Exhibit 10.17

 

Execution Copy

 

DEVELOPMENT AND MANUFACTURING SERVICES AGREEMENT

 

THIS DEVELOPMENT AND MANUFACTURING SERVICES AGREEMENT is made and entered into
as of October 16, 2007 (the “Effective Date”) by and between RADIUS
HEALTH, INC., a Delaware corporation having an address at 300 Technology Square,
5th Floor, Cambridge, MA 02139 (together with its Affiliates, “RADIUS”) and
LONZA Sales Ltd, a Swiss company having an address at Muenchensteinerstrasse 38,
CH-4002 Basel, Switzerland (together with its Affiliates, “Manufacturer”).

 

RECITALS:

 

WHEREAS, RADIUS desires to engage Manufacturer to perform certain Development or
Manufacturing Services (as those terms are defined below), on the terms and
conditions set forth below, and Manufacturer desires to perform such Services
for RADIUS.

 

AGREEMENT:

 

NOW, THEREFORE, in consideration of the foregoing premises and the mutual
covenants of the parties set forth in this Agreement, the parties hereto agree
as follows:

 

1.             Definitions.  Unless this Agreement expressly provides to the
contrary, the following terms, whether used in the singular or plural, have the
respective meanings set forth below:

 

1.1          “Affiliate” means, with respect to a party, any person or entity
which controls, is controlled by or is under common control with such party.  As
used in this Section, “control”  means (a) in the case of corporate entities,
direct or indirect ownership of at least fifty percent (50%) of the stock or
shares having the right to vote for the election of directors, and (b) in the
case of non-corporate entities, the direct or indirect power to manage, direct
or cause the direction of the management and policies of the non-corporate
entity or the power to elect at least fifty percent (50%) of the members of the
governing body of such non-corporate entity.

 

1.2          “Agreement” means this Development and Manufacturing Services
Agreement, together with all Appendices attached hereto, as amended from time to
time by the parties in accordance with Section 15.6, and all fully signed Work
Orders entered into by the parties.

 

1.3          “API/Drug Substance”  means the active pharmaceutical ingredient
identified on the applicable Work Order or any intermediate of such active
pharmaceutical ingredient.

 

1.4          “Applicable Law” means all applicable ordinances, rules,
regulations, laws, guidelines, guidances, requirements and court orders of any
kind whatsoever of any Authority, as amended from time to time, including
without limitation, cGMP (if applicable).

 

1.5          “Authority” means any government regulatory authority responsible
for granting approvals for the performance of Services under this Agreement or
for issuing regulations

 

CONFIDENTIAL

 

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pertaining to the Manufacture and/or use of Product in the intended country of
use, including, without limitation, the FDA.

 

1.6          “Batch” means a specific quantity of Product that is intended to be
of uniform character and quality, within specified limits, and is produced
during the same cycle of Manufacture as defined by the applicable Batch Record.

 

1.7          “Batch Documentation” has the meaning set forth in Section 6.2.

 

1.8          “Certificate of Analysis” means a document, signed by an authorized
representative of Manufacturer, describing Specifications for, and testing
methods applied to, Product, and the results thereof.

 

1.9          “Certificate of Compliance” means a document, signed by an
authorized representative of Manufacturer, certifying that a particular Batch
was Manufactured in accordance with cGMP (if applicable), all other Applicable
Law, and the Specifications.

 

1.10        “cGMP” means current good manufacturing practices applicable to the
Manufacture of Product promulgated by any Authority.

 

1.11        “Change Order” has the meaning set forth in Section 5.3.

 

1.12        “Confidential Information”  has the meaning set forth in Section 10.

 

1.13        “Develop” or “Development” means the studies and other activities
conducted by Manufacturer under this Agreement to develop all or any part of a
Manufacturing Process including, without limitation, analytical tests and
methods, formulations and dosage forms.

 

1.14        “Equipment” means any equipment or machinery used by Manufacturer in
the Development and/or Manufacturing of Product, or the holding, processing,
testing, or release of Product.

 

1.15        “Facility” means the facilities of Manufacturer’s Affiliate Lonza
S.A., Chausée de Tubize 297, B-1420 Braine l’Alleud, Belgium, unless otherwise
identified in the applicable Work Order.

 

1.16        “FDA” means the United States Food and Drug Administration, and any
successor agency having substantially the same functions.

 

1.17        “FDCA” means the United States Federal Food, Drug and Cosmetic Act,
21 U.S.C.  §321 et seq., as amended from time to time.

 

1.18        “force majeure” has the meaning set forth in Section 15.3.

 

1.19        “Improvements” means all Technology and discoveries, inventions,
developments, modifications, innovations, updates, enhancements, improvements,
writings or rights (whether or not protectable under patent, trademark,
copyright or similar laws) that are

 

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conceived, discovered, invented, developed, created, made or reduced to practice
in the performance of Services under this Agreement.

 

1.20        “IND” means an Investigational New Drug application filed with the
FDA in accordance with Applicable Law.

 

1.21        “Manufacture” and “Manufacturing” means any steps, processes and
activities necessary to produce Product, including without limitation, the
manufacturing, processing, packaging, labeling, quality control testing,
release, storage or supply of Product.

 

1.22        “Manufacturer Indemnitee” has the meaning set forth in Section 12.2.

 

1.23        “Manufacturer Technology” means the Technology of Manufacturer
(a) existing prior to the Effective Date, or (b) developed or obtained by or on
behalf of Manufacturer independent of this Agreement and without reliance upon
Confidential Information of RADIUS.

 

1.24        “Manufacturing Process” means any and all processes (or any step in
any process) used or planned to be used by Manufacturer to Manufacture Product,
consistent with the relevant Work Order and as evidenced in the Batch
Documentation or master Batch Documentation.

 

1.25        “Product” means any API/Drug Substance or drug product comprised of
API/Drug Substance, and any intermediates of the foregoing, in each case as
specified in the applicable Work Order, including, if applicable, bulk packaging
and/or labeling as provided in such Work Order.

 

1.26        “Quality Agreement” has the meaning set forth in Section 2.2.

 

1.27        “RADIUS Indemnitee” has the meaning set forth in Section 12.1.

 

1.28        “RADIUS Equipment” means the Equipment, if any, identified on the
applicable Work Order as being provided by RADIUS or purchased or otherwise
acquired by Manufacturer at RADIUS’ expense.

 

1.29        “RADIUS Materials” means the materials, and any intermediates or
derivatives thereof, identified in the applicable Work Order as being provided
by RADIUS including labels (if any) for Product.

 

1.30        “RADIUS Technology” means (a) RADIUS Materials, (b) Product and any
intermediates or derivatives thereof, (c) Specifications, and (d) the Technology
of RADIUS owned, developed or obtained by or on behalf of RADIUS prior to the
Effective Date, or developed or obtained by or on behalf of RADIUS independent
of this Agreement and without reliance upon the Confidential Information and
Technology of Manufacturer.

 

1.31        “Records” has the meaning set forth in Section 5.4(a).

 

1.32        “Representative” has the meaning set forth in Section 3.1.

 

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1.33        “Reprocess” and “Reprocessing” means introducing a Product back into
the process and repeating appropriate manipulation steps that are part of the
established Manufacturing Process.  Continuation of a process step after an
in-process control test show the process to be incomplete is not considered
reprocessing.

 

1.34        “Rework” and “Reworking” means subjecting a Product to one or more
processing steps that are different from the established Manufacturing Process.

 

1.35        “Services” means the Development, Manufacturing and/or other
services described in a Work Order entered into by the parties.

 

1.36        “Specifications” means the list of tests, references to any
analytical procedures and appropriate acceptance criteria which are numerical
limits, ranges or other criteria for tests described in order to establish a set
of criteria to which Product at any stage of Manufacture should conform to be
considered acceptable for its intended use that are provided by or approved by
RADIUS, as such specifications are amended or supplemented from time to time by
RADIUS in writing.

 

1.37        “Technology” means all methods, techniques, trade secrets,
copyrights, know-how, data, documentation, regulatory submissions,
specifications and other intellectual property of any kind (whether or not
protectable under patent, trademark, copyright or similar laws).

 

1.38        “Work Order” means a written work order, substantially in the form
attached hereto as Appendix A, for the performance of Services by Manufacturer
under this Agreement.

 

2.             Engagement of Manufacturer.

 

2.1          Services and Work Orders.  From time to time, RADIUS may wish to
engage Manufacturer to perform Services for RADIUS.  Such Services will be set
forth in a Work Order.  Each Work Order will be appended to this Agreement and
will set forth the material terms for the project, and may include the scope of
work, specified Services, Specifications, deliverables, estimated timelines,
milestones (if any), quantity, budget, payment schedule and such other details
and special arrangements as are agreed to by the parties with respect to the
activities to be performed under such Work Order.  No Work Order will be
effective unless and until it has been agreed to and signed by authorized
representatives of both parties.  Documents relating to the relevant project,
including without limitation Specifications, proposals, quotations and any other
relevant documentation, will be attachments to the applicable Work Order and
incorporated in the Work Order by reference.  Each fully signed Work Order will
be subject to the terms of this Agreement and will be incorporated herein and
form part of this Agreement.  Manufacturer will perform the Services specified
in each fully signed Work Order, as amended by any applicable Change Order(s),
and in accordance with the terms and conditions of such Work Order and this
Agreement.  Notwithstanding the foregoing, nothing in this Agreement will
obligate either party to enter into any Work Order under this Agreement.

 

2.2          Quality Agreement.  If appropriate or if required by Applicable
Law, the parties will also agree upon a Quality Agreement containing quality
assurance provisions for the Manufacture of Product (“Quality Agreement”), which
agreement will also be attached to the applicable Work Order and incorporated by
reference in the Work Order.

 

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2.3          Conflict Between Documents.  If there is any conflict, discrepancy,
or inconsistency between the terms of this Agreement and any Work Order, Quality
Agreement, purchase order, or other form used by the parties, the terms of this
Agreement will control.

 

3.             Project Performance.

 

3.1          Representatives.  Each party will appoint a representative having
primary responsibility for day-to-day interactions with the other party for the
Services (each, a “Representative”), who will be identified in the applicable
Work Order.  Each party may change its Representative by providing written
notice to the other party in accordance with Section 15.3; provided that
Manufacturer will use reasonable efforts to provide RADIUS with at least
forty-five (45) days prior written notice of any change in its Representative
for the Services.  Except for notices or communications required or permitted
under this Agreement, which will be subject to Section 15.3, or unless otherwise
mutually agreed by the parties in writing, all communications between
Manufacturer and RADIUS regarding the conduct of the Services pursuant to such
Work Order will be addressed to or routed directly through the parties’
respective Representatives.

 

3.2          Communications.  The parties will hold project team meetings via
teleconference or in person, on a periodic basis as agreed upon by the
Representatives.  Manufacturer will make written reports to RADIUS as specified
in the applicable Work Order.

