the other two panels.
In all cases, HIV-1 p24 Ag reactive specimens were reactive with the Procleix HIV-1/HCV Assay and the HIV-1 Discriminatory Assay. 

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Table XIV. Testing for HIV-1 RNA with the Procleix HIV-1/HCV and HIV-1 Discriminatory Assays on HIV-1 Seroconversion Panels  

	 
	 	Days Earlier Detection Than HIV Antibody
	 	Days Earlier Detection Than HIV-1 p24 Ag

	 
	 	 
	 	 
	 	HIV-1 Discriminatory
	 	 
	 	 
	 	HIV-1 Discriminatory

	 
	 	HIV-1/HCV
	 	HIV-1/HCV

	Panel ID
 

	 	Neat
	 	1/16
	 	Neat
	 	Neat
	 	1/16
	 	Neat

	BCP 6240	 	12	 	7	 	12	 	7	 	2	 	7
	BCP 6248	 	14	 	11	 	11	 	7	 	4	 	4
	PRB923*	 	12	 	17	 	17	 	2	 	7	 	7
	PRB926**	 	27	 	25	 	27	 	7	 	5	 	7
	PRB929***	 	11	 	11	 	11	 	0	 	0	 	0
	PRB932^	 	0	 	0	 	0	 	0	 	0	 	0
	PRB943	 	9	 	9	 	9	 	2	 	2	 	2
	PRB945**	 	13	 	10	 	13	 	13	 	10	 	13
	PRB946^^	 	11	 	7	 	7	 	7	 	3	 	3
	PRB950**	 	28	 	10	 	28	 	18	 	0	 	18
	 	 	
	 	
	 	
	 	
	 	
	 	

	Median	 	12	 	10	 	12	 	7	 	3	 	6

	*
	Intermittent
HIV-1/HCV reactivity at 11 and 35 days prior to ramp up is not used for this calculation.

	**
	HIV-1/HCV
positive in first bleed of seroconversion panel.

	***
	Single
reactive in the HIV-1 Discriminatory Assay 14 days prior to ramp up is not used for this calculation.

	^
	HIV
antibody was negative at day 78 of the seroconversion series during HIV-1/HCV reactivity.

	^^
	No
seroconversion to HIV antibody in this panel which spans 11 days. 

        The
Procleix HIV-1/HCV and HCV Discriminatory Assays were able to detect infection with a median value of 25 days earlier than the HCV antibody tests (Table
XV) when tested diluted or undiluted. Reduction of the seroconversion window period by the Procleix HIV-1/HCV and HCV Discriminatory Assays was observed in 10 of 10 panels compared
to the HCV antibody test. 

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Table XV. Testing for HCV RNA with the Procleix HIV-1/HCV and HCV Discriminatory Assays on HCV Seroconversion Panels  

	 
	 	Days Earlier Detection Than HCV Antibody

	 
	 	 
	 	 
	 	HCV Discriminatory

	Panel ID
 
	 	HIV-1/HCV

	 	Neat
	 	1/16
	 	Neat

	BCP 6213	 	26	 	26	 	26
	BCP 6225	 	39	 	33	 	39
	BCP 6226*	 	39	 	39	 	39
	BCP 6228*	 	31	 	31	 	31
	BCP 9045*	 	41	 	41	 	41
	PHV904*	 	14	 	14	 	14
	PHV907*	 	21	 	21	 	21
	PHV908*	 	19	 	19	 	19
	PHV914*	 	24	 	24	 	24
	PHV916*	 	23	 	23	 	23
	 	 	
	 	
	 	

	Median	 	25	 	25	 	25

*HIV-1/HCV
Assay reactive in first bleed of seroconversion panel vs. Ortho HCV 3.0. 

Subtype Detectability  

        Since there are no recognized international standards for HCV or HIV-1 other than HCV subtype 1a and HIV-1 subtype B, multiple specimens
and isolates (59 different HIV-1 and 53 different HCV specimens) were tested to determine detectability of these viral subtypes31. HIV-1 specimens of subtypes A,
B, C, D, E, F, and G were quantified for HIV-1 RNA concentrations using commercial quantitative HIV-1 RNA assays or an in-house developed quantitative test, the
latter using the same technology as the Procleix assays. HIV-1 subtypes N and O were quantified with an in-house quantitative HIV-1 RNA test. Specimens were diluted
into negative human plasma to target viral concentrations of 300 or 100 copies/mL and diluted specimens were tested in the HIV-1/HCV and HIV-1 Discriminatory Assays. All
HIV-1 subtypes were reactive with both the Procleix HIV-1/HCV and HIV-1 Discriminatory Assays at 300 and 100 copies/mL (Table XVI). 

        HCV
specimens of subtypes 1, 2, 3, 4, 5 and 6 were quantified for HCV RNA using commercially available quantitative HCV RNA assays. Specimens were diluted into negative human plasma to
target viral concentrations of 300 or 100 copies/mL and diluted specimens were tested with the HIV-1/HCV and HCV Discriminatory Assays. All HCV subtypes were reactive by the
HIV-1/HCV and HCV Discriminatory Assays at 300 and 100 copies/mL, except one HCV subtype 2 specimen which was reactive at 300 copies/mL, but nonreactive at 100 copies/mL (Table XVI). 

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Table XVI. HIV-1 and HCV Subtype Detectability  

	Specimen
 
	 	Subtype
	 	Copies/mL
	 	HIV-1/HCV

Reactive/Total
	 	HIV-1 Discriminatory

Reactive/Total

	HIV	 	A*	 	300

100	 	11/11

9/9	 	11/11

9/9
	 	 	B	 	300

100	 	10/10

10/10	 	11/11

11/11
	 	 	C	 	300

100	 	9/9

9/9	 	9/9

9/9
	 	 	D	 	300

100	 	6/6

6/6	 	6/6

6/6
	 	 	E	 	300

100	 	8/8

8/8	 	8/8

8/8
	 	 	F	 	300

100	 	5/5

5/5	 	5/5

5/5
	 	 	G	 	300

100	 	3/3

3/3	 	3/3

3/3
	 	 	N	 	300

100	 	1/1

1/1	 	1/1

1/1
	 	 	O	 	300

100	 	6/6

6/6	 	6/6

6/6

	
 Specimen
 
	
 	

Subtype
	
 	

Copies/mL
	
 	

HIV-1/HCV

Reactive/Total
	
 	

HIV Discriminatory

Reactive/Total

	HCV	 	1	 	300

100	 	10/10

10/10	 	10/10

10/10
	 	 	2	 	300

100	 	13/13

12/13	 	13/13

13/13
	 	 	3	 	300

100	 	11/11

11/11	 	11/11

11/11
	 	 	4	 	300

100	 	10/10

10/10	 	11/11

11/11
	 	 	5	 	300

100	 	4/4

4/4	 	4/4

4/4
	 	 	6	 	300

100	 	4/4

5/5	 	4/4

5/5

*
Two samples were quantified at < 1000 copies/mL and were reactive when tested undiluted and at 1:3 dilution. 

