Document ID: FDA-1998-D-0025-0002
Agency: fda
Document Type: Supporting & Related Material
Title: 
Posted Date: 2005-09-20T04:00Z

Guidance

PET Drug Products – Current Good Manufacturing Practice (CGMP) 

DRAFT GUIDANCE

	This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be
submitted within 60 days of publication in the Federal Register of the
notice announcing the availability of the draft guidance.  Submit
comments to Dockets Management Branch (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD  20852.  All
comments should be identified with the docket number listed in the
notice of availability that publishes in the Federal Register.

For questions regarding this draft document contact Brenda Uratani,
301-827-8941.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

September 2005

Compliance

Guidance 

PET Drug Products – Current Good Manufacturing Practice (CGMP) 

Additional copies are available from:

Office of Training and Communications

Division of Communications Management

Drug Information Branch, HFD-210

5600 Fishers Lane

Rockville, MD  20857

(Tel) 301-827-4573

(Internet)  http://www.fda.gov/cder/guidance/index.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

September 2005

Compliance



TABLE OF CONTENTS

  TOC \o "1-3"  I.	INTRODUCTION	  PAGEREF _Toc114473622 \h  1 

II.	Background	  PAGEREF _Toc114473623 \h  2 

III.	PET Drugs and Cgmp Requirements	  PAGEREF _Toc114473624 \h  4 

A.	What is a PET Drug?	  PAGEREF _Toc114473625 \h  4 

B.	What is CGMP?	  PAGEREF _Toc114473626 \h  5 

C.	Distinguishing Between PET Drug Production and the Practice of
Pharmacy	  PAGEREF _Toc114473627 \h  5 

IV.	PERSONNEL RESOURCES	  PAGEREF _Toc114473628 \h  5 

A.	Regulatory Requirements	  PAGEREF _Toc114473629 \h  5 

B.	Organization and Staffing	  PAGEREF _Toc114473630 \h  6 

C.	Personnel Qualifications	  PAGEREF _Toc114473631 \h  6 

V.	QUALITY Assurance	  PAGEREF _Toc114473632 \h  7 

A.	Regulatory Requirements	  PAGEREF _Toc114473633 \h  7 

B.	The Activity and Responsibility of the Quality Assurance Function	 
PAGEREF _Toc114473634 \h  7 

VI.	FACILITIES AND EQUIPMENT	  PAGEREF _Toc114473635 \h  8 

A.	Regulatory Requirements	  PAGEREF _Toc114473636 \h  8 

B.	Facilities	  PAGEREF _Toc114473637 \h  8 

1.	General	  PAGEREF _Toc114473638 \h  8 

2.	Aseptic Processing Area	  PAGEREF _Toc114473639 \h  9 

C.	Equipment	  PAGEREF _Toc114473640 \h  10 

1.	Production Equipment	  PAGEREF _Toc114473641 \h  10 

2.	Quality Control Equipment	  PAGEREF _Toc114473642 \h  13 

VII.	CONTROL OF COMPONENTS, CONTAINERS, AND CLOSURES	  PAGEREF
_Toc114473643 \h  15 

A.	Regulatory Requirements	  PAGEREF _Toc114473644 \h  15 

B.	Control of Components, Containers, and Closures	  PAGEREF
_Toc114473645 \h  15 

1.	Vendor Selection	  PAGEREF _Toc114473646 \h  15 

2.	Receipt of materials	  PAGEREF _Toc114473647 \h  15 

3.	Acceptance, release, and storage of materials	  PAGEREF _Toc114473648
\h  16 

4.	Acceptance Testing	  PAGEREF _Toc114473649 \h  16 

5.	Handling of components, containers, and closures	  PAGEREF
_Toc114473650 \h  17 

6.	Records	  PAGEREF _Toc114473651 \h  18 

VIII.	PRODUCTION AND PROCESS CONTROLS	  PAGEREF _Toc114473652 \h  18 

A.	Regulatory Requirements	  PAGEREF _Toc114473653 \h  18 

B.	Master Production and Control Records/Batch Production and Control
Records	  PAGEREF _Toc114473654 \h  18 

C.	Microbiological Control on Aseptic Processing and Sterilizing
Filtration	  PAGEREF _Toc114473655 \h  21 

1.	Water	  PAGEREF _Toc114473656 \h  21 

2.	Glassware	  PAGEREF _Toc114473657 \h  22 

3.	Transfer Lines	  PAGEREF _Toc114473658 \h  22 

4.	Resin columns	  PAGEREF _Toc114473659 \h  22 

5.	Components	  PAGEREF _Toc114473660 \h  22 

6.	Qualification for aseptic processing	  PAGEREF _Toc114473661 \h  22 

7.	Sterilizing filtration	  PAGEREF _Toc114473662 \h  23 

8.	Environmental and personnel monitoring	  PAGEREF _Toc114473663 \h  23

D.	Process Verification and Computer Control	  PAGEREF _Toc114473664 \h 
23 

1.	Process verification under 212.50(f) (2)	  PAGEREF _Toc114473665 \h 
23 

2.	Computer control	  PAGEREF _Toc114473666 \h  24 

IX.	LABORATORY CONTROLS	  PAGEREF _Toc114473667 \h  24 

A.	Regulatory Requirements	  PAGEREF _Toc114473668 \h  24 

B.	Laboratory Controls	  PAGEREF _Toc114473669 \h  25 

X.	STABILITY TESTING	  PAGEREF _Toc114473670 \h  26 

A.	Regulatory Requirements	  PAGEREF _Toc114473671 \h  26 

B.	Guidance on Stability	  PAGEREF _Toc114473672 \h  26 

XI.	FINISHED DRUG PRODUCT CONTROLS AND ACCEPTANCE CRITERIA	  PAGEREF
_Toc114473673 \h  27 

A.	Regulatory Requirements	  PAGEREF _Toc114473674 \h  27 

B.	Finished Product Testing	  PAGEREF _Toc114473675 \h  27 

C.	Microbiological Tests for Sterile PET Drugs	  PAGEREF _Toc114473676
\h  27 

D.	Accepting and Releasing a Batch (Lot)	  PAGEREF _Toc114473677 \h  28 

E.	Conditional Final Release	  PAGEREF _Toc114473678 \h  29 

F.	Rejection and Reprocessing	  PAGEREF _Toc114473679 \h  29 

XII.	LABELING AND PACKAGING	  PAGEREF _Toc114473680 \h  29 

A.	Regulatory Requirements	  PAGEREF _Toc114473681 \h  29 

B.	Recommendations on Labeling and Packaging	  PAGEREF _Toc114473682 \h 
29 

XIII.	DISTRIBUTION	  PAGEREF _Toc114473683 \h  30 

A.	Regulatory Requirements	  PAGEREF _Toc114473684 \h  30 

B.	Recommendations	  PAGEREF _Toc114473685 \h  30 

XIV.	COMPLAINT HANDLING	  PAGEREF _Toc114473686 \h  31 

A.	Regulatory Requirements	  PAGEREF _Toc114473687 \h  31 

B.	Recommendations	  PAGEREF _Toc114473688 \h  31 

XV.	RECORDS	  PAGEREF _Toc114473689 \h  31 

A.	Regulatory Requirements	  PAGEREF _Toc114473690 \h  31 

B.	Recommendations	  PAGEREF _Toc114473691 \h  31 

REFERENCES	  PAGEREF _Toc114473692 \h  33 

 

Guidance

PET Drug Products –

Current Good Manufacturing Practice (CGMP)

This draft guidance, when finalized, will represent the Food and Drug
Administration's (FDA's) current thinking on this topic.  It does not
create or confer any rights for or on any person and does not operate to
bind FDA or the public.  You can use an alternative approach if the
approach satisfies the requirements of the applicable statutes and
regulations.  If you want to discuss an alternative approach, contact
the FDA staff responsible for implementing this guidance.  If you cannot
identify the appropriate FDA staff, call the appropriate number listed
on the title page of this guidance.

If you plan to submit comments on this draft guidance, to expedite FDA
review of your comments, please:

Clearly explain each issue/concern and, when appropriate, include a
proposed revision and the rationale/justification for the proposed
change.

Identify specific comments by line number(s); use the PDF version of the
document, whenever possible.

I.	INTRODUCTION	

This draft guidance is intended to help PET drug producers better
understand FDA’s thinking concerning compliance with the proposed CGMP
regulations.  The guidance addresses resources, procedures, and
documentation for all PET drug production facilities, academic and
commercial.  In some cases, the guidance provides practical examples of
methods or procedures that PET production facilities could use to comply
with the proposed CGMP requirements.  In developing this draft guidance,
FDA has taken into consideration relevant issues, concerns, and
questions raised at the public meetings held with professional
associations, producers of PET drug products, and other interested
parties.  A first draft version of this guidance was issued in April
2002 in conjunction with revised preliminary draft proposed regulations.
 

FDA's guidance documents, including this guidance, should not be viewed
as establishing legally enforceable responsibilities.  Instead,
guidances describe the Agency's current thinking on a topic and should
be viewed only as recommendations.  The use of the word should in Agency
guidances means that something is suggested or recommended, but not
required.