 

3.3          Subcontracting.  Manufacturer may not subcontract with any third
party to perform any of its obligations under this Agreement without the prior
written consent of RADIUS.  Manufacturer will be solely responsible for the
performance of any permitted subcontractor, and for costs, expenses, damages, or
losses of any nature arising out of such performance as if such performance had
been provided by Manufacturer itself under this Agreement.  Manufacturer will
cause any such permitted subcontractor to be bound by, and to comply with, the
terms of this Agreement, as applicable, including without limitation, all
confidentiality, quality assurance, regulatory and other obligations and
requirements of Manufacturer set forth in this Agreement.

 

3.4          Duty to Notify.  If Manufacturer, at any time during the term of
this Agreement, has reason to believe that it will be unable to perform or
complete the Services, Manufacturer will promptly notify RADIUS thereof. 
Compliance by Manufacturer with this Section 3.4 will not relieve Manufacturer
of any other obligation or liability under this Agreement.

 

4.             Materials and Equipment.

 

4.1          Supply of Materials.  Unless the parties otherwise agree in a Work
Order, Manufacturer will supply, in accordance with the relevant approved raw
material specifications, all materials to be used by Manufacturer in the
performance of Services under a Work Order other than the RADIUS Materials
specified in such Work Order.  RADIUS or its designees will provide Manufacturer
with the RADIUS Materials.  Manufacturer agrees (a) to account for all RADIUS
Materials, (b) not to provide RADIUS Materials to any third party without the
express prior written consent of RADIUS, (c) not to use RADIUS Materials for any
purpose other than

 

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conducting the Services, including, without limitation, not to analyze,
characterize, modify or reverse engineer any RADIUS Materials or take any action
to determine the structure or composition of any RADIUS Materials unless
required pursuant to a signed Work Order, and (d) to destroy or return to RADIUS
all unused quantities of RADIUS Materials according to RADIUS’ written
directions.

 

4.2          Ownership of Materials.  RADIUS will at all times retain title to
and ownership of the RADIUS Materials, Product, any intermediates (and
components thereof), and any work in process at each and every stage of the
Manufacturing Process.  Manufacturer will provide within the Facility an area or
areas where the RADIUS Materials, Product, any intermediates (and components
thereof), and any work in process are segregated and stored in accordance with
the Specifications and cGMP (if applicable), and in such a way as to be able at
all times to clearly distinguish such materials from products and materials
belonging to Manufacturer, or held by it for a third party’s account. 
Manufacturer will at all times take such measures as are required to protect the
RADIUS Materials, Product, any intermediates (and components thereof), and any
work in process from risk of loss or damage at all stages of the Manufacturing
Process.  Manufacturer will ensure that RADIUS Materials, Product, any
intermediates (and components thereof), and any work in process are free and
clear of any liens or encumbrances.  Manufacturer will immediately notify RADIUS
if at any time it believes any Product or RADIUS Materials have been damaged,
lost or stolen.

 

4.3          Supply of Equipment.  Unless otherwise agreed in a Work Order,
Manufacturer will supply all Equipment necessary to perform the Services.

 

5.             Development and Manufacture of Product.

 

5.1          Resources; Applicable Law.  Manufacturer will comply with all
Applicable Law in performing Services.

 

5.2          Facility.

 

(a)           Performance of Services.  Manufacturer will perform all Services
at the Facility, provide all staff necessary to perform the Services in
accordance with the terms of the applicable Work Order and this Agreement, and
hold at such Facility all Equipment, RADIUS Equipment, RADIUS Materials and
other items used in the Services.  Manufacturer will not change the location of
such Facility or use any additional facility for the performance of Services
under this Agreement without at least ninety (90) days prior written notice to,
and prior written consent from, RADIUS, which consent will not be unreasonably
withheld or delayed (it being understood and agreed that RADIUS may withhold
consent pending satisfactory completion of a quality assurance audit and/or
regulatory impact assessment of the new location or additional facility, as the
case may be).  Manufacturer will maintain, at its own expense, the Facility and
all Equipment required for the Manufacture of Product in a state of repair and
operating efficiency consistent with the requirements of the cGMP (if
applicable) and all Applicable Law.

 

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(b)           Validation.  Manufacturer will be responsible for performing all
validation of the Facility, Equipment and cleaning and maintenance processes
employed in the Manufacturing Process in accordance with cGMP, Manufacturer’s
internal SOPs, the applicable Quality Agreement, Applicable Law, and in
accordance with any other reasonable validation procedures established by RADIUS
and made known in writing to Manufacturer.  Manufacturer will also be
responsible for ensuring that all such validated processes are carried out in
accordance with their terms.

 

(c)           Licenses and Permits.  Manufacturer will be responsible for
obtaining, at its expense, any Facility or other licenses or permits, and any
regulatory and government approvals necessary for the performance of Services by
Manufacturer under this Agreement.  At RADIUS’ request, Manufacturer will
provide RADIUS with reasonable copies of all such approvals and submissions to
Authorities, and RADIUS will have the right to use any and all information
contained in such approvals or submissions in connection with regulatory
approval and/or commercial development of Product.

 

(d)           Access to Facility.  Upon prior notice, Manufacturer will permit
RADIUS or its duly authorized representatives, such representatives having to
enter into a reasonable separate confidentiality agreement with Manufacturer, to
reasonably observe and consult with Manufacturer during the performance of
Services under this Agreement, including without limitation the Manufacturing of
any Batch of Product.  Manufacturer also agrees that RADIUS and its duly
authorized agents, upon prior notice, will have reasonable access, during
operational hours and during active Manufacturing, to inspect the Facility and
Manufacturing Process to ascertain compliance by Manufacturer with the terms of
this Agreement, including, without limitation, inspection of (i) the Equipment
and materials used in the performance of Services, (ii) the holding facilities
for such materials and Equipment, and (iii) all Records relating to such
Services and the Facility.  RADIUS will also have the right, at its expense, to
reasonably conduct “mock” pre-approval audits upon prior notice to Manufacturer,
and Manufacturer agrees to cooperate with RADIUS in such “mock audits.”

 

5.3          Changes to Work Orders, Manufacturing Process and Specifications.

 

(a)           Changes to Work Orders.  If the scope of work of a Work Order
changes, especially the estimated timelines, then the applicable Work Order may
be amended as provided in this Section 5.3(a).  If a required modification to a
Work Order is identified by RADIUS, or by Manufacturer, the identifying party
will notify the other party in writing as soon as reasonably possible. 
Manufacturer will provide RADIUS with a change order containing a description of
the required modifications and their effect on the scope, fees and estimated
timelines specified in the Work Order (“Change Order”) and will use reasonable
efforts to do so within ten (10) business days of receiving or providing such
notice, as the case may be.  No Change Order will be effective unless and until
it has been signed by authorized representatives of both parties.  If RADIUS
does not approve such Change Order, and has not terminated the Work Order, but
requests the Work Order to be amended to take into account the modification,
then the parties will use reasonable efforts to agree on a Change Order that is
mutually acceptable.  If practicable, Manufacturer will continue to work on the
existing Work Order during any such negotiations, provided such efforts would
facilitate the completion of the work envisioned in the

 

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proposed Change Order, but will not commence work in accordance with the Change
Order until it is authorized in writing by RADIUS.

 

(b)           Process/Specifications Changes.  Any change or modification to the
Manufacturing Process or Specifications for any Product must be approved in
advance by both parties and will be made in accordance with the change control
provisions of the applicable Quality Agreement.  Any such change or modification
can result in lower or higher costs, and the parties herewith agree to enter
into good-faith negotiations concerning any such price deviation; provided,
however, that RADIUS will not be responsible for any increase in price unless
agreed in writing by RADIUS.

 

5.4          Record and Sample Retention.

 

(a)           Records.  Manufacturer will keep complete and accurate records
(including without limitation reports, accounts, notes, data, and records of all
information and results obtained from performance of Services) of all work done
by it under this Agreement, in form and substance as specified in the applicable
Work Order, the applicable Quality Agreement, and this Agreement (collectively,
the “Records”).  Manufacturer will not transfer, deliver or otherwise provide
any such Records to any party other than RADIUS, without the prior written
approval of RADIUS.  Upon prior notice, Records will be available at reasonable
times for inspection, examination and copying by or on behalf of RADIUS.  All
original Records of the Development and Manufacture of Product under this
Agreement will be retained and archived by Manufacturer in accordance with cGMP
(if applicable) and Applicable Law, but in no case for less than a period of
five (5) years following completion of the applicable Work Order.  Upon RADIUS’
request, Manufacturer will promptly provide RADIUS with copies of such Records. 
Five (5) years after completion of a Work Order, all of the aforementioned
records will be sent to RADIUS or RADIUS’ designee; provided, however, that
RADIUS may elect to have such records retained in Manufacturer’s archives for an
additional period of time at a reasonable charge to RADIUS.  For the avoidance
of doubt, RADIUS herewith takes note that certain Records are written in French
as the Facility is in Belgium.  RADIUS shall pay all costs incurred with any
translation of such Records requested by RADIUS.

 

(b)           Sample Retention.  Manufacturer will take and retain, for such
period and in such quantities as may be required by cGMP (if applicable) and the
applicable Quality Agreement, samples of Product from the Manufacturing Process
produced under this Agreement.  Further, Manufacturer will submit such samples
to RADIUS, upon RADIUS’ written request.

 

5.5          Regulatory Matters.

 

(a)           Regulatory Approvals.  RADIUS will be responsible for obtaining,
at its expense, all regulatory and governmental approvals and permits necessary
for RADIUS’ use of any Product Developed and/or Manufactured under this
Agreement, including, without limitation, IND submissions and any analogous
submissions filed with the appropriate Authority of a country other than the
United States.  Manufacturer will be responsible for providing

 

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RADIUS with all supporting data and information relating to the Development
and/or Manufacture of Product reasonably necessary for obtaining such approvals,
including, without limitation, all Records, raw data, reports, authorizations,
certificates, methodologies, Batch Documentation, raw material specifications,
SOPs, standard test methods, Certificates of Analysis, Certificates of
Compliance and other documentation in the possession or under the control of
Manufacturer relating to the Development and Manufacture of Product (or any
component thereof).

 

(b)           Regulatory Inspections.  Manufacturer will permit RADIUS or its
agents to be present and participate in any visit or inspection by any Authority
of the Facility (to the extent it relates in any way to any RADIUS Product) or
the Manufacturing Process.  Manufacturer will give as much advance notice as
possible to RADIUS of any such visit or inspection.  Manufacturer will provide
to RADIUS a copy of any report or other written communication received from such
Authority in connection with such visit or inspection, and any written
communication received from any Authority relating to any RADIUS Product, the
Facility (if it relates to or affects the Development and/or Manufacture of
Product) or the Manufacturing Process, within twenty-four (24) hours after
receipt thereof, and will consult with RADIUS before responding to each such
communication.  Manufacturer will provide RADIUS with a copy of its final
responses within five (5) business days after submission thereof.

 

5.6          Waste Disposal.  The generation, collection, storage, handling,
transportation, movement and release of hazardous materials and waste generated
in connection with the Services will be the responsibility of Manufacturer at
Manufacturer’s sole cost and expense.  Without limiting other applicable
requirements, Manufacturer will prepare, execute and maintain, as the generator
of waste, all licenses, registrations, approvals, authorizations, notices,
shipping documents and waste manifests required under Applicable Law.