PERFORMANCE OF INDIVIDUAL DONATION TESTING  

Clinical Sensitivity  

        The clinical sensitivity of the HIV-1/HCV Assay, HIV-1 Discriminatory and HCV Discriminatory Assays were evaluated by testing clinical
samples without dilution (neat). The HIV-1/HCV Assay was used to test a total of 867 confirmed HIV positive, 967 HCV positive and 180 HIV and HCV positive samples. As summarized in Table
VII, the overall sensitivity based on this study was 99.8% (95% CI: 99.4-99.9). Specifically, the sensitivity for HIV positive samples was 99.9% (95% CI: 99.4-100.0) while 

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that for HCV positive samples and HIV and HCV positive samples was 99.6% (95% CI: 98.9-99.9) and 100% (95% CI: 98.0-100.0), respectively. Three HCV
positive samples tested non-reactive as undiluted samples, but reactive at 1:16 dilution. However, one of the three showed a viral load lower than the Limit of Detection for the Procleix
HIV-1/HCV Assay as determined by an alternate nucleic acid test. The other two consistently tested reactive at 1:16 dilution but non-reactive with the undiluted sample and the
nature of this discordance is under investigation.

        The
sensitivity for the discriminatory assays was evaluated as well. As shown in Table VII, the sensitivity for the HIV-1 Discriminatory Assay was 100% (95% CI:
99.6-100.0) for HIV positive samples and 100% (95% CI: 97.9-100.0) for HIV and HCV positive samples. The HCV Discriminatory Assay showed a sensitivity of 99.6% (95% CI:
98.9-99.9) for HCV positive samples and 100% (95% CI: 92.6-100.0) for HIV and HCV positive samples. 

        The
data in the aforementioned studies were re-analyzed according to the disease stages and the results are presented in Tables VIII (for HIV/AIDS) and IX (for HCV). Overall,
the assays showed similar sensitivity for samples from various disease stages. 

Seroconversion Panel Testing  

        When a limited number of HIV-1 seroconversion panel members were tested as undiluted (neat), an average of two days earlier detection was observed as
compared to 1:16 dilution (Table XIV). No difference was observed between the HIV-1/HCV Assay and HIV-1 Discriminatory Assay. Both assays were more sensitive for detecting
window period samples as compared to the HIV-1 p24 Antigen assay. 

        For
HCV seroconversion panels, no differences were observed between the Procleix HIV-1/HCV Assay and the HCV Discriminatory Assay when testing was performed on undiluted
samples or 1:16 diluted samples (Table XV). Both assays were able to detect HCV infection on average 25 days earlier than the antibody test. 

Clinical Specificity  

        The clinical specificity for individual donation testing was determined for the HIV-1/HCV assay by testing individual donor specimens that were never
pooled (Table XVII). Seventy-one of 34,557 (0.21%) individual donor specimens were initially reactive in the Procleix HIV-1/HCV assay. Twenty-one of these 71
specimens were also reactive in the HCV Discriminatory Assay and were seropositive for HCV. Three of the 71 were reactive in the HIV-1 Discriminatory Assay and seropositive for
HIV-1/HIV-2. Forty-five specimens were nonreactive by both the HCV and HIV-1 Discriminatory Assays and HCV and HIV-1/HIV-2
antibody assays yielding an adjusted (false) reactive rate of 0.13% (45/34,533). One specimen had incomplete assay results and could not be discriminated. One specimen was Procleix HCV Discriminated,
HCV EIA repeatedly Reactive with no RIBA available. Seventeen samples with Nonreactive Procleix assay results had incomplete serologic results and were excluded from the specificity calculations,
yielding a specificity in individually tested donor samples of 99.87% (34,229/34,274). 

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Table XVII. Procleix HIV-1/HCV Assay Reactivity in Volunteer Blood Donors  

	 
	 	Procleix HIV-1/HCV Assay

Individual Donation

	Samples Tested*	 	34,557
	Initial Reactive	 	71
	Initial Reactive Rate	 	0.21%
	Adjusted Reactive Rate	 	0.13%
	Combined Mean S/CO on Negative Analytes	 	0.17 ± 0.07

*
Combined data across all sites and Clinical Lots. 

        This
specificity study was conducted primarily in three military sites. The military donor population may differ from the civilian donor population. However, when
sub-analyses were conducted across donor age groups, gender and race, comparable clinical specificity was observed across all categories ranging from 99.7% to 100% (all 95% confidence
intervals overlapped). These sub-analyses included evaluation of 5,743 females; 1,102 donors over the age of 50; and at least 2,900 donors in each of the race categories of
Black/Non-Hispanic, White/Hispanic, and White/Non-Hispanic. These results suggest that the specificity of the Procleix HIV-1/HCV Assay with individual donations is
not affected by race, age or gender. 

Table XVIII. Summary of Procleix Assay Yield Under IND Testing  

	Individual Donation Testing

	Number of Donations Tested	 	103,357
	Procleix HCV

Yield Case	 	1

(1:103,357)
	Procleix HIV-1

Yield Case	 	0

        A
total of 103,357 individual donations were screened under IND from April 2000 to November 2001 (Table XVIII). One Procleix HCV yield case (1:103,357) was identified
across the three Procleix individual donation test sites. The yield case was confirmed to be positive for HCV RNA, but negative in serology testing. No HIV-1 yield cases were identified
with individual donation testing. 

LIMITATIONS OF THE PROCEDURE  

	•
	This
assay has been evaluated with the Procleix instrument only.

	•
	The
concentrations for HIV-1 subtype N and group O virus used for assessing analytical sensitivity were determined by an in-house
quantitative test, which used the same technology as the Procleix assays. This may result in inaccurate assessment of analytical sensitivity for these viral subtypes.

	•
	The
Procleix Assay may not be used to replace antibody-detection tests such as an EIA test for HIV-1 or HCV, a Western Blot for
HIV-1, or a RIBA for HCV.

	•
	The
clinical sensitivity for the Procleix HIV-1/HCV assay has been evaluated only for specimens with viral concentrations equal to or greater
than 100 copies RNA/mL or those with unknown viral concentration. 

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CONCLUSIONS  

        Overall specificity for the Procleix HIV-1/HCV Assay (16-member pools, single donors), HIV-1 Discriminatory Assay (single
donors) and HCV Discriminatory Assay (single donors) is shown in Table XIX. Sensitivity for the Procleix HIV-1/HCV Assay (based on known HIV-1 and HCV RNA positives run neat
and diluted 1:16), HIV-1 Discriminatory Assay (based on known HIV-1 RNA positives run neat), and HCV Discriminatory Assay (based on known HCV RNA positives run neat) are also
shown in Table XIX. 

Table XIX. Overview  

	 
	 	 
	 	Specificity (95% C.I.)
	 	Sensitivity (95% C.I.)

	Procleix HIV-1/HCV	 	16-member Pool	 	99.67% (99.55-99.77%)	 	99.3% (98.8-99.6%)*
	 	 	Individual donation	 	99.87% (99.83-99.91%)	 	99.8% (99.4-99.9%)
	HIV-1 Discriminatory	 	Individual donation	 	99.76% (99.48-99.91%)	 	100%

(99.6-100%)
	HCV Discriminatory	 	Individual donation	 	99.71% (99.41-99.88%)	 	99.6% (99.0-99.9%)

C.I.
= Confidence intervals. 

	*
	Sensitivity
in 2,012 known-positive samples diluted 1:16; Sensitivity was 100% in 204 pools. 

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	14.
	Busch, M. P., S. L. Stramer, and S. H. Kleinman. 1997. Evolving applications of nucleic acid amplification assays for prevention of
virus transmission by blood components and derivatives. In: Garrity G (ed): Applications of Molecular Biology to Blood Transfusion Medicine. AABB. Bethesda, MD. 123-176.

	15.
	Stramer, S. L., S. Caglioti, and D. M. Strong. 2000. NAT of the United States and Canadian Blood Supply. Transfusion.  40:1165-1168.