II.	Background

Section 121(c)(1)(A) of the Food and Drug Administration Modernization
Act of 1997 (the Modernization Act) directed the Food and Drug
Administration (FDA) to establish current good manufacturing practice
(CGMP) requirements for positron emission tomography (PET) drugs. 
Concurrently with the issuance of this draft guidance, FDA is proposing
such requirements under 21 CFR Part 212.  In 1999, FDA published a
preliminary draft of the proposed PET CGMP regulations.  The FDA
received comments on the preliminary draft proposed regulations at a
public meeting on the subject on September 28, 1999.  The FDA made
changes in the working draft in response to the public comments.  In
2002, a revised preliminary draft of the CGMP regulations was published
in conjunction with a first draft of this guidance.  The FDA received
comments on the preliminary proposed rule and the draft guidance at a
public meeting on May 21, 2002, and in writing after the meeting and has
taken all comments into consideration in revising the proposed rule and
this draft of the guidance.  This second version of the draft guidance
provides more details for discussion purposes on acceptable approaches
to complying with the proposed regulations should they be published in
final form.

As directed by Congress in the Modernization Act, to help in developing
the proposed regulation and this draft guidance, we closely examined the
operations of many PET drug producers, including not-for-profit
institutions and commercial manufacturers.  Since the Modernization Act
became law, significant changes have occurred in PET drug production in
the United States.  The number of PET production facilities has
increased, as has the number of facilities where PET scans are
performed.  The business of PET drug production has changed as well. 
Historically, PET drug products were produced by academicians and
researchers at PET production facilities located in universities and
similar not-for-profit institutions.  An academically oriented PET
production facility usually produces small amounts (a few doses per day)
of a few PET drug products for on-site patient use and a larger variety
of PET drug products for clinical investigation and academic research. 

An increasing number of PET production facilities are now operated by
for-profit corporate entities that contract with academic and medical
institutions (many of which have not-for-profit status) to manage the
production of PET drugs at those institutions.  Most of these PET drug
products are administered on site, although often there is some
distribution to other local or regional hospitals.  In addition, a
growing number of independent PET production facilities are not
affiliated with any university or hospital.  These for-profit, often
contractually managed, and independently operated PET production
facilities distribute PET drug products to significantly greater numbers
of patients, sometimes hundreds of miles from the production site.  

Our review of PET drug production has lead to the conclusion that a PET
drug producer’s status as either a not-for-profit or for-profit entity
has little bearing on the quality of PET drugs that it produces and
distributes for administration to patients, or on the methods,
facilities, and controls that a PET production facility needs to ensure
product quality.  Instead, production and CGMP differences among PET
drug producers are primarily a function of the size, scope, and
complexity of their production operations.  We have also found that
implementing certain production standards and controls can ensure the
production of quality PET drugs, regardless of differences among the
various PET production facilities.  The Agency believes that the welfare
of a patient undergoing a PET scan should not depend on where a
particular PET drug was manufactured. 

The proposed regulations on CGMP requirements contain what we believe
are the minimum standards for quality production of PET drugs at all
types of PET production facilities.  We have designed the CGMP
regulations to be sufficiently flexible to accommodate not-for-profit,
academically oriented institutions as well as commercial producers. 

The proposed regulations also incorporate principles from the United
States Pharmacopeia (USP) general chapter on PET drug compounding.  The
USP contains standards that are of significant regulatory importance for
PET drugs.  Currently, under section 501(a)(2)(C) of the Federal Food,
Drug, and Cosmetic Act (the Act), a compounded PET drug is adulterated
unless it is produced in compliance with USP compounding standards and
official monographs for PET drugs.  Section 121(b) of the Modernization
Act added this provision as a safety net during the time it takes the
Agency to develop the final regulations.  Under section 121(b) however,
section 501(a)(2)(C) of the Act will expire 2 years after the date on
which we establish approval procedures and CGMP requirements for PET
drugs.  At that time, compliance with the final version of the
regulation will be required.  Nevertheless, the USP general chapter on
PET drug compounding largely reflects the consensus views of the PET
community and FDA on how to properly produce PET drug products. 
Consequently, we believe it is appropriate to incorporate many of the
principles and concepts in the USP general chapter into the proposed
CGMP requirements.

Proposed § 212.5(b) specifies the CGMP requirements for
investigational, research, and approved PET drugs.  Proposed
§ 212.5(b)(1) states that the regulations in part 212 apply to all PET
drug products for human use, other than research and investigational PET
drug products. We believe that it is appropriate to have less detailed
CGMP requirements for investigational and research PET drugs to allow
more flexibility during the development of these drugs.  We also
recognize that many investigational PET drugs may not have commercial
potential.  Therefore, proposed § 212.5(b)(2) states that the
regulations in part 212 do not apply to investigational PET drugs for
human use produced under an investigational new drug application in
accordance with part 312 and research PET drugs that are produced with
the approval of a Radioactive Drug Research Committee (RDRC) in
accordance with § 361.1.

Instead, proposed § 212.5(b)(2) states that, for investigational and
research PET drugs, the requirement under the Act to follow CGMP is met
by producing drugs in accordance with Chapter <823> of the 26th edition
of the USP (2003).  Chapter <823> sets forth requirements for PET drug
production, including control of components, materials, and supplies;
verification of procedures; stability testing and expiration dating;
quality control; and sterilization and sterility assurance.  Because
most PET drug producers are very familiar with the requirements in
Chapter <823>, adopting the Chapter <823> provisions as the CGMP
requirements for investigational and research PET drugs should greatly
facilitate producers’ compliance with those requirements.  Although
the provisions in Chapter <823>, including those on documentation, are
generally less specific and explicit than the requirements in proposed
part 212, we believe that they are adequate to ensure that
investigational and research PET drugs are produced safely under
appropriate conditions, consistent with section 501(a)(2)(B) of the Act.

Although we propose that USP Chapter <823>, rather than part 212, would
constitute the minimum CGMP requirements for investigational and
research PET drugs, FDA would retain the authority to inspect facilities
where investigational and research PET drugs are produced to verify
compliance with Chapter <823>.  However, as with inspection of
investigational studies of non-PET drugs, we generally would conduct
inspections of facilities that produce investigational or research PET
drugs only on a for-cause basis (i.e., when we become aware of a
potential safety concern related to the production of an investigational
or research drug).

PET drugs, other than investigational and research PET drugs, would have
to meet the requirements of proposed part 212.  PET drug products that
would have to be marketed under an approved new drug application (NDA)
or an approved abbreviated new drug application (ANDA) would have to be
produced in accordance with proposed part 212.

PET Drugs and Cgmp Requirements

A.	What is a PET Drug?

+).  PET drugs are used to provide dual photon positron emission
tomographic images.  The radionuclide is generally produced by a
particle accelerator (e.g., a cyclotron) and has a short half life.
Currently, a batch, or lot, of a PET drug typically consists of one
multiple-dose vial containing the PET drug product in a sterile
solution.  A sample from the vial, which is representative of all doses
to be administered, is tested to verify that the batch or the lot
conforms to all established specifications.

A PET drug product is typically administered to patients within a few
minutes to a few hours following preparation.  Because of the short half
life of the radionuclide and the mode of production, PET drug products
have unique storage, shipping, and handling concerns.  Under Section 121
of the Modernization Act, PET producers must comply with the standards
in the USP General Chapter <823> Radiopharmaceuticals for Positron
Emission Tomography-Compounding, until FDA establishes approval
procedures and CGMPs for PET drug products. 

 

B.	What is CGMP?

Current good manufacturing practice (CGMP) is a minimum standard that
ensures that a drug meets the requirements of safety and has the
identity strength, quality, and purity characteristics it is represented
to possess.  The Agency is proposing CGMP regulations that would require
manufacturers of PET drugs to follow certain CGMP requirements.  CGMP is
demonstrated through written documentation of procedures and practices. 
The documents and practices may be similar or identical to documents and
practices requested by other oversight bodies (e.g., Nuclear Regulatory
Commission and state and local agencies).  Documents produced for
others, where appropriate, can be used to provide the documentation of
compliance with CGMP requirements.  However, because of institutional,
local, or state differences, some of these documents may not have
sufficient overlap to address the issues in this guidance.  Therefore,
to ensure uniformity for all patients and human subjects, where overlap
does not exist, we recommend that PET producers develop supplemental
documentation. 

C.	Distinguishing Between PET Drug Production and the Practice of
Pharmacy

FDA regulates the production of PET drug products.  Section 121 of the
Modernization Act directs FDA to establish appropriate approval
procedures for PET drugs pursuant to section 505 of the Act as well as
appropriate CGMP requirements.  In the course of developing these
approval procedures and CGMP requirements, a question has been raised
concerning how to distinguish PET drug production from the practice of
pharmacy (regulation of which FDA has traditionally deferred to State
and local authorities).

FDA has determined that the production of a PET drug product includes
all operations to the point of final release of a finished dosage form,
and these activities would be subject to CGMP.  A PET drug product may
be released to a hospital, institution, imaging facility, nuclear
pharmacy (e.g., pharmacy bulk packages for use in accordance to USP <1>
Injections), or other entity or part of an entity.  After a finally
released PET drug product is received by the receiving facility, FDA
generally regards subsequent dispensing of a patient-specific dose and
use of the drug product to be part of the practice of medicine and
pharmacy.  FDA generally will defer to State and local authorities
concerning regulation of these activities.  In general, a routine FDA
inspection to ensure compliance with CGMP would focus on activities up
to and including the point of final release of a PET drug product.  

In the following sections, the draft guidance introduces each section by
identifying the relevant requirements from the proposed regulations.  
The section then provides more detailed current thinking.  Certain CGMP
requirements in the proposed regulations are self-explanatory and have
not been further clarified in this guidance.