 

5.7          Safety Procedures.  Manufacturer will be solely responsible for
implementing and maintaining health and safety procedures for the performance of
Services and for the handling of any materials or hazardous waste used in or
generated by the Services.  Manufacturer, in consultation with RADIUS, will
develop safety and handling procedures for API/Drug Substance and Product;
provided, however, that RADIUS will have no responsibility for Manufacturer’s
health and safety program.  Should such safety and handling procedures
materially deviate from Manufacturer’s existing health and safety program and
require additional investment on the part of Manufacturer, the parties shall
agree in writing in advance on reasonable charges to RADIUS for such procedures.

 

5.8          Technology Transfer.  If RADIUS elects to Manufacture Product, or
to have Product Manufactured by a third party, then Manufacturer will provide to
RADIUS, or its designee, all Manufacturing information, including, without
limitation, documentation, technical assistance, materials and cooperation by
appropriate employees of Manufacturer as RADIUS or its designee may reasonably
require in order to Manufacture Product.  RADIUS will compensate Manufacturer
for such assistance at the hourly-rate(s) set forth in the applicable Work
Order, or such other reasonable rate(s) as the parties may agree in writing.  If
such a move or replication of

 

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Manufacture of Product involves Manufacturer Technology incorporated into the
Manufacturing Process pursuant to the express terms of any relevant Work Order,
the parties will negotiate in good-faith in order to determine a reasonably
royalty fee or other reasonable consideration to be paid to Manufacturer by
RADIUS for the right to continue to use such Manufacturer Technology.

 

6.             Testing and Acceptance Process.

 

6.1          Testing by Manufacturer.  The Product to be Manufactured under this
Agreement will be Manufactured in accordance with cGMP, unless otherwise stated
in the Work Order, and the Manufacturing Process approved by RADIUS.  Each Batch
of Product will be sampled and tested by Manufacturer against the
Specifications, and the quality assurance department of Manufacturer will review
the records relating to the Manufacture of the Batch and will assess if the
Manufacture has taken place in compliance with cGMP (if applicable) and the
Manufacturing Process.

 

6.2          Provision of Records.  If, based upon such tests, a Batch of
Product conforms to the Specifications and was Manufactured according to cGMP
(if applicable) and the Manufacturing Process, then a Certificate of Compliance
will be completed and approved by the quality assurance department of
Manufacturer.  This Certificate of Compliance, a Certificate of Analysis and the
Specifications (collectively, the “Batch Documentation”, excluding any batch and
master batch records) for each Batch of Product will be delivered to RADIUS by a
reputable overnight courier or by registered or certified mail, postage prepaid,
return receipt required to verify delivery date.  Upon reasonable request,
Manufacturer will also deliver to RADIUS all raw data, reports, authorizations,
certificates, methodologies, raw material specifications, SOPs, standard test
methods, and other documentation in the possession or under the control of
Manufacturer relating to the Manufacture of each Batch of Product.  If RADIUS
has not received all such Batch Documentation at the time of receipt of the
Batch, RADIUS will notify Manufacturer in writing.  If RADIUS requires
additional copies of such Batch Documentation, these will be provided by
Manufacturer to RADIUS at cost.

 

(a)           Review of Batch Documentation; Acceptance.  RADIUS will review the
Batch Documentation for each Batch of Product and may test samples of the Batch
of Product against the Specifications.  For the avoidance of doubt, RADIUS
herewith takes note that certain parts of the Batch Documentation will be
written in French as the Facility is in Belgium.  RADIUS shall pay all costs
incurred with any translation of such Records requested by RADIUS.  RADIUS will
notify Manufacturer in writing of its acceptance or rejection of such Batch
within six (6) weeks of receipt of the complete Batch Documentation relating to
such Batch.  During this review period, the parties agree to respond promptly,
but in any event within ten (10) days, to any reasonable inquiry by the other
party with respect to such Batch Documentation.  RADIUS has no obligation to
accept a Batch if such Batch does not comply with the Specifications and/or was
not Manufactured in compliance with cGMP (if applicable) and the Manufacturing
Process.

 

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6.3          Disputes.  In case of any disagreement between the parties as to
whether Product conforms to the applicable Specifications or cGMP (if
applicable), the quality assurance representatives of the parties will attempt
in good faith to resolve any such disagreement and RADIUS and Manufacturer will
follow their respective SOPs to determine the conformity of the Product to the
Specifications and cGMP (if applicable).  If the foregoing discussions do not
resolve the disagreement in a reasonable time (which will not exceed thirty (30)
days), a representative sample of such Product will be submitted to an
independent testing laboratory mutually agreed upon by the parties for tests and
final determination of whether such Product conforms with such Specifications. 
The laboratory must meet cGMP (if applicable), be of recognized standing in the
industry, and consent to the appointment of such laboratory will not be
unreasonably withheld or delayed by either party.  Such laboratory will use the
test methods contained in the applicable Specifications.  The determination of
conformance by such laboratory with respect to all or part of such Product will
be final and binding on the parties.  The fees and expenses of the laboratory
incurred in making such determination will be paid by the party against whom the
determination is made.

 

6.4          Product Non-Compliance and Remedies.  If a Batch of Product fails
to conform to the Specifications due to the fault of Manufacturer or was not
Manufactured in compliance with cGMP (if applicable) and the Manufacturing
Process, then Manufacturer will, at RADIUS’ sole option:

 

(a)           refund in full the fees and expenses paid by RADIUS for such
Batch, including the costs of RADIUS Materials used in the Manufacture of such
Batch; or

 

(b)           at Manufacturer’s cost and expense, including the costs of RADIUS
Materials used in the Manufacture of such Batch, produce a new Batch of Product
as soon as reasonably possible; or

 

(c)           Rework or Reprocess the Product, at Manufacturer’s cost and
expense, so that the Batch can be deemed to have been Manufactured in compliance
with cGMP (if applicable) and the Manufacturing Process, and to conform to
Specifications.

 

Moreover, the parties will meet to discuss, evaluate and analyze the reasons for
and implications of the failure to comply with cGMP (if applicable) and/or the
Manufacturing Process and will decide whether to proceed with or to amend the
applicable Work Order, or to terminate such Work Order.

 

6.5          Disposition of Non-Conforming Product.  The ultimate disposition of
non-conforming Product will be the responsibility of RADIUS’ quality assurance
department and RADIUS’ expense.

 

7.             Shipping and Delivery.

 

7.1          Shipping; Delivery.  Manufacturer agrees not to ship Product to
RADIUS or its designee until it has received a written approval to ship from
RADIUS.  Manufacturer will

 

11

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ensure that each Batch will be delivered to RADIUS’ designee, (a) on the
estimated delivery date and to the destination designated by RADIUS in writing,
and (b) in accordance with the instructions for shipping given to Manufacturer
by RADIUS and packaging specified by RADIUS in the applicable Work Order or as
otherwise agreed to by the parties in writing.  Delivery terms will be FCA the
Facility (Incoterms 2000).  A bill of lading will be furnished to RADIUS with
respect to each shipment.  For the avoidance of doubt, RADIUS will reimburse
Manufacturer for any packaging materials that are outside of the packaging
normally used by Manufacturer for like products as the Product.

 

8.             Price and Payments.

 

8.1          Price.  The price of Product and/or the fees for the performance of
Services will be set forth in the applicable Work Order.

 

8.2          Invoice.  Upon performance of Services and/or release of Batch(es),
such release to be conducted exclusively by Manufacturer, Manufacturer will
invoice RADIUS according to the payment schedule in the applicable Work Order. 
Payment of undisputed invoices will be due thirty (30) days after date of
Manufacturer’s invoice.  Any undisputed invoices that remain unpaid by RADIUS
after the aforementioned timeframe shall be subject to a late payment charge of
1% (one percent) per calendar month for each full calendar month that the
payment remains outstanding in Manufacturer’s accounts.

 

8.3          Payments.  RADIUS will make all payments pursuant to this Agreement
by check or wire transfer to a bank account designated in writing by
Manufacturer.  All payments under this Agreement will be made in Euros (EUR).

 

8.4          Financial Records.  Manufacturer will keep accurate records of all
Services performed and invoice calculations, and, upon the request of RADIUS,
will permit an independent accountant appointed by RADIUS to examine such
records upon prior notice and during normal business hours for the purpose of
verifying the correctness of all such calculations.

 

8.5          Taxes.  Duty, sales, use or excise taxes imposed by any
governmental entity that apply to the provision of Services will be borne by
RADIUS (other than taxes based upon the income of Manufacturer).

 

9.             Intellectual Property Rights.

 

9.1          RADIUS Technology.  All rights to and interests in RADIUS
Technology will remain solely in RADIUS and no right or interest therein is
transferred or granted to Manufacturer.  Manufacturer acknowledges and agrees
that it does not acquire a license or any other right to RADIUS Technology
except for the limited purpose of carrying out its duties and obligations under
this Agreement and that such limited, non-exclusive, license will expire upon
the completion of such duties and obligations or the termination or expiration
of this Agreement, whichever is the first to occur.

 

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9.2          Manufacturer Technology.  All rights to and interests in
Manufacturer Technology will remain solely in Manufacturer and no right or
interest therein is transferred or granted to RADIUS.  RADIUS acknowledges and
agrees that it will not acquire a license or any other right to Manufacturer
Technology except as otherwise set forth in this Agreement.  If RADIUS wishes to
move or replicate the Manufacture of Product, where the relevant Manufacturing
Process involves Manufacturer Technology incorporated into the Manufacturing
Process pursuant to the express terms of any relevant Work Order, the parties
will negotiate in good-faith in order to determine a reasonably royalty fee or
other reasonable consideration to be paid to Manufacturer by RADIUS for the
right to continue to use such Manufacturer Technology.

 

9.3          Improvements.  Manufacturer agrees that all Improvements will be
the sole and exclusive property of RADIUS and are hereby assigned to RADIUS (or
its designee) without additional compensation to Manufacturer.  Manufacturer
will take such steps as RADIUS may reasonably request (at RADIUS’ expense) to
vest in RADIUS (or its designee) ownership of the Improvements.

 

9.4          Non-Exclusive License.  RADIUS agrees to grant to Manufacturer a
non-exclusive, perpetual, fully paid-up, worldwide license, with the right to
sub-license, to use Improvements that relate solely to Manufacturer Technology
or the Confidential Information of Manufacturer, in the manufacture of products
that do not contain an API/Drug Substance or derivative that is the subject of a
Work Order under this Agreement or that use other Confidential Information of
RADIUS.

 

9.5          Patent Filings.  RADIUS will have the exclusive right and option,
but not the obligation, to prepare, file, prosecute, maintain and defend at its
sole expense, any patents that claim and/or cover the Improvements.  If RADIUS
declines to file and prosecute any patent applications, or maintain any patents,
relating to Improvements, it will give Manufacturer reasonable notice to this
effect and, thereafter, Manufacturer may, upon written notice to RADIUS, file
and prosecute such patent applications and/or maintain such patents, in the name
of RADIUS and at Manufacturer’s sole expense.