	16.
	Busch, M. P., L. L. L. Lee, G. A. Satten, D. R. Henrard, H. Farzadegan, K. E. Nelson, S. Read, R. Y. Dodd, and L. R. Petersen. 1995.
Time course of detection of viral and serologic markers preceding human immunodeficiency virus type 1 seroconversion: implications for screening of blood and tissue donors. Transfusion.  35:91-97.

	17.
	Schreiber, G. B., M. P. Busch, S. H. Kleinman, and J. J. Korelitz. 1996. for the Retrovirus Epidemiology Study: The risk of
transfusion-transmitted viral infections. The New Eng J of Med. 334:1685-1690.

	18.
	McDonough, S., C. Giachetti, Y. Yang, D. Kolk, B. Billyard, and L. Mimms. 1998. High throughput assay for the simultaneous or separate
detection of human immunodeficiency virus (HIV-1) and hepatitis C virus (HCV). Infusion Therapy and Transfusion Medicine.  25:164-169.

	19.
	Kacian, D. L. and T. J. Fultz. 1995. Nucleic acid sequence amplification methods. U. S. Patent 5,399,491.

	20.
	Arnold, L. J., P. W. Hammond, W. A. Wiese, and N. C. Nelson. 1989. Assay formats involving acridinium-ester-labeled DNA probes. Clin
Chem. 35:1588-1594.

	21.
	Nelson, N. C., A. BenCheikh, E. Matsuda, and M. Becker. 1996. Simultaneous detection of multiple nucleic acid targets in a homogeneous
format. Biochem. 35:8429-8438.

	22.
	Centers for Disease Control. 1987. Recommendations for prevention of HIV transmission in health care settings.
In United States Morbid. And Mortal. Weekly Rep. 36, Supplement No. 2S.

	23.
	National Committee for Clinical Laboratory Standards. 1986. Clinical laboratory hazardous waste; proposed guidelines. NCCLS Document
GP5-P. Villanova, PA. 

IN0076 Rev. F

50

 
	24.
	U.S. Environmental Protection Agency. EPA guide for infectious waste management. Washington, DC: U.S. Environmental Protection Agency,
Publication No. EPA/530-SW-86-014, 1986.

	25.
	Title 42, Code of Federal Regulations, Part 72, 1992.

	26.
	29 CFR Part 1910.1030. Occupational Exposure to Bloodborne Pathogens; Final Rule, Federal Register/ Vol. 56, No. 235/
December 6, 1991.

	27.
	Valinsky, J.E., C. Bianco. 2000. Supplemental testing for HCV: To what extent could nucleic acid amplification testing (NAT) replace
HCV RIBA 3.0. Transfusion. 40, 10S, 32S.

	28.
	Damen, M., H.L. Zaijjer, H.T.M. Cuypers, H. Vrielink, CL van der Poel, HW Reesink, PN Lelie. 1995. Reliability of the third-generation
recombinant immunoblot assay for hepatitis C virus. Transfusion. 35, 745-749.

	29.
	MMWR. 1992. 41:1-9.

	30.
	Stramer, S.L. et al. Application of Nucleic Acid Testing to Blood Borne Pathogens and Emerging Technologies OBRR/CBER/FDA
Workshop—December 4, 2001.

	31.
	Linnen, J.M., J.M. Gilker, A. Menez, A. Vaughn, A. Broulik, J. Dockter, K. Gillote-Taylor, K. Greenbaum, D.P. Kolk, L. T. Mimms, C.
Giachetti. 2002. Sensitive detection of genetic variants of HIV-1 and HCV with an HIV-1/HCV assay based on transcription-mediated amplification. J.
Virol. Methods. 102, 135-139. 

Gen-Probe
U.S. LICENSE 1592 

IN0076
Rev. F

2002-02 

Developed and manufactured by:
  Gen-Probe Incorporated

10210 Genetic Center Drive

San Diego, CA 92121

(858) 410-8000 

Distributed in U.S. by:
  Chiron Corporation

4560 Horton Street

Emeryville, CA 94608-2916

Telephone (In U.S.): (800) CHIRON-8

(510) 655-8730 

Distributed in rest of world by:
  Chiron Ireland, Limited

United Drug House

Belgard Road, Tallaght

Dublin 24, Ireland 

Chiron Blood Testing Technical Support:
  (North America)

Telephone: (800) 452-6877

FAX: (800) 462-3938 

(Europe,
Middle East, Latin America, Africa)

Telephone: +33 (4) 78 37 99 04

FAX: +33 (4) 78 37 99 04 

IN0076 Rev. F

51

 

(Asia/Pacific)

Telephone: +61 (4) 1044 5810

FAX: +61 (2) 9974 5411 

Chiron,
RIBA and Procleix are trademarks of Chiron Corporation; TECAN, GENESIS (stylized), and RSP are trademarks of Tecan AG; eppendorf (stylized) and COMBITIPS are trademarks of Eppendorf-
Netheler-Hinz GmbH; PROCLIN (stylized) is a trademark of Rohm and Haas Company. 

This
product and its intended use are covered by one or more of the following: U.S. patent no. 5,030,557; 5,185,439; 5,283,174; 5,399,491; 5,437,990; 5,480,784; 5,585,481; 5,612,200; 5,639,604;
5,656,207; 5,656,744; 5,658,737; 5,696,251; 5,714,596; 5,750,338; 5,756,011; 5,756,709; 5,766,890; 5,827,656; 5,840,873; 5,863,719; 5,888,779; 5,948,899; 5,955,261; 6,004,745; 6,031,091; 6,074,816;
6,090,591; 6,110,678; 6,245,519; 6,252,059; 6,280,952; and international counterparts. 

©
2000, 2001, 2002 Gen-Probe Incorporated 

IN0076 Rev. F

52

  

	 
	 	 

	CONFIDENTIAL	 	REDACTED VERSION

 
 

SCHEDULE C
  
    TERMS AND CONDITIONS FOR USE OF BLOOD SCREENING SYSTEMS    
  

Chiron
will make available Blood Screening Systems to ABC on the following terms and conditions: 

	1.
	Sale of Blood Screening Systems. Chiron shall sell the Blood Screening Systems currently installed and in use by Participating Members
as listed in Exhibit 4 to each Member Supplement (the "Transferred Instruments"), subject to the provisions hereof. Each Participating Member
will acquire, at it's sole expense, any additional instrumentation it wishes to use in connection with the conduct of testing of blood donations, including any instruments required to perform pooling
operations and sample archiving.

	2.
	Location & Use of Blood Screening Systems. Participating Members shall use the Blood Screening Systems only at the Testing
Centers identified in Exhibit 2 to the applicable Member Supplements. Participating Members shall not remove, customize, or alter the Blood
Screening Systems, including Software, without the prior written consent of Chiron. Blood Screening Systems shall only be used to perform testing of the Participating Member's blood donations using
Blood Screening Assays sold by Chiron. Chiron bears no responsibility with respect to any use of such Blood Screening Systems with Blood Screening Assays other than those supplied by Chiron hereunder.
Any such alternate use shall invalidate all warranties with respect to the Blood Screening Systems.

	3.
	Title to the Blood Screening Systems. As between Chiron and each Participating Member, upon payment of the amount specified in the
applicable Member Supplement, Chiron shall transfer all right, title and interest held by it in and to the Transferred Instruments to the applicable Participating Member. Each Participating Members
acquiring Transferred Instruments shall remove any markings from the Transferred Instruments which identify Chiron as the owner. If a Participating Member selects the installment payment option, title
to the Transferred Instruments will transfer on execution, but the Participating Member will grant a security interest in such Transferred Instruments to Chiron as further described in the applicable
Member Supplement.