IV.	PERSONNEL RESOURCES

A.	Regulatory Requirements

Proposed 21 CFR 212.10 would require a PET production facility to have a
sufficient number of personnel with the necessary education, background,
training, and experience to enable them to perform their assigned
functions correctly.  Each center also would have to provide adequate
resources, including equipment and facilities, to enable their personnel
to perform their functions.

The following section of the guidance addresses personnel. Guidance on
resources  (facilities and equipment) is provided in Section VI.

B.	Organization and Staffing

We recommend that staffing levels correspond to the size and complexity
of the operation of the PET production facility and enable a PET
production facility to satisfactorily complete all intended tasks in a
timely manner before administration of a finished PET drug to humans. 
We recommend that the responsibilities and assigned duties of all staff
be clearly identified in written policies.

For a PET production facility that typically produces one or two batches
of a product daily, it may be adequate to employ one or two persons to
accomplish all production and quality control functions.  We recommend
the PET facility demonstrate that the production and quality control
functions can be consistently accomplished in a timely and appropriate
manner before administration of a drug to humans.  One individual can be
designated to perform the production as well as quality control
functions, provided he or she is highly qualified in the performance of
all such functions (i.e., has a degree, documented training, and
significant experience in the technical area).

Under current CGMP regulations in 21 CFR Part 211, FDA normally requires
second-person checks at various stages of production as well as test
verification.  In a PET production facility with only one person
assigned to perform production and quality control tasks, it is
recommended that that person recheck his or her own work.  Self-checks
involve the confirmation of the operator’s own action and would be
documented.  Examples of self-check activities include reviewing batch
records (e.g., review the batch record to ensure that all
finished-product test results are within the acceptance criteria) before
release of the drug product for distribution and verifying calculations
in analytical tests. 

At a PET production facility that produces multiple PET drugs, we
recommend the staffing level be adequate to perform all quality
assurance functions and to prevent mix-ups and cross contamination.  

C.	Personnel Qualifications

As mentioned above, each person performing an activity or a function in
the production and quality control of a PET drug product would have to
have the appropriate education, training, and experience related to that
function and should be trained in CGMP relevant to their assigned tasks.
 We recommend that PET production facilities have adequate ongoing
programs or plans in place for training employees in new procedures and
operations and in the areas where deficiencies have occurred.  

We recommend PET production facilities maintain an updated file (e.g.,
curriculum vitae, copies of degree certificates, certificate of
training) for each employee.

V.	QUALITY Assurance

A.	Regulatory Requirements

Proposed 21 CFR 212.20 would require PET production facilities to have a
quality assurance function.  Under the proposed regulations, the
following activities are defined as the responsibilities of the quality
assurance function:

Oversee production operations to ensure that PET drug products have
adequately defined identity, strength, quality, and purity 

Examine and approve or reject components, containers, closures,
in-process materials, packaging materials, and labeling used in the
production of PET drug products to ensure that all these meet their
current specifications

Examine any procedure affecting production, testing, and specifications 

Review production records for accuracy and completeness

Ensure that all errors are investigated and corrective action is taken

B.	The Activity and Responsibility of the Quality Assurance Function

The quality assurance function in a PET production facility typically
consists of execution and oversight activities. 

We recommend that the execution of quality assurance functions include
the following:

Examine and evaluate each lot of incoming material before use to ensure
that the material meets its established specifications 

Review the production batch records and laboratory control records for
accuracy, completeness, and conformance to established specifications
before authorizing the final release or rejection of a batch or lot PET
drug product

We recommend that the oversight of quality assurance functions include
the following:

Approve procedures, specifications, process, and methods 

Ensure that personnel are properly trained and qualified, as appropriate

Ensure that PET drugs have adequately defined identity, strength,
quality and purity

Investigate errors and ensure that appropriate corrective action is
taken to prevent their recurrence

Conduct periodic audits to monitor compliance with established
procedures and practices

For PET production facilities currently producing one or two PET drugs,
employees located at the facility can perform both the daily execution
and oversight functions.  

On the other hand, a commercial PET firm managing multiple production
facilities may choose to have an entity located outside the PET
production facility help to achieve the objective of manufacturing
oversight and more efficient management.  For example, a corporate
quality assurance/quality control department, or consultants, can
provide oversight. 

VI.	FACILITIES AND EQUIPMENT

A.	Regulatory Requirements

Proposed 21 CFR 212.30(a) would require that a PET production facility
have adequate facilities to ensure the orderly handling of materials and
equipment, the prevention of mix-ups, and the prevention of
contamination of equipment or product by substances, personnel, or
environmental conditions.

Proposed 21 CFR 212.30(b) and (c) would require that all equipment that
would reasonably be expected to adversely affect the strength, quality,
or purity of a PET drug, or give erroneous or invalid test results when
improperly used or maintained, is clean, suitable for its intended
purposes, properly installed, maintained, and capable of repeatedly
producing valid results.  Equipment would have to be constructed so that
surfaces that contact components, in-process materials, or drug products
are not reactive, additive, or absorptive so as to alter the quality of
the PET drug product. 

B.	Facilities

1.	General

The design of the PET drug production facility should promote orderly
operations during the production process and protect the product from
contamination originating from personnel and surrounding areas.  To
achieve this, a facility should contain adequate work areas suitable for
the intended tasks (e.g., area for analytical testing, aseptic
manipulation, chemical production, radiochemical production, and
component storage) and to allow completion of all production-related
tasks in an orderly manner.  Potential sources of contamination include
particulate matter and chemical and microbiological materials.

Phases of production with the potential for microbiological
contamination should be performed under environmental conditions that
minimize the possibility of such contamination (e.g., in a laminar
airflow workbench (LAFW), or barrier isolator system).  

The placement of equipment and materials should be carefully evaluated
to promote efficient operation and eliminate errors, mix-ups, and
cross-contamination.  All equipment used in production (e.g., particle
accelerator, synthesis units, or other specialized equipment) should be
appropriately located and housed (e.g., with shielding) so that all the
work areas during the normal course of production are easily accessible.

We recommend that related work areas be organized and proximally located
so as to promote efficient operation and eliminate the potential for
errors in the production and control operations.  Access to work areas,
production and testing equipment, components, containers and closures,
and the PET drug products, should be restricted to authorized personnel.
    

In most PET production facilities, the same area or room can be used for
multiple purposes.  For example, the production (e.g., radiochemical
synthesis), laboratory operation (e.g., release testing), and storage of
approved components, including containers and closures, can be located
in the same room.  Components that are approved for use as well as those
that are under quarantine can be stored in the same area or on a
different shelf in a cabinet, provided each lot is properly labeled as
to its status and contents and organized in a manner that avoids mix-up
or unintended use.  Rejected components, containers and closures, and
other materials should be kept separate from quarantined or approved
materials. 

As the complexity in a PET production facility increases (production of
multiple PET drug products), it is important to develop the appropriate
level of control required to prevent mix-ups and contamination).
Separate and well-defined areas or rooms may be warranted for each
independent function of the operation, such as production, testing, and
storage of components. It is also important to consider what impact a
greater number of personnel and activities could have on the aseptic
processing portion of the process. 

2.	Aseptic Processing Area 

An aseptic work area should be suitable for the assembly of the aseptic
components required for the preparation of a sterile PET drug product. 
We recommend that air quality in the aseptic processing area be
controlled to limit the presence of microorganisms and particulate
matter.  Critical activities in the production and testing of a PET drug
product that expose the PET drug product or the sterile surface of the
container/closure system to the environment should be conducted within
an aseptic workstation (e.g., a LAFW or barrier isolator).  Examples of
such activities include the aseptic assembly of sterile components
(syringe, needle, filter and vial) for sterile filtration of the PET
drug product, and sterility testing of the finished PET drug product. 
We recommend that the following precautions be taken to help maintain
the appropriate air quality of the aseptic workstation:

The aseptic workstation is sanitized before each operation.

Items within a laminar airflow aseptic workstation are kept to a minimum
and not interrupt the airflow. 

Operators wear clean lab coats and sanitized gloves when conducting an
aseptic manipulation within the aseptic workstation. 

Gloved hands are frequently sanitized or changed when working in the
aseptic workstation.  Gloves are examined for damage (tears or holes)
and replaced if they are compromised.  

The surface of nonsterile items (e.g., test tube rack, and the overwrap
for sterile syringes, and filters) are sanitized and wiped with an
appropriate disinfectant (e.g., sterile 70 percent isopropyl alcohol)
before being placed in the aseptic workstation.

 

We recommend that conditions in the room where aseptic manipulations are
conducted not present a challenge to the operating capability of the
aseptic workstation.  For example, the room should not be carpeted nor
have overhanging pipes or hanging light fixtures.  All areas of the
production and processing room should be easily accessible for cleaning.
 Surfaces of the walls, floors, and ceilings in the aseptic work areas
should be easily cleaned.  Cleaning  should be performed frequently to
ensure consistent control of the environmental quality.  In addition,
the aseptic processing area (e.g., LAFW) should be situated in the
section of the room with the lowest traffic and lowest activity. 
Cartons and boxes should not be stored or opened in the production area
to minimize ingress of dust and particulate into the aseptic work area.