 

10.          Confidentiality.

 

10.1        Definition.  As used in this Agreement, “Confidential Information” 
means any scientific, technical, trade or business information which is given by
one party to the other under this Agreement or any confidentiality agreement
entered into in contemplation of this Agreement and which is treated by the
disclosing party as confidential or proprietary, or which is developed by one
party for the other under the terms of this Agreement.  The disclosing party
will, to the extent practical, use reasonable efforts to label or identify as
confidential, at the time of disclosure all such Confidential Information that
is disclosed in writing or other tangible form.  Confidential Information of
Manufacturer includes, but is not limited to, Manufacturer Technology, whether
or not labeled confidential.  Confidential Information of RADIUS includes, but
is not limited to, RADIUS Technology and Improvements, whether or not labeled
confidential.

 

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10.2        Obligations.  Each party agrees (a) to keep confidential the
Confidential Information of the other party, (b) not to disclose the other
party’s Confidential Information to any third party without the prior written
consent of such other party, and (c) to use such Confidential Information only
as necessary to fulfill its obligations or in the reasonable exercise of rights
granted to it under this Agreement; provided, however, that the foregoing
obligations shall not apply to Confidential Information that is (i) in
possession of the receiving party at the time of disclosure, as reasonably
demonstrated by written records and without obligation of confidentiality,
(ii) later becomes part of the public domain through no fault of the receiving
party, (iii) received by the receiving party from a third party without
obligation of confidentiality, or (iv) developed independently by the receiving
party without use of, reference to, or reliance upon the disclosing party’s
Confidential Information by individuals who did not have access to Confidential
Information.  Notwithstanding the foregoing, a party may disclose
(y) Confidential Information of the other party to its Affiliates, and to its
and their directors, employees, consultants, and agents in each case who have a
specific need to know such Confidential Information and who are bound by a like
obligation of confidentiality and restriction on use, and (z) Confidential
Information of the other party to the extent such disclosure is required to
comply with Applicable Law or the rules of any stock exchange or listing entity,
or to defend or prosecute litigation; provided, however, that the receiving
party provides prior written notice of such disclosure to the disclosing party
and takes reasonable and lawful actions to avoid or minimize the degree of such
disclosure.  Moreover, RADIUS may disclose Confidential Information of
Manufacturer relating to the Development and/or Manufacture of Product to
entities with whom RADIUS has (or may have) a marketing and/or development
collaboration or to bona fide actual or prospective underwriters, investors,
lenders or other financing sources or to potential acquirors of the business to
which this Agreement relates, and who in each case have a specific need to know
such Confidential Information and who are bound by a like obligation of
confidentiality and restrictions on use.

 

10.3        Public Statements.  Except to the extent required by Applicable Law
or the rules of any stock exchange or listing entity, neither party will make
any public statements or releases concerning this Agreement or the transactions
contemplated by this Agreement, or use the other party’s name in any form of
advertising, promotion or publicity, without obtaining the prior written consent
of the other party, which consent will not be unreasonably withheld or delayed.

 

11.          Representations and Warranties.

 

11.1        Manufacturer’s Representations and Warranties.  Manufacturer
represents and warrants to RADIUS that:

 

(a)           it has the full power and right to enter into this Agreement and
that there are no outstanding agreements, assignments, licenses, encumbrances or
rights of any kind held by other parties, private or public, inconsistent with
the provisions of this Agreement;

 

(b)           the Services will be performed with requisite care, skill and
diligence, in accordance with Applicable Law and industry standards, and by
individuals who are appropriately trained and qualified;

 

14

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(c)           to the best of its knowledge, the Services will not infringe the
intellectual property rights of any third party and it will promptly notify
RADIUS in writing should it become aware of any claims asserting such
infringement;

 

(d)           at the time of delivery to RADIUS, the Product Manufactured under
this Agreement (i) will have been Manufactured in accordance with cGMP (if
applicable) and all other Applicable Law, the Manufacturing Process, the
applicable Quality Agreement, and Specifications, and (ii) will not be
adulterated or misbranded under the FDCA or other Applicable Law; and

 

(e)           it has not been debarred, nor is it subject to a pending
debarment, and that it will not use in any capacity in connection with the
Services any person who has been debarred pursuant to section 306 of the FDCA,
21 U.S.C.  § 335a, or who is the subject of a conviction described in such
section.  Manufacturer agrees to notify RADIUS in writing immediately if
Manufacturer or any person who is performing Services is debarred or is the
subject of a conviction described in section 306, or if any action, suit, claim,
investigation, or proceeding is pending, or to the best of Manufacturer’s
knowledge, is threatened, relating to the debarment or conviction of
Manufacturer or any person performing Services.

 

11.2        RADIUS Representations and Warranties.  RADIUS represents and
warrants to Manufacturer that:

 

(a)           it has the full power and right to enter into this Agreement and
that there are no outstanding agreements, assignments, licenses, encumbrances or
rights held by other parties, private or public, inconsistent with the
provisions of this Agreement, and

 

(b)           to the best of its knowledge, the use of RADIUS Technology as
contemplated in the Services will not infringe the intellectual property rights
of any third party and that it will promptly notify Manufacturer in writing
should it become aware of any claims asserting such infringement.

 

11.3        Disclaimer of Other Representations and Warranties.  EXCEPT AS
EXPRESSLY SET FORTH IN THIS AGREEMENT, NEITHER PARTY MAKES ANY REPRESENTATIONS
OR EXTENDS ANY WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING, BUT
NOT LIMITED TO, WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE,
OR NON-INFRINGEMENT.

 

12.          Indemnification.

 

12.1        Indemnification by Manufacturer.  Manufacturer will indemnify,
defend and hold harmless RADIUS, its Affiliates and their respective officers,
directors, employees and agents (each a “RADIUS Indemnitee”) from and against
any and all losses, damages, liabilities or expenses (including reasonable
attorneys fees and other costs of defense) (collectively, “Losses”)  in
connection with any and all actions, suits, claims or demands that may be
brought or instituted against any RADIUS Indemnitee by any third party based on,
arising out of, or resulting from, any (a) breach by Manufacturer of its
representations, warranties or covenants under this

 

15

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Agreement, or (b) negligent act or omission or the willful misconduct of any
Manufacturer Indemnitees in performing obligations under this Agreement.

 

12.2        Indemnification by RADIUS.  RADIUS will indemnify, defend and hold
harmless Manufacturer, its Affiliates and their respective officers, directors,
employees and agents (each a “Manufacturer Indemnitee”) from and against any and
all Losses in connection with any and all actions, suits, claims or demands that
may be brought or instituted against any Manufacturer Indemnitee by any third
party based on, or arising out of, or resulting from (a) the use of the Product,
except to the extent that such Losses are within the scope of the
indemnification obligation of Manufacturer under Section 12.1, (b) any breach by
RADIUS of its representations, warranties or covenants under this Agreement, or
(c) any negligent act or omission or the willful misconduct of any RADIUS
Indemnitees in performing obligations under this Agreement.

 

12.3        Procedures.  Each party agrees to notify the other party within
thirty (30) days of receipt of any claims made for which the other party might
be liable under Section 12.1 or 12.2, as the case may be.  Subject to
Section 12.4, the indemnifying party will have the right to defend, negotiate,
and settle such claims.  The party seeking indemnification will provide the
indemnifying party with such information and assistance as the indemnifying
party may reasonably request, at the expense of the indemnifying party.  The
parties understand that no insurance deductible will be credited against losses
for which a party is responsible under this Section 12.

 

12.4        Settlement.  Neither party will be responsible or bound by any
settlement of any claim or suit made without its prior written consent;
provided, however, that the indemnified party will not unreasonably withhold or
delay such consent.  If a settlement contains an absolute waiver of liability
for the indemnified party, and each party has acted in compliance with the
requirements of Section 12.3, then the indemnified party’s consent will be
deemed given.  Notwithstanding the foregoing, Manufacturer will not agree to
settle any claim on such terms or conditions as would impair RADIUS’ ability or
right to Manufacture, market, sell or otherwise use Product, or as would impair
Manufacturer’s ability, right or obligation to perform its obligations under
this Agreement.

 

12.5        Limitation of Liability.  NOTWITHSTANDING ANYTHING IN THIS AGREEMENT
TO THE CONTRARY, IN NO EVENT WILL EITHER PARTY BE LIABLE FOR ANY
SPECIAL, INCIDENTAL, CONSEQUENTIAL OR INDIRECT DAMAGES ARISING OUT OF THIS
AGREEMENT, HOWEVER CAUSED AND ON ANY THEORY OF LIABILITY.  THIS LIMITATION WILL
APPLY EVEN IF THE OTHER PARTY HAS BEEN ADVISED OF THE POSSIBILITY OF SUCH
DAMAGE; PROVIDED, HOWEVER, THAT THIS LIMITATION WILL NOT APPLY TO DAMAGES
RESULTING FROM BREACHES BY A PARTY OF ITS DUTY OF CONFIDENTIALITY AND NON-USE
IMPOSED UNDER SECTION 10 OR ITS INDEMNIFICATION OBLIGATIONS UNDER THIS
SECTION 12.

 

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13.          Insurance.

 

13.1        Manufacturer Insurance.  Manufacturer will secure and maintain in
full force and effect throughout the term of this Agreement (and for at least
five (5) years thereafter for claims made coverage), insurance with coverage and
minimum policy limits set forth as follows:

 

(a)           Comprehensive General Liability and Personal Injury, including
coverage for contractual liability assumed by Manufacturer and coverage for
Manufacturer’s independent contractor(s), with per occurrence limits of at least
One Million dollars ($1,000,000) each and a general aggregate limit of Two
Million dollars ($2,000,000);

 

(b)           Products Liability, exclusive of the coverage provided by the
Comprehensive General Liability policy, with an aggregate limit of at least Five
Million dollars ($5,000,000); and

 

(c)           “All Risk” Property, valued at replacement cost, covering loss or
damage to the Facility and RADIUS’ property and materials in the care, custody,
and control of Manufacturer.

 

13.2        Evidence of Insurance.  Upon request, Manufacturer will furnish to
RADIUS a certificate from an insurance carrier (having a minimum AM Best rating
of A) demonstrating the insurance requirements set forth above.  Thirty (30)
days prior written notice will be given to RADIUS of cancellation or any
material change in the policies.

 

13.3        Insurance Information.  Manufacturer will comply, at RADIUS’
expense, with reasonable requests for information made by RADIUS’ insurance
provider representative(s), including permitting such representative(s) to
inspect the Facility during operational hours and upon reasonable notice to
Manufacturer.  In regard to such inspections, the representative(s) will adhere
to such guidelines and policies pertaining to safety and non-disclosure as
Manufacturer may reasonably require.

 

14.          Term and Termination.

 

14.1        Term.  This Agreement will take effect as of the Effective Date and,
unless earlier terminated pursuant to this Section 14, will expire on the later
of (a) two (2) years from the Effective Date, or (b) the completion of Services
under the last Work Order executed by the parties prior to the second
anniversary of the Effective Date.  The term of this Agreement may be extended
by RADIUS continuously for additional two (2) year periods upon written notice
to Manufacturer at least thirty (30) days prior to the expiration of the then
current term.