	4.
	Warranties; Limitation of Liability. Chiron represents and warrants that the Blood Screening Systems will operate in accordance with
their Specifications and will be free from defects in materials and workmanship. This warranty does not apply to Blood Screening Systems (a) not installed by a Chiron representative;
(b) not used or maintained in accordance with the instructions provided by Chiron or their manufacturer, including without limitation of the maintenance obligations set forth in  Schedule D;
(c) damaged by alteration, misuse, tampering or abuse; or (d) for which the Participating Member has failed to pay the
Services Fee. Except to the extent of Chiron's obligations under Section 7.7 of this Association Agreement, Chiron's sole liability with respect to a breach of the foregoing warranty is to
repair or replace the Blood Screening System. Participating Members will be responsible for all other repairs or replacements of Blood Screening Systems that fail to operate in accordance with their
Specifications, including by reason of (i) any loss or damage caused by or attributable to the Participating Members or their agents (ii) a failure by the Participating Members to use
the Blood Screening Systems in accordance with the manufacturer's instructions, (iii) any negligence on the part of the Participating Members or (iv) any failure by the Participating
Members to carry out their obligations hereunder. Chiron disclaims all other warranties and further limits its liability in accordance with Sections 7.4 and 7.12 of this Association Agreement,
respectively. 

53

 
	5.
	Software. Chiron shall provide to Participating Members, at no additional charge, the Software and Documentation, pursuant to the
following terms and provisions:

	5.1
	Title.

	(a)
	Chiron
or the applicable licensor shall own and retain title to the Software, including all intellectual property rights embodied therein. Any copy which a Participating Member makes
of the Software, in whole or in part, is and shall remain the property of Chiron or the applicable licensor.

	(b)
	If
ownership of the Software or any work product does not result as provided in this Agreement or by operation of law, then the parties each assign and shall cause their respective
employees, agents, and contractors to assign, without further consideration, the ownership thereof, including all associated
intellectual property rights, as necessary to give effect to the ownership terms specified in this Agreement. Each party agrees to perform, at the reasonable request of the other party, such further
acts as may be necessary or desirable to transfer ownership of, and to perfect and defend, the Software or work product in order to give effect to such ownership terms. 

	5.2
	Grant of Rights and Restrictions on Use

	(a)
	Grant of Rights. Chiron hereby grants, and each Participating Member hereby accepts, subject to the terms and conditions of this
Agreement including this Schedule C, a nonexclusive, nontransferable and nonassignable (except as permitted under Section 12.4
[Assignment] of this Association Agreement) object code license to use the Software at the Testing Centers solely for Participating Member's own use in connection with the
operation of the Blood Screening Assays on the Blood Screening Systems during the term of the applicable Member Supplement, and to copy the Software solely for the purposes expressly authorized under
this Section 5 of this Schedule C. In addition, Chiron hereby grants to each Participating Member the right to use the Documentation in
connection with its use of the Software hereunder. Documentation may not be copied. Additional copies may be obtained from Chiron at Chiron's charges then in effect. No right to use, copy, display, or
print the Software or Documentation, in whole or in part, is granted, except as expressly provided in this Agreement.

	(b)
	Restrictions on Use. The grant of rights stated in Section 5.2(a) of this Schedule C  is subject
to the terms and conditions of this Agreement as well as the following restrictions:

	(i)
	Use
of the Software may be subsequently transferred to other Testing Centers maintained by a Participating Member, provided (A) the total number of Testing Centers at which the
Software is used by such Participating Member does not exceed the number of Testing Centers specified in the applicable Member Supplement and (B) such Participating Member provides Chiron with
written notice thirty (30) days before such transfer.

	(ii)
	In
the event that disaster or other circumstances prevent Participating Member from using the Software at the Testing Centers identified in the applicable Member Supplement, the
effected Participating Member shall have the right to use the Software at a disaster recovery facility without prior notice to Chiron, but shall promptly notify Chiron as soon as circumstances permit.

	(iii)
	Participating
Members shall not use (or cause to be used) the Software for rental, in the operation of a service bureau, or for any similar purpose; nor shall Participating Members
allow access to the Software through terminals located outside Participating 

54

 

Member's
business premises by persons who are not Participating Member's employees or authorized agents, contractors or representatives. 

	(iv)
	Participating
Members shall not distribute the Software, in whole or in any part, to any Third Party or parties, nor permit its sublicensing, leasing, or other transfer, except as
permitted under Section 12.4 [Assignment] of this Association Agreement.

	(v)
	Participating
Members shall not, either directly, or through a Third Party, reverse engineer, disassemble or decompile the Software, or make any attempt in any fashion except as
specifically provided in this Agreement to obtain the source code to any Software.

	(vi)
	Any
use of the Software not in accordance with this Agreement, or any modification or alteration of the Software not expressly authorized in writing by Chiron, shall void all
representations and warranties with regard to the Software and shall be deemed a breach of this Agreement.

	(vii)
	Upon
expiration or termination of a Member Supplement, the applicable Participating Member shall (A) cease all use of the Software and the Documentation; (B) return to
Chiron the Software and the Documentation and any copies thereof (unless required to retain such material for regulatory purposes); and (C) erase from memory all copies of the Software (unless
required to retain such material for regulatory purposes). The applicable Participating Member shall certify in writing to Chiron that it has not retained the Software and Documentation or any copies
thereof (unless required to retain such material for regulatory purposes). 

	5.3
	Warranties; Limitation of Liability.

	(a)
	Performance. Chiron warrants that the Software, under normal use and service, will perform all of the material functions described in
the Documentation of such Software. Chiron warrants that the Documentation shall be free from material defects in materials and workmanship. If any such defect or deviation appears during the
applicable periods, the Software or Documentation may be returned to Chiron for replacement by Chiron without charge.

	(b)
	Anti-Virus. Chiron warrants that to the best of its knowledge after employing reasonable technical means to detect computer
viruses, the Software at the time of delivery will not contain any virus or computer software code, routines or devices (other than as set forth in the Documentation) designed to disable, damage,
impair, or erase the Software or other software or data. For failure to comply with this warranty, Chiron shall, at Chiron's expense, immediately replace all copies of the affected Software in the
possession of a Participating Member.

	(c)
	Right to License. Chiron warrants that it has, and on the effective date of each Member Supplement of the Software will have, full
rights and authority to license the Software to Participating Members and
otherwise as needed for it to perform its obligations hereunder, or has the authority to do so without infringing the rights of any Third Party.

	(d)
	Limitation of Liability. Chiron disclaims all other warranties and further limits its liability in accordance with Sections 7.4 and
7.12 of this Association Agreement. 

	5.4
	Source Code Escrow. 

CHIRON
agrees that it will provide that Participating Member will be a named beneficiary under Chiron's Source Code Escrow Agreement. 

55

 

	 
	 	 

	CONFIDENTIAL	 	REDACTED VERSION

 
 

SCHEDULE D
  
    BLOOD SCREENING SYSTEMS AND SOFTWARE
  SERVICE & SUPPORT    
  

	1.
	Maintenance & Troubleshooting.

	1.1
	The
Participating Member shall operate and maintain the Blood Screening Systems in accordance with Chiron and manufacturer guidelines and recommendations, which may be amended from
time to time.

	1.2
	In
the event that any Testing Center resolves a problem with a Blood Screening System, such problem shall be logged in writing, including a description of the problem and the steps
taken by the Participating Member to resolve it. The Participating Member shall maintain a log for each Blood Screening System and make available all such logs to Chiron Technical Support upon
request.

	1.3
	If
a Testing Center is unable to resolve a problem, the Testing Center shall refer the problem to Chiron Technical Support for resolution in accordance with Section 2 of this  Schedule D.