C.	Equipment

1.	Production Equipment

Equipment used in the production, processing, or packaging of a PET drug
product would have to be appropriate for the performance of its intended
function and not contaminate the product.  We recommend that each piece
of equipment be suitably located to facilitate its use, cleaning, and
maintenance.  We also recommend that each PET production facility
establish and follow written procedures that address the following
issues, where applicable:

Assignment of responsibility and frequency for cleaning and maintenance
of equipment

Description of cleaning and maintenance procedures in sufficient detail
to include disassembly and reassembly of equipment

  

Protection of clean equipment from contamination prior to use

Inspection of equipment and calibration, if indicated, prior to use

We recommend that each PET production facility select suitable cleaning
agents and cleaning techniques and ensure that their cleaning operations
not contaminate the drug product. 

We recommend that newly installed equipment be qualified before first
use to verify that it was installed correctly and is capable of
operating as intended. Normally, the equipment vendor verifies that the
equipment is installed correctly (installation qualification (IQ)) and
operates according to specifications (operational qualification (OQ)). 
Before the equipment is used for production, personnel in the PET
production facility should verify that the equipment, when operated
under actual production parameters or selected method, produces
consistent results within established specifications (performance
qualification (PQ)). 

We recommend developing a preventive maintenance schedule with
sufficient frequency to ensure the correct performance of the equipment.
 Where needed, calibration should be performed prior to the use of the
equipment for the intended task.  We recommend facilities follow
calibration checks recommended by equipment vendors unless the PET
production facility has determined that more frequent calibrations are
appropriate.  Major repairs or upgrades in equipment may warrant
requalification.  We recommend not using malfunctioning or incorrectly
operating equipment until repairs or corrective action have been made
and the equipment has been found to operate correctly.  All
qualification, calibration, and maintenance activities should be
properly documented, including the date of such performance and who
performed them.  

FDA recognizes that, after they become subject to the requirements of
the final CGMP regulations, a number of PET production facilities may
continue to use existing equipment.  If they do, PET production
facilities would have to make sure that the existing equipment is
working properly and is being maintained and calibrated according to
written procedures.

We recommend that PET production facilities establish procedures to
check the correct functioning of the equipment that is developed
in-house.  Representative equipment is discussed below to illustrate how
it might be controlled in a PET production facility.  

a.	Automated radiochemical synthesis apparatus

The apparatus enables the PET production facility to carry out the
production process reliably and reproducibly.  The provisions contained
in the USP General Chapter <1015> Automated Radiochemical Synthesis
Apparatus can help ensure proper functioning of a synthesis apparatus. 

Prior to the production of a PET drug product each day, we recommend
that the operator should conduct a performance check to ensure the
following: 

The synthesis apparatus has been cleaned/flushed according to the
established procedures.

 

All appropriate tubing, reaction vessels, purification columns or
cartridges, and other materials have been replaced and connected as
required.

 

The monitoring and or recording devices (e.g., temperature, pressure,
flow rate) are functioning properly.

When the process is under microprocessor control, the operator ensures
that the system is functioning and recording correctly and that the
correct program and operational parameters are used.

b.	Aseptic Workstation 

The aseptic workstation should provide an appropriate environment for
aseptic procedures. Examples of workstations include a laminar air flow
workbench (LAFW) or barrier isolator system.  We recommend that an
integrity test be conducted at installation (including after each change
of the high-efficiency particulate air (HEPA) filter) to ensure proper
performance.  We recommend that certification (integrity testing of the
HEPA filter) of the aseptic workstation be performed when the unit is
initially installed and at least every 6 months thereafter to ensure the
desired air quality.  More frequent testing may be appropriate if air
quality is found to be unacceptable, for example, as part of an
investigation into a finding of sterility failure in a PET drug, or if
leakage or decrease in optimal airflow is found.  

We recommend that a qualified operator change the prefilters in the
aseptic workstation periodically in accordance with written procedures
and preventive maintenance schedules.  Some laminar flow hoods are
equipped with easily readable static pressure gauges that indicate when
the pressure builds up behind the filter because of the clogging of the
filter.  We recommend that the filter be changed when clogging is
detected.

We recommend laminar airflow velocities be monitored periodically at the
work surface as well as at the HEPA filter face to ensure adequate
uniformity of flow throughout the critical area.  We recommend that
operators be trained on the importance of minimizing objects and
equipment within the critical area so laminar airflow is not disrupted. 
We recommend that microbiological monitoring (e.g., using settle plate)
in the LAFW be conducted during sterility testing and critical aseptic
manipulation.

c.	Electronic or analytical weight balance

We recommend that written procedures, if not already available, be
developed, describing the proper use of the balance, assessment of
accuracy, and a schedule for calibration.  We recommend that performance
be checked by weighing two or more standard weights on each day of use. 
We recommend that the calibrated weights used for assessing daily
performance bracket the range of the weights being measured.  We also
recommend that the balance be fully calibrated periodically, or upon
failure to meet daily performance checks (see USP <41> Weights and
Balances). 

d.	Dry-heat ovens

  

If glassware and heat-stable materials are depyrogenated and sterilized
on-site, we recommend that the PET production facility demonstrate and
document that the depyrogenation cycle will achieve at least a 3-log
reduction of an endotoxin challenge, as measured by a bacterial
endotoxins test.  A suitable challenge study usually involves random
placement of endotoxin indicators in a representative oven load of
materials.  Suitable endotoxin indicators include glass vials that
contain 1,000 to 10,000 Endotoxin Units. 

e.	High performance liquid chromatograph (HPLC) 

When an HPLC is used for purification of a PET drug, we recommend the
operator ensure that the system is working properly and there is no
bleeding of unintended materials (e.g., column material) into the mobile
phase. 

f.	Temperature recording device 

We recommend that the temperature and humidity (where appropriate) of
the dry heat oven, refrigerator, freezer, and incubator be recorded on
each workday when in use.  Automated recording devices are recommended
for ease of documentation and for recording any deviations.  

2.	Quality Control Equipment 

We recommend that PET production facility have the appropriate equipment
to adequately perform each quality control function that it intends to
perform. Representative quality control equipment can include:

a.	Gas chromatograph (GC)

Prior to each day of its use, the analyst should make sure that the GC
system is functioning correctly by conducting system suitability
testing. At least one injection of the standard preparation (reference
standard or internal standard) should be done before the injection of
test samples (see USP General Chapter <621> Chromatography). 

b.	High performance liquid chromatograph (HPLC)

We recommend that the HPLC system have detectors suitable for the
intended purpose and be of sufficient sensitivity.  Prior to each day of
its use, the analyst should make sure that the HPLC system is
functioning correctly by conducting system suitability testing (see USP
General Chapter <621> Chromatography and FDA reviewer guidance, Reviewer
Guidance Validation of Chromatographic Methods (November 1994). At least
one injection of the standard preparation (reference standard or
internal standard) should be done before the injection of test samples.

c.	Dose calibrator  

We recommend a dose calibrator be used to measure the radioactivity of
PET drug products.  Accuracy and linearity should be assessed at
installation and at appropriate intervals thereafter.  The instrument
should be calibrated in accordance with nationally recognized standards
or the manufacturer's instructions. System suitability testing should
include a constancy check with a suitable high-energy radionuclide
standard source.

d.	Radiochromatogram scanner 

We recommend that a radiochromatogram scanner (or equivalent equipment
that provides a radiochromatogram) be used to measure radioactivity
distribution in the developed thin layer chromatography plate (e.g.,
instant thin-layer chromatography (ITLC), paper or plate).  The scanner
should have sufficient sensitivity and spatial resolution for the
intended discriminatory and quantitative objective.  Manufacturer
recommended checks and maintenance should be performed on the
radiochromatogram scanner  (see USP General Chapter <821>
Radioactivity).

e.	Multichannel analyzer (MCA)

A multichannel spectrometer coupled to a calibrated sodium iodide
scintillation detector (or preferably with the higher resolution
germanium lithium compensated, Ge (Li) detector) can be useful to
determine radionuclidic purity and to identify the radionuclide.  The
overall system should have sufficient sensitivity and resolution for the
intended purpose (see USP General Chapter <821> Radioactivity). 
Adequate calibration using National Institute of Standards and
Technology (NIST) traceable standards and preventive maintenance should
be performed at intervals specified in a written procedure and as
recommended by the equipment manufacturer.  More frequent intervals
should be used if problems in the operation of the MCA are encountered. 

VII.	CONTROL OF COMPONENTS, CONTAINERS, AND CLOSURES

A.	Regulatory Requirements 

Proposed 21 CFR 212.40(a) and (b) would require PET production
facilities to establish, maintain, and follow written procedures for the
control of components, containers, and closures.  There would have to be
appropriate written specifications for components, containers, and
closures. 

 

Proposed 21 CFR 212.40(c) would establish the minimum standards for
controlling components, containers, and closures from receipt to
consumption. 

Proposed 21 CFR 212.40(d) would require that components, containers, and
closures be handled and stored in a manner that prevents contamination,
mix-ups, and deterioration.

Proposed 21 CFR 212.40(e) would require that PET production facilities
keep a record of each shipment of each lot of components, containers,
and closures that they receive.     

B.	Control of Components, Containers, and Closures

The written procedures would have to specify how each material
(components, containers, and closures) will be selected and controlled
in PET production facilities.  Procedures should cover the life cycle of
a material, from time of receipt to ultimate consumption.  The process
for procurement and use of materials should include the following
elements, where applicable:

1.	Vendor Selection 

We recommend only qualified vendors be used.  A vendor is qualified when
there is evidence to support its ability to supply a material that
consistently meets all quality specifications.  We also recommend that
PET production facilities ask the vendor to report any major changes in
the manufacture of an item.  It is preferable to have more than one
qualified vendor for a component.  A vendor should be replaced if there
is an indication that it is supplying unsatisfactory materials. 