 

14.2        Termination by RADIUS.  RADIUS will have the right, in its sole
discretion, to terminate this Agreement and/or any Work Order (a) upon thirty
(30) days prior written notice to Manufacturer, or (b) immediately upon written
notice if (i) in RADIUS’ reasonable judgment, Manufacturer is or will be unable
to perform the Services in accordance with the agreed upon timeframe and/or
budget set forth in the applicable Work Order, or (ii) Manufacturer fails to

 

17

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obtain or maintain any material governmental licenses or approvals required in
connection with the Services.

 

14.3        Termination by Either Party.  Either party will have the right to
terminate this Agreement or any signed Work Orders that are pending by written
notice to the other party, upon the occurrence of any of the following:

 

(a)           the other party files a petition in bankruptcy, or enters into an
agreement with its creditors, or applies for or consents to the appointment of a
receiver or trustee, or makes an assignment for the benefit of creditors, or
becomes subject to involuntary proceedings under any bankruptcy or insolvency
law (which proceedings remain undismissed for sixty (60) days);

 

(b)           the other party fails to start and diligently pursue the cure of a
material breach of this Agreement within thirty (30) days after receiving
written notice from the other party of such breach; or

 

(c)           a force majeure event that will, or continues to, prevent
performance (in whole or substantial part) of this Agreement or any pending Work
Order for a period of at least ninety (90) days.  In the case of a force majeure
event relating to a pending Work Order, the right to terminate will be limited
to such Work Order.

 

14.4        Effect of Termination.  Manufacturer will, upon receipt of a
termination notice from RADIUS, promptly cease performance of the applicable
Services and will take all reasonable steps to mitigate the out-of-pocket
expenses incurred in connection therewith.  In particular, Manufacturer will use
its best efforts to:

 

(a)           immediately cancel, to the greatest extent possible, any third
party obligations;

 

(b)           promptly inform RADIUS of any irrevocable commitments made in
connection with any pending Work Order(s) prior to termination;

 

(c)           promptly return to the vendor for a refund all unused, unopened
materials in Manufacturer’s possession that are related to any pending Work
Order; provided that RADIUS will have the option, but not the obligation, to
take possession of any such materials;

 

(d)           promptly inform RADIUS of the cost of any remaining unused,
unreturnable materials ordered, or work in progress pursuant to any pending Work
Order(s), and either deliver such materials to RADIUS (or its designee) or
properly dispose of them, as instructed by RADIUS, upon which Manufacturer shall
invoice RADIUS for any such associated costs; and

 

(e)           perform only those services and activities mutually agreed upon by
RADIUS and Manufacturer as being necessary or advisable in connection with the
close-out of any pending Work Order(s).

 

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14.5        Return of Materials/Confidential Information.  Upon the expiration
or termination of this Agreement, each party will promptly return all
Confidential Information of the other party that it has received pursuant to
this Agreement, provided however that Manufacturer is allowed to keep one copy
of such Confidential Information for archival purposes only.  Manufacturer will
also promptly return all RADIUS Materials, RADIUS Equipment, retained samples,
data, reports and other property, information and/or know-how in recorded form
that was provided by RADIUS, or developed in the performance of the Services,
that are owned by or licensed to RADIUS.

 

14.6        Inventories.  Upon expiration or termination of this Agreement or a
pending Work Order, RADIUS (a) will purchase from Manufacturer any existing
inventories of Product conforming to the Specifications and Manufactured in
accordance with cGMP (if applicable) and the Manufacturing Process, at the price
for such Product set forth in the applicable Work Order, and (b) may either
(i) purchase any Product in process held by Manufacturer as of the date of the
termination, at a price to be mutually agreed (it being understood that such
price will reflect, on a pro rata basis, work performed and non-cancelable
out-of-pocket expenses actually incurred by Manufacturer with respect to the
Manufacture of such in-process Product), or (ii) direct Manufacturer to dispose
of such material at RADIUS’ cost.

 

14.7        Payment Reconciliation.  Within thirty (30) days after the close-out
of a Work Order, Manufacturer will provide to RADIUS a written itemized
statement of all work performed by it in connection with the terminated Work
Order, an itemized breakdown of the costs associated with that work, and a final
invoice for that Work Order.  If RADIUS has pre-paid to Manufacturer more than
the amount in a final invoice then Manufacturer agrees to promptly refund that
money to RADIUS, or to credit the excess payment toward another existing or
future Work Order, at the election of RADIUS.

 

14.8        Survival.  Expiration or termination of this Agreement for any
reason will not relieve either party of any obligation accruing prior to such
expiration or termination or of any rights and obligations of the parties that
by their terms survive termination or expiration of this Agreement or of any
Work Order, including, without limitation, Sections 1, 2.3, 4, 5.2(c), 5.2(d),
5.4, 5.5, 5.6, 5.7, 5.8, 6, 9 through 13, 14.4, 14.5, 14.6, 14.7, 14.8 and 15,
and the provisions of the applicable Quality Agreement.

 

15.          Miscellaneous.

 

15.1        Independent Contractor.  All Services will be rendered by
Manufacturer as an independent contractor and this Agreement does not create an
employer-employee relationship between RADIUS and Manufacturer.  Manufacturer
will not in any way represent itself to be a partner or joint venturer of or
with RADIUS.

 

15.2        Force Majeure.  Except as otherwise expressly set forth in this
Agreement, neither party will have breached this Agreement for failure or delay
in fulfilling or performing any term of this Agreement when such failure or
delay is caused by or results from causes

 

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beyond the reasonable control of the affected party, including, without
limitation, fire, floods, embargoes, shortages, epidemics, quarantines, war,
acts of war (whether war be declared or not), insurrections, riots, civil
commotion, strikes, acts of God or acts, omissions, or delays in acting, by any
governmental authority (“force majeure”).  The party affected by any event of
force majeure will promptly notify the other party, explaining the nature,
details and expected duration thereof.  Such party will also notify the other
party from time to time as to when the affected party reasonably expects to
resume performance in whole or in part of its obligations under this Agreement,
and to notify the other party of the cessation of any such event.  A party
affected by an event of force majeure will use its reasonable efforts to remedy,
remove, or mitigate such event and the effects thereof with all reasonable
dispatch.  If a party anticipates that an event of force majeure may occur, such
party will notify the other party of the nature, details and expected duration
thereof.  Upon termination of the event of force majeure, the performance of any
suspended obligation or duty will promptly recommence.

 

15.3        Notices.  All notices must be written and sent to the address or
facsimile number identified below or in a subsequent notice.  All notices must
be given (a) by personal delivery, with receipt acknowledged, (b) by facsimile
followed by hard copy delivered by the methods under (c) or (d), (c) by prepaid
certified or registered mail, return receipt requested, or (d) by prepaid
recognized next business day delivery service.  Notices will be effective upon
receipt or at a later date stated in the notice.

 

If to Manufacturer, to:

Lonza Ltd

 

Legal Department

 

Muenchensteinerstrasse 38

 

CH-4002 Basel

 

Switzerland

 

 

 

Facsimile number: +41 61 316 83 14

 

 

If to RADIUS, to:

Chief Financial Officer

 

Radius Health, Inc.

 

300 Technology Square, 5th Floor

 

Cambridge, MA 02139

 

15.4        Assignment.  This Agreement may not be assigned or otherwise
transferred by either party without the prior written consent of the other
party; provided, however, that RADIUS may, without such consent, but with notice
to the Manufacturer, assign this Agreement, in whole or in part, (a) in
connection with the transfer or sale of all or substantially all of its assets
or the line of business or Product to which this Agreement relates, (b) to a
successor entity or acquirer in the event of a merger, consolidation or change
of control, (c) to any Affiliate, or (d) to any licensee of RADIUS’ rights to
the relevant Product.  Any purported assignment in violation of the preceding
sentence will be void.  Any permitted assignee will assume the rights and
obligations of its assignor under this Agreement.

 

15.5        Entire Agreement.  This Agreement, including the attached Appendices
and any fully-signed Work Orders, each of which are incorporated herein,
constitute the entire agreement between the parties with respect to the specific
subject matter hereof and all prior agreements

 

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with respect thereto are superseded.  Each party hereto confirms that it is not
relying on any representations or warranties of the other party except as
specifically set forth herein.

 

15.6        No Modification.  This Agreement and and/or any Work Order or
Quality Agreement may be changed only by a writing signed by authorized
representatives of both parties.

 

15.7        Severability; Reformation.  Each provision in this Agreement is
independent and severable from the others, and no restriction will be rendered
unenforceable because any other provision may be invalid or unenforceable in
whole or in part.  If the scope of any restrictive provision in this Agreement
is too broad to permit enforcement to its full extent, then such restriction
will be reformed to the maximum extent permitted by law.

 

15.8        Governing Law.  This Agreement will be construed and interpreted and
its performance governed by the laws of the State of New York, USA, without
regard to any choice of law principle that would dictate the application of the
law of another jurisdiction.  The application of the 1980 United Nations
Convention on Contracts for the International Sale of Goods is hereby
specifically excluded.

 

15.9        Arbitration.  Any dispute which may arise between the parties in
relation to this Agreement shall be settled amicably between the parties.  If,
contrary to expectation, no amicable settlement can be reached, both parties
hereto agree to settle the dispute by arbitration in accordance with the
rules and regulations of the International Chamber of Commerce.  The number of
arbitrators shall be three, the seat of the arbitration shall be in New York,
New York, USA and the language that the proceedings are held in shall be
English.  The decision or award rendered by the arbitrator shall be final and
non-appealable, and judgment may be entered upon it in any court of competent
jurisdiction.

 

15.10      Waiver.  No waiver of any term, provision or condition of this
Agreement in any one or more instances will be deemed to be or construed as a
further or continuing waiver of any other term, provision or condition of this
Agreement.  Any such waiver, extension or amendment will be evidenced by an
instrument in writing executed by an officer authorized to execute waivers,
extensions or amendments.

 

15.11      Counterparts.  This Agreement may be executed in any number of
counterparts, each of which will be deemed an original and all of which together
will constitute one and the same instrument.

 

15.12      Headings.  This Agreement contains headings only for convenience and
the headings do not constitute or form a part of this Agreement, and should not
be used in the construction of this Agreement.

 

15.13      No Benefit to Third Parties.  The representations, warranties,
covenants and agreements set forth in this Agreement are for the sole benefit of
the parties hereto and their successors and permitted assigns, and they will not
be construed as conferring any rights on any other persons.

 

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IN WITNESS WHEREOF, the parties hereto have caused this Agreement to be executed
by their duly authorized representatives as of the date first above written.

 

RADIUS HEALTH, INC.