	1.4
	Except
for routine maintenance and troubleshooting activities of Primary Operators as provided in this Schedule D, or otherwise
with the prior permission of Chiron, during the term of this Agreement only Chiron or Chiron's agents shall install, service, alter or replace the Blood Screening Systems. Chiron may inspect the Blood
Screening Systems at reasonable times upon reasonable notice. Chiron will assure that activities of Primary Operators authorized under this Schedule D  will not invalidate any manufacturers'
warranties with respect to the Blood Screening Systems. 

	2.
	Technical Support and Service.

	2.1
	Installation. Chiron support personnel will provide installation and set up of all Blood Screening Systems, and shall ensure that the
Blood Screening Systems operate in conformance with all relevant Specifications. Without limiting the foregoing, such setup and installation shall include the installation of the Software and
verification of the operation of the Software in conjunction with the Blood Screening Systems. At such time as Chiron determines that such setup and installation has been completed, the Participating
Member shall acknowledge the completion of such setup and installation and its acceptance of the Blood Screening Systems in writing.

	2.2
	Project Management. Chiron will provide reasonable project management support to assist the Participating Member project manager in
coordinating the activities of Chiron and the Participating Member in connection with testing blood using the Blood Screening Assays and the Blood Screening Systems.

	2.3
	Data & Materials. The Participating Member shall make available to Chiron on a timely basis all data, information and other
materials which are reasonably necessary for Chiron to perform the Services. Such data shall be treated as confidential Data in accordance with Section 6.4 of the Association Agreement. Chiron
shall have no liability for any failure to perform, or for the late performance, of any Services to the extent such Services require data, information or materials possessed, prepared or generated by
the Participating Member, if the Participating Member fails to provide the same in accordance with Chiron reasonable requests. 

56

 

	2.4
	Preventative Maintenance.

	(a)
	Chiron
shall carry out scheduled Preventative Maintenance (PM) visits at six month intervals (2 per year). The PM services will be arranged at least two weeks before the due date for
PM service at a time mutually agreeable between Chiron and the Participating Member. The Participating Member will be required to make the Blood Screening Systems available at a reasonable time within
the working day (Monday to Friday excluding Holidays) to allow PM services to be completed within normal working hours.

	(b)
	Each
PM service will cover thorough cleaning, lubrication, replacement of tubing and other parts, electronic/mechanical adjustments and safety checks, all in accordance with the Blood
Screening Systems manufacturers' recommended procedures, as detailed in the applicable manufacturer's approved checklist/s. Defective components discovered during PM services will be replaced at no
charge. Parts used to perform PM service will be provided by Chiron at its expense.

	(c)
	Appropriate
testing will be performed in order to return the Blood Screening Systems back to the user. Tecan instruments will be "certified" as fully functional with required testing
performed according to the manufacturers' specifications. Liquid precision checks will utilize the appropriate volume for testing.

	(d)
	Documentation
of PM service performed will be provided to each site upon completion of all maintenance tasks. Information will be reviewed and signed by Participating Member personnel
before Chiron service personnel leave the facility.

	(e)
	Additional
PM service may be performed at the request of the Participating Member for an additional charge. 

	2.5
	Support and Service.

	(a)
	Chiron
Technical Support is available 24 hours a day, 7 days a week including weekends and holidays via telephone. The Participating Member will refer problems to Chiron
Technical Support through a central toll-free telephone number [**]. A service representative will be available at
this number to receive problem referrals and provide troubleshooting assistance, from 7:30 a.m. to 5 p.m. PST, Monday through Friday, holidays excepted ("Normal Support Hours"). Messages
left outside Normal Support Hours (including weekends and holidays) will automatically page the on-call Technical Support personnel. Required message information left outside Normal
Support Hours should include a contact
name, phone number and brief description of the problem. Telephone support will be initiated within the Priority/Response timeframes set forth below. If a problem cannot be resolved through telephone
support within a reasonable amount of time, taking into account its Priority status, the problem will be escalated to Chiron's Product Support Center, for analysis by Blood Screening System
specialists and if necessary, OEM support personnel. If a problem cannot be resolved following such 

57

 

escalation,
Chiron Technical Support will be dispatched to the Testing Center to provide service in accordance with the Priority/Response Time Schedule set forth below. 

	Priority
 
	 	Response*

	Priority 1:	 	Instrument not operating and alternate or back-up equipment not available; tests cannot be performed	 	• Immediate telephone support

• Support Technician on site ASAP but no later than next morning

• Resolution within 24 hours (may be temporary workaround)
	

Priority 2:	
 	

Instrument operational but testing process (processing time) is affected	
 	

• Telephone support within 2 hours

• Support Technician on site within 24 hours

• Resolution within 48 hours
	

Priority 3:	
 	

Instrument is operational; no impact on testing process	
 	

• Telephone support next business day

• Work commenced within 24 hours

• Resolution within 1 week

	*
	All
timeframes are approximate; actual response times may vary due to flight availability, weather-related delays, nature of the problem, etc.

	(b)
	Chiron
will maintain full records of all problem referrals and subsequent actions pursuant to FDA regulation. 

	2.6.
	Replacement Parts.

	(a)
	Chiron
agrees to maintain at each Testing Center a suitable stock of replacement parts for use in Blood Screening System minor repair and maintenance at each Testing Center in the
Territory. The Participating Member shall provide Chiron a secure facility at each Testing Center for storage of such replacement parts.

	(b)
	Replacement
parts not available from existing on-site inventory will be delivered within the resolution timeframes in accordance with the Priority/Response time Schedule
set forth above.

	(c)
	The
Participating Member will document and inform Chiron if any replacement parts are used by Participating Member personnel and return to Chiron (at Chiron's expense) the part that
was replaced. An inventory of replacement parts will be performed quarterly by Chiron personnel. The cost of replacement part(s) not in inventory that have not been reported used by the Participating
Member will be charged to the Participating Member. Replacement parts to be placed into on site inventory will be agreed upon by Chiron and the Participating Member management. The initial inventory
of replacement parts will be provided at Chiron's expense. 

	2.7.
	Replacement Instruments. If during the performance of any repair of a Blood Screening System Chiron determines in its sole discretion
to substitute an entire instrument or instrument component in order to complete service in accordance with the Priority/Response Time Schedule, Chiron will remove and repair the failing instrument or
instrument component. Chiron may substitute reconditioned, refurbished and/or serviceable used instrument or instrument component (tested to Chiron's quality assurance standards) for this purpose.
Following completion of such repair, Chiron will replace the substituted instrument or instrument component with the repaired instrument or instrument component at the next scheduled PM service, or
earlier if requested by the Participating Member. 

58

 

	3.
	Warranty; Limitation of Liability.

	3.1
	Chiron
warrants that the Services provided by Chiron, its agents, employees or contractors pursuant to this Agreement will be rendered in a competent workmanlike manner and in
accordance with industry standards. Chiron warrants that any replacement part or substituted instrument or instrument component installed by Chiron during the performance of the Services shall
function in accordance with all applicable Specifications and be free from defects. Chiron reserves the right to use reconditioned, refurbished and/or serviceable used parts (tested to Chiron's
quality assurance standards) for service hereunder.