2.	Receipt of materials

We recommend that each lot of material be checked upon receipt to
determine that the order was filled correctly and arrived in good
condition.  Each lot should be logged in and assigned a new
identification code number.  The code number would be used in the
disposition of that lot.  Sufficient information should be documented to
enable the PET production facility to have full traceability of each
lot.  We recommend that, before release for use, incoming materials be
segregated and placed under quarantine and labeled as Quarantined.  A
lot can then be inspected, sampled, and tested, if applicable.

3.	Acceptance, release, and storage of materials 

Analytical results in the certificate of analysis (COA) for each lot of
incoming material should be inspected against the PET production
facility's current specification sheet to ensure that acceptance
criteria are met.  Where appropriate, certain components described below
(see Acceptance Testing) can be tested to confirm their identity before
they are accepted and released for use in the production of a PET drug
product. 

Materials that meet a PET production facility’s specifications can be
approved and released for use.  Such release should be recorded and the
examination and testing data maintained.  It may be helpful to have a
component logbook to record information such as receipt date, quantity
of the shipment, supplier's name, lot number, expiration date, results
of any testing performed, and person responsible for release.  Approved
materials can be labeled Approved with an identifying code number,
storage conditions, and expiration date.  We recommend that materials be
stored under the proper storage conditions and in an area designated for
approved materials.  If a lot is rejected, we recommend it be labeled
Rejected, segregated, properly disposed of, and each of these actions be
documented. 

We recommend that items be stored under the conditions recommended by
the vendor (e.g., temperature and humidity).  Moisture sensitive
materials should be stored in desiccated devices in sealed containers.
There should be an expiration date for each item.  We recommend that PET
production facilities have a policy that guides the expiration dating of
items, by category.  Vendor assigned expiration dates could be used
unless the in-house date is sooner. 

4.	Acceptance Testing

a.	Reagents, solvents, gases, purification columns, and other auxiliary
materials 

We recommend that PET production facilities have procedures in place to
ensure that only materials meeting applicable specifications from
approved reliable sources are used.  The COA and container label for
each lot of each shipment of incoming materials should be examined to
ensure that all specifications are met. 

Components that yield an active pharmaceutical ingredient (API) and
inactive ingredients

Under proposed § 212.40(c)(1)(i), for the production of PET drugs where
finished-product testing ensures that the correct components have been
used (e.g., production of F18 FDG) PET producers may rely on the
certificate of analysis (COA) from the suppliers.  Analytical results in
the COA for each lot of component would have to be examined and compared
against the PET production facility's current specifications to ensure
that acceptance criteria are met.  We recommend that PET producers have
scientific rationale and supporting data to justify why identity testing
is not needed.

Under proposed § 212.40(c)(1)(ii), for the production of a PET drug
where the finished-product testing does not ensure that the correct
components have been used, identity testing would have to be performed.
When specific identity tests exist, we recommend that they be used. 

The inactive ingredients in PET drugs usually consist of a diluent, a
stabilizer, and/or a preservative.  Under proposed § 212.40(c)(1)(ii),
if a product that is marketed as a finished drug product intended for
intravenous administration is used as an inactive ingredient, it would
not be necessary to perform a specific identity test for that
ingredient.  Proposed § 212.40(c)(1)(ii) also states that if an
inactive ingredient (e.g., 0.9 percent sodium chloride solution) was
prepared on site, an identity test on the components used to make the
inactive ingredient would have to be performed before it was released
for use.  

 

c.	Commercially available ready-to-use sterile, pyrogen-free, sealed
container/closure systems for injections, syringes, transfer sets, and
filters used in aseptic process

We recommend that PET production facilities use reliable sources for
these items. Most PET production facilities use sterile and
depyrogenated containers (sealed vials with stoppers and crimps) that
are commercially available (510K product).  Under proposed §
212.40(c)(2), a visual identification of each lot of containers and
closures would have to be conducted.  We recommend that a COA showing
conformance with the established specifications be obtained before
accepting a lot of the container/closure system.  We recommend that the
container/closure system be properly stored under appropriate
environmental conditions (e.g., correct temperature, humidity, and
sterility).  

If the sterilization and depyrogenation of the container/closure are
performed on site, we recommend that the efficacy of each process be
demonstrated.  We recommend that established procedures be shown to be
reproducible and used in such cases.  

5.	Handling of components, containers, and closures

When a lot of material has met all acceptance criteria, the material can
be labeled Approved.   Under proposed § 212.40(d), approved materials
would have to be handled and stored in a manner that prevents
degradation or contamination.  Unacceptable materials should be promptly
rejected, identified, and segregated to prevent their use prior to
appropriate disposal.  

6.	Records 

Under proposed § 212.40(e), records would have to be kept for each
shipment of each lot of components, containers, and closures that the
PET production facility receives, including results of any testing
performed.  

VIII.	PRODUCTION AND PROCESS CONTROLS

A.	Regulatory Requirements

Proposed 21 CFR 212.50 would require adequate production and process
controls to ensure consistent production of a PET drug product that
meets the applicable standards for identity, strength, quality, and
purity.  Under proposed § 212.50(a), PET production facilities would
be required to have written production and process control procedures to
ensure and document that all key process parameters are controlled and
that any deviations from the procedures are justified.  

Proposed § 212.50(b) would require PET production facilities to have
master production and control records that document all steps in the PET
drug production process.  Proposed § 212.50(b) also specifies what
would be required in the master production and control records.

Proposed § 212.50(c) would require that a batch production record be
generated from the master production record template for each new batch
of a PET drug product.  Each batch of a PET drug product would have to
be uniquely identified, and its batch record would have to include each
major production step, weights, and identification codes of components
used, dates of production steps, identification of major equipment,
testing results, labeling,  initials or signatures of persons performing
or checking each significant step in the operation, and results of any
investigations conducted.

Proposed § 212.50(f) would require that when the results of the
production of an entire batch of a PET drug product are not fully
verified through finished-product testing or when only the initial
sub-batch in a series is tested, the PET drug producer would have to
demonstrate that the process for producing the PET drug product is
reproducible and is capable of producing a drug product that meets the
predetermined acceptance criteria.  Process verification activities and
results would have to be documented.  Documentation would have to
include the date and signature of the individual(s) performing the
verification, the monitoring and control methods and data, and the major
equipment qualified.

 

B.	Master Production and Control Records/Batch Production and Control
Records

Master production and control records are the principal documents
describing how a product is made.  The master production record serves
as a template for all batch records, documenting how each batch will be
produced.  The designated individual should approve the master
production and control records, or any changes to them, before they are
implemented.  

We recommend that the master production and control records present
logical, chronological step-by-step instructions that document how the
PET drug is to be produced.  Production should be discussed under
headings, where applicable, such as accelerator operation, radiochemical
synthesis, purification steps, and formulation of the finished product. 
We recommend the entire production process be pre-established and fully
described in the master production and control record.  The SOP in
performing a specific step can be referenced.  The master production and
control records would include specifications for each critical step. 
Critical steps include the process step, process condition, or other
relevant parameters that are controlled within predetermined criteria to
ensure that the API meets its specification.  Under proposed §
212.50(b), the master production and control records should include the
following:

The name and strength of the PET drug product in MBq/ml or mCi/ml
(strength should be measured at a calibration time immediately after
production)

If applicable, the name and radioactivity or other measurement of each
API as well as any inactive ingredient (e.g., diluent, stabilizer, or
preservative) per batch or per unit of weight or measure of the drug
product and a statement of the total radioactivity or measurement of any
dosage unit

A complete list of components designated by names and codes (component
code) sufficiently specific to indicate any special quality
characteristic

Identification of all major equipment used in production of the drug
product

An accurate statement of the weight or measurement of each component
(e.g., batch formula).  In the process of producing FDG F 18, for
example, multiple components are weighed or measured by volume.  The
radioactive component should be recorded in terms of radioactivity
units.

A statement of the action limit on radiochemical yield (i.e., the
minimum percentage of yield beyond which investigation and corrective
action would be required) 

Complete instructions (or references) for production, control, and
testing of the PET drug.  The synthesis of certain PET drugs, such as
FDG F 18, involves multiple steps including drying, exposure to organic
solvents, heating, pH adjustments, passage through purification media,
and sterilizing filtration.  We recommend there be a description of all
in-process steps and their controls so that the operator can confirm
that all steps are completed within specified conditions, where
feasible.  Controls for movement of liquids or gases should also be
provided.  For automated radiochemical synthesis equipment, it may be
sufficient to reference the equipment manufacturer’s manual that
contains a full description of the automated production steps and
controls.

A description of the PET drug product containers, closures, and
packaging materials, including a specimen or copy of each label and all
other labeling. 

Proposed § 212.1 defines a batch of a PET drug product as a specific
quantity of PET drug product intended to have uniform character and
quality.  In the case of FDG F 18, a batch normally consists of the PET
drug product produced in a single synthesis and purification operation. 
For ammonia N 13, a batch normally consists of multiple sub-batches
having uniform character and quality, that are produced according to a
single preparation order during one succession of multiple irradiation
using a synthesis and/or purification operation.  