LONZA SALES LTD

 

 

 

 

 

 

 

 

 

 

By:

/s/ B.N. Harvey

 

By:

/s/ Daniel Burgin / Y. Kesch

 

 

 

 

 

Print Name:

B. Nicholas Harvey

 

Print Name:

Daniel Burgin / Y. Kesch

 

 

 

 

 

Title:

CPO

 

Title:

Director Director Sales & BD / legal counsel

 

 

 

 

 

Date:

October 16, 2007

 

Date:

October 9, 2007

 

22

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

 

APPENDIX A

SAMPLE WORK ORDER

 

THIS WORK ORDER is by and between RADIUS HEALTH, INC. (“RADIUS”) and [FULL
MANUFACTURER NAME] (“Manufacturer”), and upon execution will be incorporated
into the Development and Manufacturing Services Agreement between RADIUS and
Manufacturer dated [EFFECTIVE DATE OF AGREEMENT] (the “Agreement”).  Capitalized
terms in this Work Order will have the same meanings as set forth in the
Agreement.

 

RADIUS hereby engages Manufacturer to provide Services, as follows:

 

1.             API/Drug Substance and Product.

 

Describe the specific API/Drug Substance(s) and Product(s).

 

2.             Services.  Manufacturer will render to RADIUS the following
Services:

 

Describe the specific Services to be conducted by Manufacturer (summarize) or
attach Manufacturer’s proposal.  If Manufacturer Technology is to be
incorporated in any Manufacturing Process, expressly indicate that here.

 

3.             Facilit(ies).  The Services described above will be rendered at
the Facility unless another facility of Manufacturer is indicated below:

 

Include alternate Facility address(es).

 

4.             RADIUS Materials.  RADIUS will provide to Manufacturer the
following materials to be used by Manufacturer to perform the Services:

 

Describe specific materials being provided by RADIUS to Manufacturer.

 

5.             RADIUS Equipment.

 

Include any equipment that will be provided by RADIUS to Manufacturer to be used
by Manufacturer in performance of the Services.

 

6.             Manufacturer Representative.       Name and Title

 

7.             RADIUS Representative.                  Name and Title

 

8.             Compensation.  The total compensation due Manufacturer for
Services under this Work Order is INSERT WRITTEN AMOUNT (numerical amount). 
Such compensation will be paid INSERT PAYMENT SCHEDULE OR REFERENCE PROPOSAL. 
RADIUS and Manufacturer must agree in advance of either party making any change
in compensation.  Manufacturer will invoice RADIUS to the attention of INSERT
NAME for Services rendered under this Agreement.  Manufacturer will invoice
RADIUS for all amounts due under this Work Order.  All undisputed payments will
be made by RADIUS within thirty (30) days of date of invoice.

 

23

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

 

9.             [Quality Agreement.  The provisions of the Quality Agreement,
attached hereto as Attachment 1, are incorporated herein by reference.]

 

All other terms and conditions of the Agreement will apply to this Work Order.

 

WORK ORDER AGREED TO AND ACCEPTED BY:

 

RADIUS HEALTH, INC.

 

LONZA SALES LTD

 

 

 

 

 

 

 

 

 

 

By:

 

 

By:

 

 

 

 

 

 

Print Name:

 

 

Print Name:

 

 

 

 

 

 

Title:

 

 

Title:

 

 

 

 

 

 

Date:

 

 

Date:

 

 

24

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

 

[Attachment 1]

 

 

 

Lonza

Radius - Lonza QUALITY AGREEMENT

 

Radius Health
300 Technology Square, 5th Floor
Cambridge, MA 02139 USA

 

and

 

Lonza Sales Ltd
Muenchensteinerstrasse 38
4002 Basel, Switzerland

 

1

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

 

Supplier’s & Client’s Name

 

Lonza Sales Ltd (“Supplier”) and Radius Health (“Client”) wish to define the
individual responsibilities of the parties as to the quality aspects of
manufacturing and release of Product as defined in Appendix 1 to ensure
compliance with the approved Product application and/or Client requirements.

 

In order to do so, this Quality Agreement (“Quality Agreement”) takes the form,
in part, of a detailed listing of activities associated with manufacture,
supply, production, analysis, and release of Product. Unless otherwise
indicated, responsibility for each activity is assigned to either Client,
Supplier, or is assigned to both Supplier and Client.

 

In consideration of the parties’ agreement to perform the activities provided in
this Quality Agreement and for other valuable consideration the receipt dad
sufficiency of which is hereby acknowledged, and intending to be legally bound,
Supplier and Client agree as provided in this Quality Agreement as follows:

 

2

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

 

1.                                      Effective Date

 

The Effective Date of this Quality Agreement shall be the date of last signature
(the “Effective Date”).

 

2.                                      Scope

 

The purpose of this Quality Agreement between Supplier and Client is to
formalize an agreement with regard to the quality responsibilities and
activities between companies and is based on the quality procedures in place.

 

3.                                      Other Agreements

 

This Agreement is primarily a technical agreement, not a business agreement.
Examples of some standard items excluded from this Agreement are: general
business terms and conditions, pricing and escalator clauses, forecasting,
delivery terms, confidentiality obligations, liability limitations and the
protocol for resolution of disputes; which are described in the Development and
Manufacturing Service Agreement as of 16 October 2007 (DMA). Therefore, if there
are any inconsistencies between the DMSA and the Quality Agreement, the DMSA
will take precedence over the Quality Agreement; except with respect to any
specific quality issue that may adversely Regulatory Compliance or product
quality and safety.

 

4.                                      Amendments to the Quality Agreement

 

This Quality Agreement may be amended by the written consent of both parties. 
The parties agree to amend tees of this Qualify Agreement that must be amended
in order that the Product continue to meet regulator y requirements of
applicable regulatory agencies, as may exist from time to time.

 

If an amendment to this Quality Agreement is proposed, the proposing party will
circulate the proposed amendment to the appropriate contact person at Supplier
and Client for review and internal approval. The appropriate contact person at
Supplier and Client is listed in Appendix 2 (Contacts and Responsibilities).

 

5.                                      Object of the Agreement

 

The provisions of this Agreement apply to all orders for the manufacture of drug
products or other services provided by Supplier to Client after the Effective
Date and prior to its termination in effect. This Agreement also applies to
existing orders issued by CLIENT, which have not been completed at the date of
signing.

 

6.                                      Subcontracting

 

As defined in Section 3.3 of the DMSA.

 

3

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

 

If client request the use of a specific subcontractor, the client remains fully
responsible for the quality of the materials or services provided by
subcontractors and for all commitments as agreed upon with this Quality
Agreement.

 

7.                                      Survival Clause

 

All regulatory obligations contained herein that are required of either party or
both parties by an applicable regulatory authority shall survive termination of
this Quality Agreement.

 

8.                                      Assignment

 

As defined in Section 15.4 of the DMSA.

 

9.                                      Product Specifications

 

Changes to the agreed upon specifications must be mutually agreed upon and
communicated in writing between the parties to this Quality Agreement via the
Change Control process, except for applicable compendia changes which can be
;implemented without mutual agreement. Compendia changes must be implemented by
the compendia implementation date.

 

10.                               Resolution of Quality Issues

 

Quality related disagreements between Supplier and Client that are not resolved
in the normal course of business shall be brought to the attention of the
appropriate contact person for notices at the Supplier and Client; in writing,
as listed in Appendix 2 (Contacts and Responsibilities). If both parties agree
that a resolution of the disagreement is reasonably possible, then both Supplier
and Client shall agree to work jointly to develop a strategy for such
resolution. Supplier and Client further Wee to record such resolution in
writing.

 

11.                               Debarment

 

Supplier warrants and represents that it is not debarred under the Generic Drug
Enforcement Act of 1992, 21 U.S.C. 335[a] (the “Generic Drug Enforcement Act”),
and that it has not been convicted of a crime for which it could be debarred
under the Generic Drug Enforcement Act. In connection with the Product, the
Supplier further warrants and represents, in that it shall not use in any
capacity the services of any person debarred under the Generic Drug Enforcement
Act, or convicted of a crime for which a person can be debarred under the
Generic Drug Enforcement Act.

 

12.                               Confidentiality

 

The contents of this Agreement and all information, representations,
documents, etc. received from Supplier or its Affiliates are confidential in
accordance with Section 10 of the DMSA.

 

4

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

 

13.                               Choice of Law: Jurisdiction/Miscellaneous

 

The applicable law shall be as defined in Section 15.8 of the DMSA. Any dispute
shall be resolved in according to clause 15.9 of the DMSA.

 

All appendices to this Quality Agreement are attached hereto and incorporated
herein by reference. In this Quality Agreement, unless the contrary intention
appears: (a) the words “including” and “include” mean “including, but not
limited to”;(b) the singular includes the plural and vice versa; (c) a reference
to a person or entity (including Supplier or Client) includes a reference to the
person’s executors, administrators, successors, substitutes and assigns; and
(d) headings are for reference only and do not form part of this contract.

 

14.                               Manufacturing and Testing Locations

 

Product will be manufactured and tested at the following locations: Address:

 

Lonza Braine SA

Chaussée de Tubize 297

B-1420 Braine-l’Alleud, Belgium

 

SGS Laboratoires Simon s.a.

Vieux Chemin du Poète 10

B-1301 Wavre

Belgium

 

Any additional testing locations will go through Change Control process

 

15.                               Applicable GMP Standard

 

Supplier shall manufacture all products manufactured for Client (listed in
Appendix 2) in compliance with current Good Manufacturing Practices (cGMP).

 

For the purposes of this agreement; cGMP shall mean the principles (i) described
in the ICH Q7 and FDA CFR 21 Parts 11 and 211, and (ii) promulgated by any
Governmental Authority having jurisdiction over the manufacture of all products
manufactured for Client, in the form of laws or guidance documents, where the
guidance documents are to be implemented within the pharmaceutical manufacturing
industry for such products.

 

16.                               Certificate of Analysis / Conformance

 

The following documentation is required for batches of all products manufactured
for Client shipped to or on behalf of Client:

 

·                                          Certificate of Analysis and
Conformance for each batch, issued by the independent Quality Unit

 

5

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

 

·                                          Copies of investigation reports
regarding quality incidents (Critical Deviations, OOS results, or similar), if
applicable

 

The Certificates of Analysis and Conformance shall be dated and signed by a
responsible person of Supplier’s Quality Unit, or it may be produced by a
computer system which provides a degree of control equivalent to that given by a
signature. The Certificate of Analysis states that the batch is suitable for
release, and it must include — as a minimum —

 

·                                          Supplier name and address, (original
manufacturing site),

·                                          BA058 API name and grade (if
applicable),

·                                          Supplier batch/lot number,

·                                          Reference to the agreed
specification,

·                                          Test parameters and corresponding
specification requirements,

·                                          Test results (numerical, where
applicable) for each chemical, physical or microbiological test performed,

·                                          Date of release and expiration or
retest date of the all products manufactured for Client.

 

17.                               Change Control

 

Supplier shall have a documented and effective Change Control system in place
and is required to provide advanced notification to Client of Major Changes to
the process, specifications and analytical methods (API, intermediate, and raw
materials), storage, labelling and primary packaging, which may have an in act
on the quality of all products manufactured for Client, and/or on any regulatory
applications related to all products manufactured for Client.