	3.2
	The
Services shall cover wear and tear and defects in design, material or workmanship, and shall include version updates to all Software for which Chiron has the right to license or
sublicense, but shall exclude (i) replacement of operating supplies, necessaries, consumables or expendable parts; (ii) repairs required due to improper storage, accident, neglect,
misuse, electrical stress, air conditioning, humidity control, transportation, and force majeure events, use of non-approved accessories, consumables or supplies, or causes other than
intended normal use; (iii) service for Blood Screening Systems that have been tampered with, disassembled, altered, changed or modified, maintained by anyone other than Primary Operators, or
repaired (or attempts have been so made) by anyone other than Chiron-authorized personnel; (iv) movement or rearrangement of the Blood Screening Systems after initial installation not
authorized and supervised by Chiron personnel; and (v) service for any other equipment not manufactured or supplied by Chiron. In the case of (ii), (iii) and (iv) above, a
Participating Member may request that Chiron provide service comparable to the Services described herein, and Chiron will make such services available at the then-current commercial rate
for services of this type. If such service is provided, Chiron expressly disclaims any representation or warranty as to the performance of such service or the operability of the Blood Screening
Systems on which such service is performed.

	3.3
	Chiron
disclaims all other warranties and further limits its liability in accordance with Sections 7.4 and 7.12 of the Association Agreement, respectively.

	3.4
	If
any applicable law implies a condition or warranty which cannot be excluded or modified in this Agreement (a "Requirement"), then such Requirement is deemed to be included in this
Agreement. 

59

 

	 
	 	 

	CONFIDENTIAL	 	REDACTED VERSION

 
 

SCHEDULE E
  
    PRICES    
  

	1.
	Fees
	1.1
	Blood Screening Assay Fee. Each Participating Member agrees to pay to Chiron an amount equal to the number of Reportable Results
achieved by such Participating Member each month, multiplied by the applicable Per Result Fee from the chart set forth in their applicable Member Supplement (the "Assay Pricing Chart"), as adjusted
pursuant to Section 2 of this Schedule E. The applicable Per Result Fee for each Participating Member is set on an annual basis using the
Product Requirements Forecast provided by the Participating Member for that year. 

POOLED TESTING  

	 
	 	 
	 	Aggregate Participating Members Reportable Results

For Prior Calendar Year2

	Three Year Term1
 

	 	[**]
	 	[**]
	 	[**]
	 	[**]
	 	[**]
	 	[**]

	 	 	 	 	Per Reportable Result

	Individual Participating Member

Reportable Results
	 	A
	 	B
	 	C
	 	D
	 	E
	 	F

	
 P1	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

P2	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

P3	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

P4	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

P5	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

P6	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]

	1
	Discount
applicable to Three Year Grid, [**]

	2
	Includes
all testing performed by Members; e.g., Pooled Testing and Single Unit Testing. 

60

 
POOLED TESTING  

	 
	 	 
	 	Aggregate Participating Members Reportable Results

For Prior Calendar Year4

	Four Year Term3
 

	 	[**]
	 	[**]
	 	[**]
	 	[**]
	 	[**]
	 	[**]

	 	 	 	 	Per Reportable Result

	Individual Participating Member

Reportable Results
	 	A
	 	B
	 	C
	 	D
	 	E
	 	F

	
 P1	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

P2	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

P3	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

P4	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

P5	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

P6	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]

POOLED TESTING  

	 
	 	 
	 	Aggregate Participating Members Reportable Results

For Prior Calendar Year4

	Five Year Term3
 

	 	[**]
	 	[**]
	 	[**]
	 	[**]
	 	[**]
	 	[**]

	 	 	 	 	Per Reportable Result

	Individual Participating Member

Reportable Results
	 	A
	 	B
	 	C
	 	D
	 	E
	 	F

	
 P1	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

P2	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

P3	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

P4	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

P5	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

P6	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]

	3
	Discount
applicable to the Four and Five Year Grid [**].

	4
	Includes
all testing performed by Members; e.g., Pooled Testing and Single Unit Testing. 

61

 
Single Donor Testing  

	 
	 	 
	 	Aggregate Participating Members Reportable Results

For Prior Calendar Year4

	          
 

	 	[**]
	 	[**]
	 	[**]
	 	[**]
	 	[**]
	 	[**]

	 Individual Participating Member

Reportable Results
	 	A
	 	B
	 	C
	 	D
	 	E
	 	F

	
 S0	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

S1	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

S2	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

S3	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

S4	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

S5	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

S6	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]
	

S7	
 	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]

        On
or prior to the 5th of each month, each Participating Member shall provide Chiron with a report showing the Reportable Results and Reagent Utilization Factor for the
prior month for each of its Testing Centers. On or prior to the 15th of each month, Chiron shall prepare and deliver an invoice to each Participating Member based on such report,
calculating the Blood Screening Assay Fee by multiplying the Reportable Results by the applicable Per Result Fee, determined in accordance with the then current Product Requirements Forecast. If a
Participating Member's report is not timely received by Chiron, Chiron will prepare the invoice substituting one-twelfth of the then current Product Requirements Forecast and the parties
shall "true-up" payments made to the actual Reportable Results achieved on a calendar quarter basis, rectifying any under- or over-payment on the next subsequent invoice,
without application of interest. Each Participating Member shall make payment on invoices in accordance with Section 5.3 of the Association Agreement, except where modified by the applicable
Member Supplement. 

	1.2
	Blood Screening Systems Fee. Each Participating Member agrees to pay to Chiron the Blood Screening Systems Fee set forth in their
Member Supplement. Such amount will be due and payable in a lump sum on the effective date of the applicable Member Supplement. If a Participating Member elects to lease its Blood Screening Systems,
payments will be invoiced by Chiron on a monthly basis, together with the Blood Screening Assay Fee described above. Each Participating Member shall make payment on invoices in accordance with
Section 5.3 of the Association Agreement, except where modified by the applicable Member Supplement. The applicable purchase price for Blood Screening Systems will be set on a
Member-by-Member basis based on the specific requirements of each Participating Member. The pricing information set forth below is provided for informational purposes only. 

	Blood Screening System Components
 
	 	Unit Price
	 	Monthly Lease

Payment5

	Pooling TECAN6	 	[**]	 	$	 
	

Assay TECAN7	
 	
[**]	
 	
$	

 
	

ProcleixTM System8	
 	
[**]	
 	
$	

 

	5
	Based
on 36 month lease. Subject to credit approval. 

62

 
	6
	Includes
CPT-16 Pooling Software, ver. 2.0.0.2

	7
	Includes
ProcleixTM Assay Software, ver. 2.0.0.76 and ProcleixTM Assay Software LHP, ver. 2.1

	8
	Includes
ProcleixTM System Software, ver. 3.0.3.4, ProcleixTM Protocol, ver. 2.1.0.0, and ProcleixTM Worklist Editor, ver. 3.0.3.2

	1.3.
	Services Fee. Each Participating Member agrees to pay to Chiron the Services Fee set forth in their Member Supplement. Such amount
will be due and payable annually in a lump sum on each anniversary of the effective date of the applicable Member Supplement. If a Participating Member elects to lease its Blood Screening Systems,
payments will be invoiced by Chiron on a monthly basis, together with the Blood Screening Assay Fee and Blood Screening Systems Fee described above. Each Participating Member shall make payment on
invoices in accordance with Section 5.3 of the Association Agreement, except where modified by the applicable Member Supplement. The applicable purchase price for Services will be set on a
Member-by-Member basis based on the specific requirements of each Participating Member. The pricing information set forth below is provided for informational purposes only. 