Proposed § 212.50(c) would require the use of a batch record to
document the production and testing of each batch.  The batch records
provide complete traceability and accountability for production and
control of each batch.  We recommend that information in the batch
record (paper, or electronic copy) accurately reflect the information
contained in the master production and control records. The control
records may be cross-referenced and not be included as part of the batch
record.  The batch record is therefore a simplified version of the
master production and control records that should contain the
information needed for a documented history of the batch produced,
including:

Documentation of the execution of each critical production step (e.g.,
timed events occurred within specifications, heating steps occurred at
the specified temperature, and ingredients were properly transferred
into the reaction vessel) where feasible, taking radiation exposure
concern into consideration. For automated radiochemical synthesis unit,
the printout at the end of synthesis documenting the execution of the
production steps and controls could be used for the chemical synthesis
portion of the batch record. 

A compilation of tests and printouts that led to acceptance of the final
product.

Under proposed § 212.50(c), information specific to batch production
and control records would include the following:

Name and strength of the PET drug product

Unique identifier or number for each batch (an identifier or number also
can be provided for each sub-batch produced)

 The name and radioactivity or other measure of each active
pharmaceutical ingredient and each inactive ingredient per batch or per
unit of radioactivity or other measurement of the drug product;

Date and time of production steps 

Identification of major pieces of equipment where identical equipment in
the facility can be used 

Actual weights (or measures) and identification codes of components used

Labeling (a description of the finished drug product container label and
the outer container label should be included)

Initials or signatures of the person(s) performing and checking each
significant step of the operation

Results of any investigations conducted (this should include
documentation of any deviations and follow-up investigations). 
Reference to the deviation and investigation reports can be indicated if
stored separately. 

Results of testing

Batch records should include documentation that each significant step in
the production was accomplished.  When entries are made in batch
records, an entry should be made directly after performing the activity
(in the order performed) and would have to identify the person
(signature or initials) making the entry.  Corrections to paper entries
would be dated and signed or initialed, leaving the original entry still
readable. We recommend that each batch record be reviewed and approved
for final release (signature/initials and date). For requirements and
information on electronic records and signatures, interested persons
should refer to Part 11 (21 CFR Part 11, Electronic Records; Electronic
Signatures) and the Agency guidance on the scope and application of Part
11, Electronic Records; Electronic Signatures.

C.	Microbiological Control on Aseptic Processing and Sterilizing
Filtration

Most PET drug products are designed for parenteral administration and
are produced by aseptic processing.  The goal of aseptic processing is
to make a product that is free of microorganisms and toxic microbial
byproducts, most notably bacterial endotoxins.  The use of aseptic
technique and control of microbiological impurities in components can
eliminate microbial and endotoxin contamination from PET drugs.  Aseptic
processing of PET drugs should involve microbiological control over
various types of components, as discussed below.

1.	Water

Production processes that are relatively free of water or have rigorous
chemical processes are unlikely to have microbial or endotoxin
contaminants.  PET production facilities often use Water for Injection,
USP (WFI), an approved drug product.  Using finished packaged WFI
eliminates the need for the PET production facility to verify, maintain,
and document a sterile water system.  

Nonsterile water can develop significant microbial growth in a matter of
days.  We recommend that production processes that are water-intensive
have sufficient controls to avoid microbial growth and development of
biofilm (bacterial colonization).  If nonsterile water is allowed to
stagnate in a container or tubing, biofilm will develop.  To minimize
their contact with nonsterile water, it is recommended that tubing and
glassware be washed, rinsed, and promptly dried. 

2.	Glassware

Glassware and heat-resistant containers are relatively easy to keep free
of microbial growth and pyrogens because they can be appropriately
wrapped in foil and terminally sterilized by a suitable dry-heat cycle
(see Section VI).  Control procedures for these items should include
prompt cleaning after use, rinsing with purified or WFI water, wrapping
in aluminum foil, and depyrogenation by a suitable dry-heat oven cycle.

3.	Transfer Lines

Transfer lines, which are used for synthesis and transfer of solvents or
products, are usually made of durable plastic and are amenable to reuse.
 Prompt cleaning with organic solvents after use, rinsing with WFI,
flushing with a volatile solvent, and drying with nitrogen are measures
that help to control microbial contamination.  Organic solvents such as
ethanol and acetone are useful as a final rinse and are easily dried
from containers or lines.        

For PET drugs with a very short half life (e.g., ammonia N 13),
sometimes a long fluid line is used to deliver multiple batches of the
product solution to a remote area for further processing.  We recommend
that procedures be established to ensure that these fluid lines are
clean and free of pyrogen contamination prior to each  use. 

4.	Resin columns

Resin columns are a potential source of microbes and pyrogens because
they can be contaminated with microorganisms.  If available, the
purchase of low-microbial grade resin material may limit bioburden. 
Material used for preparing resin columns should be suitably processed
and rinsed with a large amount of WFI to control contamination.  The
prepared column should be appropriately flushed.  Refrigerated storage
is helpful in controlling contamination.  We recommend that wet columns
not be stored for a prolonged period of time. 

5.	Components

The selection of a reliable vendor and high-quality materials are
effective ways to limit the risk of microbiological contamination. 
Components that support microbial growth during storage should be kept
under controlled conditions and periodically assessed for microbial
growth/ contamination.

6.	Qualification for aseptic processing

Aseptic processing in PET drug production normally consists of, but is
not limited to, (1) the aseptic assembly of the container/closure system
(syringe, needle, sterilizing filter and vial) and (2) sterile
filtration of the PET drug product.  The ability of personnel to perform
aseptic processing can be assessed by conducting media fills. 
Simulations of aseptic manipulations (e.g., the aseptic assembly of the
container system, vent connection, and sterile filtration) can be
carried out by substituting a bacterial growth medium for the actual
drug product.  We recommend that an operator complete three successful
media fill runs to qualify as a new operator.  Each operator can be
requalified annually by conducting one media fill run.  Only personnel
trained in aseptic techniques should conduct aseptic processing. 

7.	Sterilizing filtration

Even if care is taken to minimize microbiological contamination during
synthesis, a drug is considered to be nonsterile until it is passed
through a sterilizing grade filter.  Generally, PET production
facilities can use commercially available, presterilized filters to
sterilize these solutions, provided that the vendor has been shown to be
reliable, the filter is certified as compatible for the product, and it
meets acceptable specifications. 

Integrity testing of membrane filters should always be performed
postfiltration.  This is to ensure that the filter has performed
according to specifications.  Testing can be accomplished by performing
the bubble-point test to show that the integrity of the filter was not
compromised during or before use. 

8.	Environmental and personnel monitoring

Environmental monitoring is crucial to maintaining aseptic conditions. 
We recommend that microbiological testing of aseptic workstations be
performed during sterility testing and critical aseptic manipulation. 
Methods can include using swabs or contact plates for surfaces and
settling plates or dynamic air samplers for air quality. 

D.	Process Verification and Computer Control 

Proposed § 212.50(f)(1) states that for PET drug production in which
every batch undergoes full finished-product testing to ensure the PET
drug product meets all specifications (e.g., F18 FDG), process
verification is not required.

Proposed § 212.50(f)(2) would require that when the results of the
production of an entire batch of a PET drug product are not fully
verified through finished-product testing or when only the initial
sub-batch in a series is tested, the PET drug producer would have to
demonstrate that the process for producing the PET drug product is
reproducible and is capable of producing a drug product that meets the
predetermined acceptance criteria.  Process verification activities and
results would have to be documented.  Documentation would have to
include the date and signature of the individual(s) performing the
verification, the monitoring and control methods and data, and the major
equipment qualified.  The determination not to conduct process
verification should be supported by scientific rationale and data.

1.	Process verification under 212.50(f) (2)

For a PET production facility that has an established history of PET
drug production, the process verification can be accomplished using
historical batch records, provided that there is adequate accumulated
data to support a conclusion that the current process yields batches
meeting predetermined acceptance criteria.  We recommend that a
comprehensive review of accumulated production, testing, and control
data be conducted according to a written protocol defining the
acceptable conditions.  The accumulated data should verify that the
process used was consistent and should document all changes to and
failures of the process.  

We recommend that new processes or significant changes to existing
processes be shown to reliably produce PET drug products meeting the
predetermined acceptance criteria before any batches are distributed. 
This verification should be conducted according to a written protocol
and generally include at least three consecutive acceptable production
runs.

Because PET drugs have short half lives, a PET producer may decide to
evaluate the reliability of a new process or a significant change to an
existing process to produce a PET product, meeting the predetermined
acceptance criteria concurrently with the distribution of the batch. 
Such a decision should be justified in writing, subjected to quality
control procedures, and performed according to a written protocol. Under
this situation, we recommend each batch be processed in strict adherence
to the written procedures, fully tested (except sterility testing), and
found to comply with all procedural and quality test requirements prior
to final release. 

2.	Computer control

Synthesis of some PET drugs can be executed under automated or computer
control.  We recommend that the computer program be verified before
first use to demonstrate that it is suitable for its intended purposes
and is capable of producing results that meet the predetermined
acceptance criteria.  We also recommend that subsequent changes or
upgrades made to the computer program be documented and the process
demonstrated to be capable of producing a PET drug product that meets
the predetermined acceptance criteria.  PET production facilities can
rely on a certification by the software or system vendor that the
specified software was verified under its operating conditions. 