 

Principles:

 

·                                          All products manufactured for Client
_produced -by a new process shall not be accepted unless the process change has
first been reviewed and delivery approved by Client.

·                                          Change requests should be supported
by appropriate technical documents to support the change and to confirm that
technical performance has not been altered.

·                                          Modifications relating to
specifications of product shall be processed according to Section 9 of this
Agreements.

·                                          For those changes required to comply
with applicable laws and regulatory agency requirements, Supplier shall notify
Client of such requirements after Supplier becomes aware of the need for such
change Client shall assess any change request received from Supplier in a timely
manner. Unless there are justified scientific reasons to reject the change
request, Client will not unreasonably withhold its approval of the request.

·                                          Client is responsible for the
submission of all necessary change notifications to all competent authorities in
full compliance with the applicable regulations, respectively.

·                                          Client will inform Supplier of the
receipt of the necessary acknowledgement of the validity of the notification
and, depending on the type of change, the acceptance or approval of the change
by the competent authorities.

 

6

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

 

18.                               Right to Audit

 

Supplier shall allow Client representatives to carry out on-site audits by
appointment. Supplier shall permit all reasonable access to the manufacturing,
packaging, warehousing and laboratory areas related to the manufacture of the
BA058 API, including pertinent documentation, during normal business hours on
reasonable prior notice.

 

The results of the audit and the observation(s) shall be sent to Supplier by
means of a written report. Supplier must ensure a satisfactory follow up to the
observations made during the audit performed by Client, and take corrective
actions mutually agreed upon by the parties.

 

The frequency of the audit shall depend upon the results of the audit and the
quality performance of Supplier. In the absence of critical quality incidents
the frequency shall be not more than once per year. If quality issues arise
Client shall have the right to audit more frequently.

 

19.                               Authority Inspections

 

Supplier shall notify Client of all regulatory authority inspections that take
place at the facility where product is manufactured or the testing laboratory
where any of the associated testing is performed. If areas of concern exist
which specifically involve any products manufactured for Client, Client should
be notified prior to the inspection. In all other cases information on the
results of the inspection is appropriate. Such notification will include;

 

·                                          Written notification of any
observation, if any, that may impact the manufacture of any products
manufactured for Client

·                                          Written notification of all related
corrective actions and planned completion dates

·                                          Any further correspondence with the
regulatory authority (if the manufacture of any products manufactured for Client
is concerned)

 

20.                               Retention of samples (BA058 API)

 

Supplier will store retention samples, sufficient to perform at least two
(2) full specification analyses, in containers that are equivalent to or more
protective than the commercial packaging. Samples are to be retained for 5
years.:

 

Samples should be labelled with the following information:

 

·                                          Product name

·                                          Supplier batch/lot number

·                                          Date of manufacture

 

Supplier will make retention sample available to Client promptly upon Client’s
justified request.

 

7

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

 

21.                               Stability

 

Supplier is responsible for performing process validation stability and
commercial stability studies per ICH guidelines and Client requirements.

 

Supplier is responsible for generating stability protocols, methods and
specifications. Client is responsible for approving stability protocols, methods
and specifications.

 

Supplier will upon request or at least annually provide updated data from the
stability program to Client.

 

Supplier will inform Client if there are any adverse trends that could impact on
current retest date.

 

22.                               Complaints

 

All complaints related to any products manufactured for Client reported,
regardless of source (e.g., consumers, doctors, pharmacists, sales
representatives) will be handled by Client and communicated to Supplier.

 

Supplier is responsible for recording and investigating all quality-related
complaints on any products manufactured for Client and will maintain the
complete complaint database and complaint files.

 

Supplier will complete their investigation and respond to Client in writing to
all complaints within one month of receipt.

 

A formal written report on the complaint detailing identifiable root causes and
corrective and preventive actions where applicable shall be prepared by Supplier
and sent to Client.

 

In case the investigation could not be finalized within 20 business days,
Supplier will provide an interim report to Client.

 

Supplier is responsible for implementing a corrective action plan to correct any
deficiencies identified during an investigation.

 

Client will make relevant information and samples of the affected product
available to assist in the investigation of Supplier.

 

23.                               Recall

 

In the event that Supplier believes a recall of any products manufactured for
Client maybe necessary or appropriate, Supplier `All immediately, i.e. within
twenty-four (24) business hours, notify Client. The two parties will take joint
decisions on the disposition of product or (if applicable) final drug product
made thereof or user information, where required. Client is responsible for. the
final decision and the coordination of any recalls or field alert activities.

 

8

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

 

Supplier shall provide any information required by Client relating to recall or
field alert activities within two (2) business days of the request, if such
information is readily available at Supplier.

 

Supplier will not initiate any notifications to health authorities concerning a
(potential) nonconformance without the prior agreement of Client.

 

Supplier will collaborate, if needed, in any recall of a defective batch of any
products manufactured for Client.

 

24.                               Storage and distribution

 

Supplier shall make commercially reasonable efforts to exclude, during packaging
and storage of any products manufactured for Client, the possibility of
deterioration, contamination, or mix-ups with any other material.

 

Supplier will send a Certificate of Analysis with each shipment of product.

 

Supplier will provide an up-to-date MSDS to Client with each shipment or at
least on an annual basis.

 

25.                               BSE/TSE

 

Supplier shall provide to Client a BSE/TSE certificate for any products
manufactured for Client listed in accordance with the EMEA Note for Guidance
EMEA/410/01 (current revision). The certificate shall indicate if any products
manufactured for Client is (are) of human or animal origin, and if materials of
human or animal origin are used during the manufacturing process of any products
manufactured for Client. An updated BSE/TSE certificate must be issued after any
change to the manufacturing process which involves new raw materials or for raw
materials that have been sourced from a different Supplier.

 

26.                               Raw materials

 

Supplier shall be responsible for the purchase, storage, handling, sampling,
testing and approval or rejection of materials used in manufacturing any
products manufactured for Client pursuant to this agreement, with the exception
of any -Material supplied by Client. Supplier shall implement a vendor
qualification program for evaluating the Suppliers of critical materials, with
the only exception of materials supplied by Client. Supplier shall only purchase
materials from qualified Suppliers.

 

Supplier must utilize documented maternal inspection, plans and testing
procedures. The results of this inspection and testing must be in accordance
with specifications filed by Client. Raw materials supplied by qualified vendors
and those supplied by Client can be subject to reduced testing but a minimum ID
testing (or visual examination in case of hazardous or highly toxic raw
materials) needs to be performed for each delivery and each lot.

 

9

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

 

Supplier shall store and handle materials used in manufacturing any products
manufactured for Client pursuant to his Agreement under appropriate conditions,
consistent with cGMPs, all applicable laws, rules and regulations, and industry
standards. Client shall inform Supplier on the storage conditions of any ‘aerial
supplied to Supplier.

 

Supplier shall have all necessary and appropriate controls in place to prevent
cross-contamination of the raw materials and intermediates used in the
manufacture of any products manufactured for Client from other chemicals stored,
used, or manufactured by Supplier, including but not limited to potent hormones,
cytotoxic compounds, highly potent drugs or non-pharmaceutical chemicals.

 

27.                               Qualification / Validation

 

Equipment qualification, process validation, analytical methods validation and
validation of computerized systems, if used, are in place and covered by Change
Control. Validation documentation shall be available for review during an audit.
On request, the Client will get copies or summaries from the process validation
reports.

 

Development (Early clinical phase)

Supplier’s equipment qualification and Change Control process are in place.
Verification of analytical methods for intended use (see Note).

 

Note: in case API lots will be used for clinical phase 3 studies, or prior to
the validation campaign at the latest, the analytical methods should be
validated according to ICH Q2 (RI) guidelines.

 

28.                               Reprocessing

 

Reprocessing shall be performed according to the current regulatory dossier and
reported to Client. Reasons for reprocessing have to be investigated, and the
results shall be communicated with Client.

 

Development:

Reprocessed batches have to be reported and agreed with the Client.

 

29.                               Reworking

 

Reworking is only possible after approval by Client.  Additional stability tests
and analytical testing of reworked batches may be required.

 

Development:

Reworked batches have to be reported and approved by Client.  Reworking process
could be part of the experience through process development.

 

10

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30.                               Deviations / OOS (incl. stability)

 

Supplier must have a formal procedure for handling deviations as well as
non-conforming laboratory test results (OOS results) that is in accordance with
cGMP.

 

Supplier will notify Client promptly (target: within 3 business days) in the
event of any Critical Deviation(s). A Critical Deviation is defined as a
departure from an approved process step, process condition, test requirement, or
other relevant parameter or item that must be controlled within predetermined
criteria to ensure that the final Product meets its specification or established
standard and that has an adverse impact on the final Product quality and/or
stability and/or physical characteristics.

 

Client may participate in any investigation concerning the OOS results. Supplier
will implement any agreed actions arising out of the completed investigation
report in order to avoid the reoccurrence of similar issues in the future. In
all cases, Supplier must investigate any confirmed OOS result and forward a copy
of the completed investigation report to Client within a reasonable period of
time. The investigation report will be maintained as part of the executed batch
record.

 

For all confirmed OOS stability test results that indicate that any products
manufactured for Client has (have) failed to remain within specifications,
Supplier will notify and discuss with Client promptly (within 3 business days)
and provide the stability data. The investigation report will be maintained as
part of the stability report.

 

31.                               Labelling

 

Supplier shall comply with the requirements in ICH Q7 in relation to labelling,
in particular:

 

·                                          Labelling operations shall be
conducted to prevent mix ups,

·                                          Labels shall be checked for accuracy
before application,

 

This agreement does not absolve Supplier from complying with any legal
requirements in relation to the transportation of any products manufactured for
Client.

 

32.                               Regulatory documents

 

Upon request by, and in mutual consultation with Client, Supplier shall be
responsible for preparation of documentation on Manufacture of any products
manufactured for Client as required for the Regulatory Submissions of Client,
limited to Supplier’s activities under this agreement.

 

Client shall provide portions of Regulatory Submissions, related to any products
manufactured by Supplier for Client and Supplier’s, activities performed under
this agreement, to Supplier for review and written consent, prior to submission
to any Regulatory Authority. Client shall, upon submission to any Regulatory
Authority, provide Supplier with current copies of portions of

 

11

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Regulatory Submissions. including amendments and supplements thereto, related to
any products manufactured by Supplier for Client and Supplier’s activities
performed under this agreement.

 

Supplier will provide, in mutually agreed timelines, all other information
related to any products manufactured by Supplier for Client that Client may
reasonably request for its Regulatory Submissions, including any data for annual
reports (e.g. annual stability reports).

 

When a change is known to require, or has the potential to require a Regulatory
Submission, Supplier with Client will develop a joint strategy to secure the
appropriate regulatory approval prior to implementation of the change at
Supplier and Client. For Change Control see section 3.

 

Supplier shall be responsible for preparation of the Drug Master File related to
any products manufactured for Client and submission of such documents to any
Regulatory Authority, including maintaining such submissions (hereafter
altogether called ‘DMF’).