	Blood Screening System Components
 
	 	Price/Year/Unit
	 	Monthly

Installment

Payment

	Pooling TECAN9	 	[**]	 	$	 
	

Assay TECAN10	
 	
[**]	
 	
$	

 
	

ProcleixTM System11	
 	
[**]	
 	
$	

 

	9
	Includes
all version updates to CPT-16 Pooling Software, ver. 2.0.0.2

	10
	Includes
all version updates to ProcleixTM Assay Software, ver. 2.0.0.76 and ProcleixTM Assay Software LHP, ver. 2.1

	11
	Includes
all version updates to ProcleixTM System Software, ver. 3.0.3.4, ProcleixTM Protocol, ver. 2.1.0.0, and ProcleixTM Worklist
Editor, ver. 3.0.3.2

	1.4.
	NAT Tracker Fee. Each Participating Member electing to purchase the NAT Tracker software solution agrees to pay to Chiron the NAT
Tracker Fee set forth in their Member Supplement. Such amount will be due and payable annually in a lump sum on the effective date of the applicable Member Supplement and on each anniversary
thereafter. Participating Members electing to purchase the NAT Tracker software solution will enter into a separate software license agreement with Chiron. 

	2.
	Adjustments to Fees.

	2.1
	Reagent Utilization Factor.

	(a)
	Chiron
and each Participating Member agree to monitor the Reagent Utilization Factor at each Testing Center during the term of this Agreement. If the Reagent Utilization Factor for
any Testing Center set forth on the report provided by a Participating Member pursuant to Section 1.1 of this Schedule E exceeds that
Participating Member's target Reagent Utilization Factor, set forth in the applicable Member Supplement (the "Target RUF"),  [**], Chiron and each Participating Member shall use their best endeavors to
identify and correct the cause of the excess.

	(b)
	The
Reagent Utilization Factor shall be calculated for each Participating Member promptly following each successive 52 week period commencing on the Effective Date of the applicable
Member Supplement (each, an "Annual RUF Measuring Period"), 

63

 

aggregating
all Testing Centers. If the Reagent Utilization Factor for a Participating Member for any Annual RUF Measuring Period exceeds the applicable Target RUF, Chiron shall invoice the
Participating Member on the next subsequent monthly invoice, and the Participating Member agrees to pay, the additional fee set forth in their Member Supplement. 

	2.2.
	[**]. 

	3.
	[**].

	4.
	Effect of Change in Nature of Testing. If a Participating Member elects to move from Pooled Testing to Single Unit Testing, or from
Single Unit Testing to Pooled Testing, pursuant to Section 11 of Schedule B-1, (i) the price per donation shall be
adjusted pursuant to the then current Assay Pricing Chart and (ii) the Target RUF will be recalculated.

	5.
	Additional Supplies. The following additional supplies are available from Chiron at the prices set forth below. Chiron reserves the
right to increase or decrease these prices at any time, without notice to each Participating Member: 

[**]                [**]

[**]                [**]

[**]                [**]

64

  

 
 

EXHIBIT 10.317    
  

	 
	 	 

	CONFIDENTIAL	 	REDACTED VERSION

[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN

OMITTED AND FILED SEPARATELY WITH THE COMMISSION.

CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH

RESPECT TO THE OMITTED PORTIONS.  

 
 

MEMBER SUPPLEMENT    
  

        This Member Supplement (this "Member Supplement"), dated as
of                        (the "Effective Date"), is by and between Chiron Corporation, a Delaware
corporation ("Chiron"), and                        ("ABC Member"). 

 
 

RECITALS    

	A.
	Chiron
and America's Blood Centers, an association of non-profit community-based blood centers ("ABC"), have entered into that certain Association Agreement dated as of
May 1, 2002 (the "Association Agreement");

	B.
	Pursuant
to and in accordance with the terms of the Association Agreement, Chiron has agreed to sell Blood Screening Assays and sell or arrange for the lease of Blood Screening Systems
to ABC members, for use to conduct nucleic acid amplification tests to detect the presence of certain viruses in blood donation samples;

	C.
	                              ,
an ABC member, wishes to acquire Blood Screening Assays and Blood Screening Systems to conduct nucleic acid amplification
tests to detect the presence of certain viruses in blood donation samples, in accordance with the terms of the Association Agreement, subject to the following additional terms and conditions. 

 
 

AGREEMENT    

        NOW,
THEREFORE, in consideration of the foregoing and the mutual covenants and agreements herein contained, and for other good and valuable consideration, the receipt and sufficiency of
which is hereby acknowledged, the parties hereto agree as follows: 

	1.
	Definitions. All capitalized terms used but not otherwise defined in this Member Supplement shall have the meanings set forth in the
Association Agreement.

	2.
	Association Agreement. The terms and conditions of the Association Agreement, attached as Exhibit 1  to
this Member Supplement, are adopted by the parties hereto and incorporated by reference. For the purpose of the Association Agreement and this Member Supplement, ABC MEMBER
shall be deemed to be a Participating Member. In the event of any conflict between the terms and conditions of this Member Supplement and the terms and conditions of the Association Agreement, the
terms and conditions of the Association Agreement govern.

	3.
	Blood Screening Assays. In accordance with Schedule B of the Association
Agreement, Chiron shall supply ABC MEMBER with its requirements of Blood Screening Assays to permit ABC MEMBER to conduct Pooled Testing or Single Unit Testing of blood donations in the Territory at
the Testing Centers
listed on Exhibit 2 to this Member Supplement. ABC MEMBER's initial Product Requirement Forecast is attached as  Exhibit 3 to this Member
Supplement. 

1

 
	4.
	Blood Screening Systems. In accordance with Schedule C of the Association
Agreement, Chiron shall sell ABC MEMBER the Blood Screening Systems described on Exhibit 4 to this Member Supplement.

	5.
	Fees. In accordance with Schedule E to the Association Agreement, ABC MEMBER
agrees to the following fees:

	5.1
	Blood Screening Assay Fee. The applicable Per Result Fee is set on an annual basis from the Assay Pricing Chart below using the Product
Requirements Forecast provided for that year. For the first year of the term of this Member Supplement, the applicable Per Result Fee for ABC MEMBER is            . 

                        TESTING  

	 
	 	 
	 	Aggregate Participating Members Reportable Results

For Prior Calendar Year2

	                        -Year Term1
 

	 	[**]
	 	[**]
	 	[**]
	 	[**]
	 	[**]
	 	[**]

	 	 	 	 	Per Reportable Result

	Individual Participating Member

Reportable Results
	 	A
	 	B
	 	C
	 	D
	 	E
	 	F

	
[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]	
 	

[**]

	1
	Discount
of [**].

	2
	Includes
all testing performed by Members; e.g., Pooled Testing and Single Unit Testing.

	5.2
	Blood Screening Systems Fee. The Blood Screening Systems Fee for the purchase of Blood Screening Systems set forth on  Exhibit 4 to this Member Supplement is $                        , payable in a lump sum in accordance with Section 1.2 of
Schedule E. Additional components will be available to the Participating Member at the then current list price for such components.

	5.3
	Services Fee. The Services Fee for the Blood Screening Systems set forth on Exhibit 4  to this Member
Supplement is
$                                         
 , payable annually in accordance with Section 1.3 of  Schedule E. The purchase of additional components will result in an increase in the Services Fee from and after the installation of the
additional component(s). The Services Fee shall not be due or payable for Blood Screening Systems purchased new until the expiration of the applicable manufacturers' warranties.

	5.4
	NAT Tracker Fee. The applicable license fee for the NAT Tracker software solution is based on the number of Testing Centers operating
the NAT Tracker software, as set forth below, and payable annually in a lump sum in accordance with Section 1.4 of Schedule E. Additional
Testing Centers may be licensed to use the NAT Tracker software at the then current license fee. 