IX.	LABORATORY CONTROLS

A.	Regulatory Requirements 

Proposed 21 CFR 212.60 would require the establishment and
implementation of procedures for testing components, in-process
materials, and finished PET drug products.  All necessary tests of
materials and products would have to be documented.   Each laboratory
would also be required to have sampling and testing procedures designed
to ensure that components, drug product containers and closures,
in-process materials, and PET drug products conform to appropriate
standards.  Analytical methods and test equipment would have to be
suitable for their intended uses.  Reagents, solutions, and supplies
used in testing procedures would have to be adequately controlled.  The
preventive maintenance, calibration, and procedures to make sure that
the equipment is functioning properly would have to be documented.  A
complete record of all tests related to the production of a PET drug
product would have to be kept to ensure compliance with established
specifications and standards, including examinations and assays, as
follows:

(	A description of the sample received for testing, including its
source, the quantity, the batch or lot number, the date (and time, if
appropriate) the sample was taken, and the date (and time, if
appropriate) the sample was received for testing. 

A description of each method used in the testing of the sample, a record
of all calculations performed in connection with each test, and a
statement of the weight or measurement of the sample used for each test.

A complete record of all data (including graphs, charts, and spectra).
For example, a print-out of the chromatogram with the calculated amounts
of each component analyzed by the test

A statement of results of the tests and their relation to acceptance
criteria

The initials or signature of the analyst and the date of the test

B.	Laboratory Controls

Under proposed § 212.60, a PET production facility would have to have
written test procedures  that describe how to conduct each test of
finished products and, where applicable, of components and in-process
materials.  Appropriate testing procedures would have to be established
to ensure that PET drug products conform to appropriate standards,
including established standards (e.g., relevant USP monographs) of
identity, strength, quality, and purity.  Analytical tests would have to
be suitable for their intended purpose and have sufficient sensitivity,
specificity, and accuracy.  

We recommend that any new analytical test method be validated, through
documented data, to show that it will consistently yield results that
accurately reflect the quality characteristics of the product tested.
The FDA and USP have published information for determining the
appropriate analytical parameters (e.g., accuracy, precision, linearity,
ruggedness) that should be used to validate a new method  (see ICH Q2A
Text on Validation of Analytical Procedures and USP General Chapter
<1225> Validation of Compendial Methods). On the other hand, validation
is not required for compendial methods. 

If a USP analytical test method is used, a PET producer should verify
that the method works under the actual conditions of use.  

Most analyses use reference standards.  We recommend that PET production
facilities establish the reference standards identified in the
analytical procedure or SOP.  When a primary reference standard is
obtained from an officially recognized source (e.g., USP), the material
usually does not need further testing if it is stored under conditions
consistent with the supplier’s recommendations.  However, where an
official standard is not available or if a PET production facility
establishes its own reference standard, we recommend that data to fully
confirm the material’s identity and purity be established and
documented.  Documentation such as reference spectra or other supporting
data to prove the identity and purity of the reference standard may be
available from the supplier.

 

Under proposed § 212.60(f), equipment would have to be routinely
calibrated and maintained according to the established written
procedures (see Section VI).  We recommend that PET production
facilities verify that the equipment is in good working condition at the
time the samples are analyzed.  We also recommend that prior to each day
of use of the HPLC and GC, a system suitability test using reference
standards be conducted to verify that the resolution and reproducibility
of the chromatographic system are adequate for the analysis to be done.

We recommend that any reagent or solution prepared on-site be adequately
controlled (including temperature control, if applicable) and properly
labeled with respect to identity, composition, and expiration date. 

Raw test data (such as chromatograms, spectra, and printouts) and any
calculations performed can be documented and become part of the batch
production and control record.  Records should have information such as
the source of the test material, a description of the appearance of the
material, the amount used, test and acceptance criteria, and an entry
for data and interpretation of results.  Laboratory controls should be
followed and documented at the time of performance.  We recommend that
deviation from written procedures be documented and justified.  Any
out-of-specification results obtained should be investigated and
documented.

X.	STABILITY TESTING

A.	Regulatory Requirements

Proposed 21 CFR 212.61 would require the establishment of a written
stability testing program for each PET drug product.  This program would
have to be used to establish suitable storage conditions as well as
expiration dates and times.

B.	Guidance on Stability

As with other drug products, PET drug molecules are expected to remain
stable during storage.  Although PET drug products have extremely short
shelf lives, because of their short half lives compared to other kinds
of drug products, there are stability concerns due to radiation-related
radiolysis.  Certain PET drug products (e.g., F18 fluorodopa) can
undergo very rapid chemical changes.  Therefore, appropriate parameters
should be evaluated to establish and document the stability of PET drug
products under proposed storage conditions.  Examples of stability
parameters include radiochemical identity and purity (including levels
of radiochemical impurities), appearance, pH, stabilizer or preservative
effectiveness, and chemical purity.  We recommend that appropriate
stability-indicating methods that can distinguish degradation products
and impurities be used.  Stability testing of the PET drug product
should be performed at the highest radioactive concentration, and the
whole batch volume in the intended container/closure should be stored. 
At least three production runs of the final product should be studied
for a time period equal to the labeled shelf life of the PET drug
product.  

Although stability studies in support of an expiration dating period
would be needed for approval of a PET drug product, subsequent changes
to the expiration date could be made without prior approval (changes
would be noted in the annual report for the drug product).

XI.	FINISHED DRUG PRODUCT CONTROLS AND ACCEPTANCE CRITERIA

A.	Regulatory Requirements

Proposed 21 CFR 212.70 would require that specifications be established
and met for each PET drug product batch, including identity, strength,
quality, purity, and, if appropriate, sterility.  The proposed
regulation would require the implementation of procedures to ensure that
a product is not released until appropriate laboratory testing is
completed, reviewed, and approved by an appropriate releasing authority.
 

Proposed 21 CFR 212.71 would require a PET production facility to reject
PET drug products that fail to meet acceptance criteria.   Procedures
would have to be established to identify and segregate the product. 
There would have to be predetermined procedures for investigating the
cause of the problem and preparing a timely report on the occurrence,
including a description of the corrective action taken, where
appropriate.

B.	Finished Product Testing

Methods of PET drug production may differ from site to site.  As a
result, there may be specific impurities to assess depending on the
method of production, such as kryptofix in FDG F 18.  We recommend using
approved NDA specifications, or the IND accepted specifications.  Under
proposed § 212.70, PET production facilities would have to ensure that
each batch of PET drug product meets its established acceptance
criteria, except for sterility (see subsection C below), before it is
given final release.

C.	Microbiological Tests for Sterile PET Drugs

Sterility testing would have to be started within 30 hours after the
completion of PET drug production.   If the sample for sterility testing
is held longer than indicated (e.g., over the weekend), PET producers
should demonstrate that the longer period does not adversely affect the
sample and the test results obtained will be equivalent.  The samples
should be stored appropriately (e.g., under refrigeration). 
Verification of equivalent results can be accomplished by inoculation of
USP indicator organism(s) and demonstrate that there is little, if any,
loss in viability of the inoculated microorganism.  The USP General
Chapter <71> Sterility Tests provides information about media and
incubation conditions.

We recommend that testing be conducted in a controlled area such as a
laminar airflow workbench (LAFW) with clean-room apparel.  Aseptic
techniques should be used for sterility testing.  The greatest risk of
false-positive results arises in the sampling and transfer of the test
aliquot from the vial to the media.  It may be convenient to apply
direct inoculation into commercial media.  We recommend that the media
be observed on days 3, 7, and 14 after inoculation, but it is prudent to
observe the media more often during the first week of incubation. 

The USP Bacterial Endotoxins Test (BET) (General Chapter <85>) should be
performed for a sterile PET drug that is intended for injection.  The
BET contains gel-clot and rapid photometric methods for endotoxin
measurement.

The product can be distributed under control after a pharmacopeial
bacterial endotoxin test is initiated.  However, the endotoxin results
should meet the acceptance criteria before administering the product to
humans.  

If the result of any bacterial endotoxin test exceeds the acceptance
limit, or if a sterility test is positive for microbial growth, we
recommend a complete investigation be conducted immediately and
documented.  We recommend that corrective actions based on the results
of the investigations be implemented promptly.

D.	Accepting and Releasing a Batch (Lot)

We recommend the designated individual review all laboratory testing and
documentation from the batch record to determine whether or not the PET
drug product has met all acceptance criteria.  If the product has met
acceptance criteria, the designated individual with quality assurance
function should sign and date the release sections of the batch record
and sign a release for human administration.  

In many cases, modifications to this standard procedure for product
release may be appropriate.  For example, transportation deadlines may
justify a prerelease for distribution before all elements of testing and
review are finalized.  Other than sterility testing, all
finished-product tests would have to be completed or in progress at the
time of shipment or distribution and PET drug products can be released
for distribution (but not administration) while some tests are pending. 
Under proposed § 212.70, these tests would have to be completed prior
to final release for human administration.  When it is determined that
all acceptance criteria have been met, the PET production facility
should then provide a notice of final release to the receiving facility
so that the dose may be given to the patient.  We recommend the
establishment of effective procedures for immediate notification of the
receiving facility if there is evidence of an out-of-specification
result.  Notification of the receiving facility due to product failure
should be documented.