	Software
 
	 	Price/Year
	 	Number of

Testing Centers
	 	Extended License

Fee

	NAT Tracker3	 	$	[**]	 	 	 	$	 

	3
	Includes
all version updates to NAT Tracker Software, ver. 1.0E.

	6.
	Reagent Utilization Factor. In accordance with Schedule E to the Association
Agreement, for each [**] increment by which the actual Reagent Utilization Factor during each Annual RUF 

2

 

Measuring
Period exceeds ABC MEMBER's Target RUF of            , ABC MEMBER agrees to pay an additional fee [**]; provided
that no additional fee shall be payable hereunder to the extent that the cause of the Reagent Utilization Factor exceeding such amount is attributable to a breach by Chiron of the limited warranty set
forth in Section 12 of Schedule B-1.

	7.
	Training. Chiron agrees to provide the following training program for ABC MEMBER personnel.

	7.1
	Initial Training. Chiron shall provide, at Chiron's sole expense, initial training to            technical
personnel from ABC
MEMBER. Initial training includes assay training on the Blood Screening System and Pooled Testing training, if applicable. Training will include theory, practical training and operation/maintenance on
all required equipment. Upon successful completion of training, individuals will be certified as Primary Operators. Chiron will provide an additional week of
"train-the-trainer" courses for up to            Primary Operators from ABC MEMBER. Upon successful completion of these courses, these Primary Operators will be issued
trainer certifications. Primary Operators with trainer certifications may train Secondary Operators in accordance with Section 7.2 of this Member Supplement. Chiron also agrees to provide, at
Chiron's expense, Bio Medical Instrument Technician ("BMIT") training to            Primary Operators from ABC MEMBER. BMIT training includes training on the Tecan Genesis instrumentation
and
includes theory, diagnostic tests, troubleshooting and basic instrument repair. Upon successful completion of the course, trainees will be certified as Bio Medical Instrument Technicians.
BMIT-certified Primary Operators must be re-certified annually by Chiron.

	7.2
	On Site Training. Training of Secondary Operators will be performed on site at the Testing Centers, by Primary Operators or by Chiron
support personnel. Each Secondary Operator will be required to pass proficiency certification prior to reporting results. Without limiting Section 7.1 of this Member Supplement, if the
Participating Member later requires training of additional personnel due to employee turnover, such additional training will be the responsibility of the Participating Member, using Primary Operators
previously trained by Chiron pursuant to this Section 7 of this Member Supplement. Chiron undertakes to co-operate with the Participating Member and if requested by the
Participating Member, provide technical personnel to assist in training such additional personnel.

	7.3
	Proficiency Panels. Chiron will provide, at no cost to the Participating Member, one proficiency panel for initial proficiency
certification of each of the operators trained pursuant to Section 7.1 of this Member Supplement. If, following initial certification, the Participating Member wishes to re-certify
an operator, or the Participating Member wishes to obtain proficiency panels for ongoing quality control or future training purposes, the Participating Member shall purchase such proficiency panels as
may be necessary for such purposes. The Participating Member agrees to provide forecasts of its needs for proficiency panels in the same manner as is set forth in Section 7 of  Schedule B-1 to
this Agreement.

	7.4
	Manuals and Documentation. The training provided under Sections 7.1 and 7.2 of this Member Supplement shall include copies of training
materials, operator manuals and documentation, including maintenance and troubleshooting documentation.

	7.5
	Changes to Blood Screening Assays, Blood Screening Systems, Software. If, in accordance with Section 6.7 of the Association
Agreement, mandatory changes are made by the manufacturer to the Blood Screening Assays, Blood Screening Systems or Software during the term of this Agreement, and as a result further staff training
is required, the training must be carried out by Chiron at its cost at the Testing Centers, unless the parties otherwise agree. Chiron must provide proficiency panels at its cost for any additional
proficiency certification required as a result of the changes referred to in this Section 7.5 of this Member Supplement. For clarity of understanding, unless otherwise agreed the Participating
Member will bear any additional 

3

 

training
costs and costs of proficiency panels arising from any optional change which the Participating Member elects to implement pursuant to Section 6.7 of the Association Agreement. 

	8.
	Insurance.

	8.1
	ABC
MEMBER shall obtain and maintain at its sole cost, a policy or policies of insurance with the following coverages, which shall be in full force and effect for the term of this
Agreement and thereafter through two years following the termination of the Agreement: a) a Commercial General Liability policy including Products and Completed Operations Liability in an
amount of not less than $                        combined single limit for each occurrence; b) Workers' Compensation coverage
with statutory limits for
each jurisdiction where the work required of such party under this Agreement is performed and an employers' liability policy with at least the following limits,
$                        per accident,
$                        per disease (policy limit), and
$                        disease (each employee); and c) Professional Liability (Errors & Omissions) Insurance in an
amount not less than
$                        each claim specifically insuring claims arising from obligations of ABC MEMBER.

	8.2
	ABC
MEMBER shall provide Chiron with certificates of insurance evidencing the coverage required herein upon execution of this Agreement, and renewal certificates on request from
Chiron. ABC MEMBER must notify Chiron within a reasonable time if there is a material change to any of the insurance policies referred to in this Section. Such certificates shall provide for thirty
(30) days prior written notice to the certificate holder in the event of non-renewal of the policies, cancellation or material change in the coverage provided. 

	9.
	Term. This Member Supplement shall become effective on the Effective Date of this Member Supplement, and shall terminate on the earlier
to occur of (i)             (            ) months from the Effective Date of this Member Supplement, or (ii) the
termination or expiration of the Association Agreement. ABC MEMBER
shall have the right to extend the term of this Member Supplement, subject to the continued effectiveness of the Association Agreement, by two extension periods, each one year in length. ABC MEMBER
shall elect an extension by delivering written notice to Chiron not less than ninety (90) days prior to the expiration of the initial term or extension.

	10.
	Notices. Notices, requests, waivers and other communications made pursuant to this Member Supplement or the Association Agreement shall
be made in accordance with Section 12.6 of the Association Agreement and, if to ABC MEMBER, shall be addressed to ABC MEMBER as set forth below: 

ABC
MEMBER

                                         
               

                                         
               

Fax: (              )
                                

Attn:
                                         
        

	11.
	[**]. 
	12.
	Survivability. Sections 2 and 9 of this Member Supplement shall survive any
expiration or termination of this Member Supplement. 

[SIGNATURE
PAGE FOLLOWS] 

4

 

        IN
WITNESS WHEREOF, the parties hereto, acting through their duly authorized officers, have executed this Agreement as of the date first set forth above. 

	 
	 	 
	 	 

	 	 	CHIRON CORPORATION
	

 	
 	

By:	
 	

	 	 	ABC MEMBER
	

 	
 	

By:	
 	

5

 
 
 

EXHIBITS    
  

	1
	Association
Agreement

	2
	Testing
Centers

	3
	Products
Requirements Forecast

	4
	Blood
 Screening Systems 

6

QuickLinks

EXHIBIT 10.317

Association Agreement Regarding the Sale and Servicing of Blood Screening Products

SCHEDULE A Definitions

SCHEDULE B-1 TERMS AND CONDITIONS FOR PURCHASE OF PROCLEIXTM HIV-1/HCV BLOOD SCREENING ASSAY

ATTACHMENT B-1 Package Insert

SCHEDULE C TERMS AND CONDITIONS FOR USE OF BLOOD SCREENING SYSTEMS

SCHEDULE D BLOOD SCREENING SYSTEMS AND SOFTWARE SERVICE & SUPPORT

SCHEDULE E PRICES

EXHIBIT 10.317

MEMBER SUPPLEMENT

RECITALS

AGREEMENT

EXHIBITS

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