PET drugs that have a very short half life (e.g., ammonia N 13) can be
produced in multiple sub-batches on the same day.  End product testing
of the initial sub-batch can be conducted, provided a sufficient number
of sub-batches (beginning, middle, and end) have been demonstrated to
produce a product meeting the predetermined acceptance criteria.  For
routine production in this circumstance, the release of subsequent
sub-batches can be qualified if the initial sub-batch meets all
acceptance criteria.  In certain cases, testing each sub-batch for
certain attributes prior to release may be appropriate (e.g., for pH
determination in ammonia N-13 production method using Devarda’s alloy
catalyst). 

E.	Conditional Final Release

When one of the required finished product tests cannot be completed due
to a breakdown of the analytical equipment, proposed 212.70 (f)
establishes criteria under which PET producers  may still release the
drug product for human use.  If equipment is properly maintained,
breakdowns should be a rare occurrence.  We recommend that PET producers
determine if the missing testing would adversely affect the safety and
effectiveness of the PET drug product.  Conditional release should be
extremely infrequent.  Only products that meets all conditional release
criteria would be able to be released.  Conditional release of a PET
drug product would not be permitted if a PET drug producer could not
perform a radiochemical identity/purity test on the active
pharmaceutical ingredient of a PET drug product. All activities of
conditional release would have to be documented.

F.	Rejection and Reprocessing

Under proposed § 212.71(a), a batch of a PET drug product that fails to
meet established specifications would have to be rejected, and
procedures would have to be established to identify and segregate the
product.  Proposed § 212.71(b) would require that documentation of the
investigation of a nonconforming product include the results of the
investigation and final disposition of any rejected product.

Under proposed § 212.70 (d), a drug product can be reprocessed if
pre-established procedures (set forth in production and process
controls) are followed and the finished product conforms to
specifications before final release.  When the option for reprocessing
is exercised, we recommend that the event be documented and conditions
described in a brief deviation report.  Examples of reprocessing could
include a second passage through a purification column to remove an
impurity, or a second passage through a filter if the original filter
failed the integrity test.

XII.	LABELING AND PACKAGING

A.	Regulatory Requirements

Proposed 21 CFR 212.80 would require that:

A PET drug product be suitably packaged and labeled to protect the
product from alteration, contamination, and damage during the
established conditions of storage, handling, and shipping.

Labels and packaging operations be controlled to prevent labeling and
product mix-ups.

All information stated on each label be contained in each batch
production record. 

B.	Recommendations on Labeling and Packaging

Regardless of the scope of operation of a PET production facility, we
recommend that appropriate measures be taken to handle labels in a way
that prevents mix-ups with any other labeling materials. 

We recommend that PET drug products be labeled with adequate, legible
identifying information to prevent errors during storage, shipment, and
use.. Once an NDA or ANDA is approved for a PET drug product, the label
approved in the NDA must be used.  Prior to approval of the NDA or ANDA,
the label should be approved by persons responsible for quality
assurance procedures.  Labels can be computer generated or handwritten.

 

Because of radiation exposure concern, it is a common practice to
prepare much of the labeling in advance.  For example, an empty product
vial can be prelabeled with partial information (e.g., product name,
batch number, date) prior to filtration of the radioactive product, and
upon completion of QC test, the outer shielded container can be labeled
with the required information (e.g., radioactivity).  Alternatively, a
string label can be used to label the immediate container provided that
there is a way to associate the label with the vial if the label were to
come off.  Different approaches can be used as long as the approach
ensures that the required information is available on the label.  A
label identical to that affixed to the container shield can be
incorporated into the batch production record.  A final check should be
made to verify that the correct and complete label has been affixed to
the container and the shield.

XIII.	DISTRIBUTION

A.	Regulatory Requirements

Proposed 21 CFR 212.90 would require the development of procedures to
ensure that the shipment will not adversely affect the product.  PET
production facilities would have to maintain distribution records for
PET drug products.

B.	Recommendations

PET drug products should be shipped in accordance with labeled
conditions (e.g., temperature) to ensure the identity, purity, or
quality of the drug product.  For PET production facilities distributing
to outside clients or outside pharmacies, information on the method of
shipment and the contact person at the final destination should be
included.  We recommend that a system be put in place by which the chain
of distribution of each batch of PET drug product can be readily
determined to permit its recall if necessary.  A recall should consist
of notifying the receiving facility, pharmacist, and the patient’s
physician, if known.  When the receiving facility disposes of the
recalled drug, the PET drug producer can obtain a notification from the
receiving facility confirming the recalled drug has been disposed of and
describing the manner in which it was disposed.

When the PET production facility ships the final released PET drug
product supplied as a pharmacy bulk package (USP<1> Injections) to a
nuclear pharmacy for dispensing into individual patient doses, FDA
generally regards subsequent distribution of the drug product as part of
the practice of pharmacy.

XIV.	COMPLAINT HANDLING

A.	Regulatory Requirements

Proposed 21 CFR 212.100 would require that procedures be developed and
implemented for receipt and handling of all complaints pertaining to a
specific PET drug product, including review by a designated individual
to determine compliance with specifications and to initiate an
investigation into the problem.  A file for drug product complaints
would have to be maintained.  The file would have to contain the name
and strength of the PET drug product, the batch number, the name of the
complainant, the date the complaint was received, the nature of the
complaint, and the response to the complaint.  The file would also have
to include the findings of any investigation and followup.  A PET drug
product implicated in a complaint could not be reprocessed and would
have to be destroyed in accordance with applicable Federal and State
law.

B.	Recommendations

We recommend that the designated individual be responsible for
collecting as much information as possible about the drug and the nature
of a complaint and for completing an investigation of the matter as soon
as possible.  Corrective action should be taken immediately if there is
any reason to believe that an adulterated drug was implicated in the
complaint.  Under proposed § 212.100(c), complaints would have to be
maintained in a file designated for that purpose.  We recommend that
complaint files be easily retrievable for review and trending.

XV.	RECORDS

A.	Regulatory Requirements

Proposed 21 CFR 212.110(a) would require that all records be maintained
at the PET production facility or another location that is reasonably
accessible to responsible officials of the PET production facility and
FDA investigators. 

Proposed § 212.110(c) would require that all records referenced in part
212 be kept for at least 1 year from the date of final or conditional
final release of a PET drug product.

B.	Recommendations

The regulation would require that records be stored at a PET production
facility or another location that is reasonably accessible.  A
reasonably accessible location is one that would enable the PET
production facility to make requested records available to an FDA
investigator in a reasonable period of time during an inspection.  The
records would have to be legible and stored in a manner that prevents
their deterioration and/or loss.

We recommend that forms for collecting data be kept to a minimum by
designing multipurpose documents and eliminating redundancy, where
possible.  It is prudent to have as much of the required information
within the batch production record as possible.  Records can be kept
electronically. 

Other records that would have to be kept include information relating to
the composition and quality of the PET drug product and operation of the
production processes, such as laboratory records, out-of-specification
results, master and batch records, distribution records, and complaint
files.  Records relevant to materials and PET drug products would have
to be kept at least 1 year from the date of final or conditional final
release.  Verification reports should be kept as long as the systems are
in use.



REFERENCES

FDA.  Guide to Inspection of Computerized Systems in Drug Processing. 
February 1983.

FDA.  General Principles of Process Validation.  May 1987.

FDA.  Sterile Drug Products Produced by Aseptic Processing.  June 1987.

FDA.  Q2B Validation of Analytical Procedures: Methodology. May 1977.

FDA. Q2A Text on Validation of Analytical Procedures. March, 1995.

FDA. Reviewer Guidance — Validation of Chromatographic Methods,
November 1994.

FDA.  21 CFR Part 11; Electronic Records; Electronic Signatures. FR
Notice 7/21/99 (64 FR 39146).

U.S. Pharmacopeia. <1> Injections. USP 26, NF 21, 2003.

U.S. Pharmacopeia. <71> Sterility Tests. USP  26, NF 21, 2003.

U.S. Pharmacopeia. <85> Bacterial Endotoxins Test. USP 26, NF 21, 2003. 

U.S. Pharmacopeia. <621> Chromatography. USP 26, NF 21, 2003.

U.S. Pharmacopeia. <821> Radioactivity.  USP 26, NF 21, 2003.

U.S. Pharmacopeia. <823> Radiopharmaceuticals for Positron Emission
Tomography-Compounding. USP 26, NF 21, 2003.

U.S. Pharmacopeia.  <1015> Automated Radiochemical Synthesis Apparatus.
USP 26, NF 21, 2003.

U.S. Pharmacopeia. <1225> Validation of Compendial Methods. USP 26, NF
21, 2003.

 This guidance has been prepared by the PET Steering Committee in the
Center for Drug Evaluation and Research (CDER) at the Food and Drug
Administration (FDA).

 See FDA's Web site at www.fda.gov/cder/fdama/212draft.htm and notice of
availability, 64 FR 51274; September 22, 1999.

 See FDA’s Web site at www.fda.gov/cder/fdama/cgmpdpr.pdf and notice
of availability, 67 FR 15344; April 1, 2002.

 See FDA’s Web site at www.fda.gov/guidance/4259dft.htm and notice of
availability, 67 FR 15404; April 1, 2002.

 A sample format for record keeping of incoming components is available
at www.fda.gov/cder/regulatory/pet.

 The draft guidance for industry PET Drug Applications — Content and
Format for NDAs and ANDAs, which was issued in March 2000, will be
available soon in final.  Also, a sample format for a batch production
and control record is available at www.fda.gov/cder/regulatory/pet. 

 This draft guidance was issued in February 2003.  Once finalized, it
will represent the Agency's thinking on this topic. 

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