 

33.                               Product release

 

Supplier quality unit has the responsibility to review and approve the executed
batch production records prior to batch release. Supplier has the responsibility
to release any products manufactured by Supplier for Client for shipment to
Client.

 

At the Client’s request, the executed batch production records will be sent to
Client for review prior to batch disposition.

 

Supplier will not ship any products manufactured for Client to any destination,
as identified by Client, until the product(s) manufactured for Client is or are
released for shipment, unless prior written approval has been received from
Client to perform such a shipment under quarantine.

 

Supplier is responsible for the issuance for each batch of product manufactured
for Client a Certificate of Analysis and Certificate of Conformance (see also
section 16).

 

34.                               Reference standards

 

All reference standards should be stored in accordance with the Suppliers
recommended storage conditions and used within their given expiry or retest
date.

 

Client is responsible for the purchase and certification of the reference
standards.

 

Client shall provide to Supplier reasonable quantities of any non-compendial or
not commercially available reference standards necessary to perform the tests
included in product specifications.

 

35.                               Analytical methods

 

Analytical methods used for testing the API(s): compendial analytical methods
must be verified and all others must be validated prior to use

 

12

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Development (early clinical phase)

Supplier provides verification of analytical methods for intended use (see
Note).

Note: in case API lots will be used for clinical phase 3 studies, or prior to
the validation campaign at the latest, the analytical methods should be
validated according to ICH Q2 (R1) guidelines.

 

Any significant changes to these analytical methods must be approved by the
Client via a formal Change Control system.

 

36.                               Manufacturing

 

Supplier shall have appropriate control procedures in place to ensure that only
authorised personnel has access to Supplier’s manufacturing facilities.

 

37.                               Division of Responsibilities Table

 

§

 

Responsibilities

 

Not
Applicable

 

Client

 

Supplier

1.

 

General Provisions

 

 

 

 

 

 

1.01

 

Follow applicable current Good Manufacturing Practices (cGMPs), including
International Conference on Harmonization (ICH) Q7 Good Manufacturing Practice
Guidance for Active Pharmaceutical Ingredients (API)) and locally imposed
requirements.

 

 

 

 

 

X

1.02

 

Manufacture, package, ship, store and test the Product and materials in an
environment meeting the applicable GMP regulations, which is designed,
constructed and maintained in a manner that a) permits the operation therein to
be performed under clean, sanitary and orderly conditions; b) permits the
effective cleaning of pertinent surfaces; and c) prevents the contamination of
the Product and the addition of extraneous material to the Product.

 

 

 

 

 

X

1.03

 

Manufacture the Product in adherence to applicable regulatory submissions, such
as Drug Master File (DMF), if applicable.

 

 

 

 

 

X

1.04

 

Operate in compliance with applicable environmental,

occupational health and safety laws and regulations.

 

 

 

 

 

X

2.

 

Organization and Personnel

 

 

 

 

 

 

2.01

 

Implement procedures and/or documented training to meet obligations under this
Agreement

 

 

 

 

 

X

2.02

 

There shall be a quality control unit that shall have the responsibility and
authority to approve or reject all components, drug product containing,
closures, in-process materials, packaging material labeling, and drug products,
and the authority to review production records to assure that no errors have
occurred or if errors have occurred, that they have been full investigated.  The
quality control unit shall be responsible for approving or rejecting drug
products manufactured, processed, packed, or held under contract by another
company.

 

 

 

 

 

X

 

13

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2.03

 

The responsibilities and procedures applicable to the quality control unit shall
be in writing; such written procedures shall be followed.

 

 

 

 

 

X

2.04

 

Maintain a quality unit that is independent of production that fulfils both
quality assurance and quality control responsibilities.

 

 

 

 

 

X

2.05

 

Involve the quality unit in all quality related matters and have them review and
approve all quality critical related documents.

 

 

 

 

 

X

2.06

 

As it relates to this Quality Agreement, notify the other party of name change,
corporate reorganization, consolidation, merger or acquisition or sale of the
party’s company. Notify other party of key personnel changes.

 

 

 

 

 

X

3.

 

Facilities and Equipment

 

 

 

 

 

 

3.01

 

Ensure that facilities, equipment and systems, pertaining to the
product(s) outlined in this Agreement, are qualified and maintained compliant to
cGMP regulations.

 

 

 

 

 

X

3.02

 

Sharing information on toxicity of API and raw materials, process aids and
intermediates, if available

 

 

 

X

 

X

3.03

 

Establishing solubility of API and intermediates in cleaning agent used

 

 

 

 

 

X

3.04

 

Assessing/verifying cleanliness of used equipment

 

 

 

 

 

X

3.05

 

Releasing equipment after cleaning

 

 

 

 

 

X

4.

 

Production and In Process Controls, Packaging and Labelling

 

 

 

 

 

 

4.01

 

Procure, test as required, and release raw materials and packaging and labelling
materials used in manufacture of Product.

 

 

 

X

 

X

4.02

 

Establish and document specifications for raw materials- Product labelling and
packaging materials and other materials that would likely affect product
quality.

 

 

 

X

 

X

4.03

 

Prepare/develop master batch production records in accordance with applicable
cGMP requirements or guidelines, as applicable for lifecycle of product.

 

it

 

 

 

X

4.04

 

Review and approval of all master batch documentation.

 

 

 

 

 

X

4.05

 

Inspect, weigh and measure raw materials used for Product manufacturing and
verify critical weighing by a second individual or validated automated system.

 

 

 

 

 

X

4.06

 

Manufacture Product in ?Mariner that prevents contamination by other materials
including carryovers.

 

 

 

 

 

X

4.07

 

Provide product label to include: name and address of the manufacturer,
identifying code, batch number, quantity of contents, storage and special
transport conditions if applicable, the retest or expiry date and any special
requirements. Revise label per Change Control as necessary.

 

 

 

 

 

X

4.08

 

Review and approval of batch production records by quality unit prior to batch
release.

 

 

 

 

 

X

4.09

 

Release Product by quality unit for shipment to the client.

 

 

 

 

 

X

4.09
bis

 

Deciding on final disposition of API

 

 

 

X

 

 

4.10

 

Provide label for intermediates, samples, and waste. Revise label per SOP as
necessary.

 

 

 

 

 

X

4.11

 

Specifying packaging material for API

 

 

 

X

 

X

 

14

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

 

4.12

 

Specifying packaging material for materials before the API, if needed

 

 

 

 

 

X

4.13

 

Purchasing packaging material

 

 

 

 

 

X

5.

 

Documentation and Records

 

 

 

 

 

 

5.01

 

Have a controlled system to initiate, review, revise, approve, obsolete and
archive all Good Manufacturing Practices documentation. At a minimum, all
production, control, and distribution records should be retained for at least 1
year after the expiry date of the batch. For APIs with retest dates, records
should be retained for at least 3 years after the batch is completely
distributed.

 

 

 

 

 

X

5.02

 

Have written procedures for the review and approval of all batch documentation.

 

 

 

 

 

X

5.03

 

Maintain a document control system for specifications and test methods,
including: raw materials, Product labeling, packaging materials and other
materials that would likely affect product quality.

 

 

 

 

 

X

5.04

 

Review and approval of specifications and test methods, including: Product
labeling, packaging materials and other materials that would likely affect
product quality.

 

 

 

X

 

X

5.05

 

Provide a complete Certificate of Analysis for the Product, containing “at
minimum” the following information:

Supplier Product number

Supplier lot/batch number.

Name of Product

Name of the tests Specification limit

Expiration or retest date, if applicable

Test result (as a numerical value, unless designated

Pass/Fail in the specification limit, statistical values can be used if data
supports their use except for assays and impurity tests), including retest
results if required

Quality Assurance approval and date.

Manufacturing Site (name and address)

Manufacturing Date

 

 

 

 

 

X

5.06

 

Provide certification that the Product was manufactured in a cGMP compliant
facility and was tested in accordance with and meets specifications

 

 

 

 

 

X

5.07

 

Where applicable, electronic  signatures used on the certificate of analysis or
other controlled documents should be authenticated and secure.

 

 

 

 

 

X

5.08

 

Archiving the original documents

 

 

 

 

 

X

6.

 

Change Control

 

 

 

 

 

 

6.01

 

Have established written procedures for control of changes impacting the Product
including manufacturing components or process, computer hardware/software,
Product specifications, test methods, vendors, and subcontractors, if
applicable.

 

 

 

 

 

X

6.02

 

Notify Client within a reasonable time of intent to make Major changes that
could impact the identity, strength, safety, potency, stability, purity, or
regulatory status prior to implementation of the change.

 

 

 

 

 

X

6.03

 

Issue to Client a written evaluation of the Major Change including change
justification so that Client can determine the

 

 

 

 

 

X

 

15

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

 

 

 

impact of use of Product in Client’s finished product.

 

 

 

 

 

 

6.04

 

Have Major Changes reviewed and approved by the Supplier’s quality unit.

 

 

 

 

 

X

6.05

 

Jointly establish a strategy to secure regulatory approvals for Major Changes,
as necessary.

 

 

 

X

 

X

7.

 

Deviations

 

 

 

 

 

 

7.01

 

Have procedures for the identification, investigation, and reporting of each
departure from an approved instruction or established standard (deviations) and
Out-of-Specification (OOS) results that occur during the manufacture and testing
of the Product.

 

 

 

 

 

X

7.02

 

Document and explain all deviations. Investigate OOS results and Critical
Deviations. Extend the investigation to other lots that may have been associated
with the failure as appropriate. Include preventive actions and track these to
completion.

 

 

 

 

 

X

7.03

 

Evaluate deviations to determine their impact on the predetermined criteria that
ensure the Product meets its g- specification or applicable
validation/qualification study.

 

 

 

 

 

X

7.04

 

Issuing notifications on atypical results on stability (e.g.. 00E) to Client
within 3 business days of occurrence

 

 

 

 

 

X

7.05

 

Issuing reports on OOS, Critical Deviations, failures to Client within 3
business days of occurrence

 

 

 

 

 

X

8.

 

Reprocess and Batch Adjustments /Rework/Retest

 

 

 

 

 

 

8.01

 

Have procedures for batch adjustments and reprocessing, if applicable.
Reprocessing is defined as introducing an intermediate or API, including one
that does not conform to standards or specifications, back into the process and
repeating a crystallization step or other appropriate chemical or physical
manipulation steps (e.g. distillation, filtration, chromatography. and milling)
that are part of the manufacturing process.

 

 

 

 

 

X

8.02

 

Will not blend Out of Specification batches with other batches for the purpose
of meeting specifications.

 

 

 

 

 

X

8.03

 

Have a protocol for Product requiring rework describing the rationale and
justification for rework for approved filed rework processes, if applicable.
Rework is defined as subjecting an intermediate or API that does not conform to
standards or specifications to one or more processing steps that are different
from the established manufacturing process to obtain an acceptable quality
intermediate or API (e.g. recrystallizing with a different solvent).

 

 

 

 

 

X

8.04

 

Receive written approval by Client for rework outside of approved filed rework
processes.

 

 

 

 

 

X

8.05

 

Will not perform recovery of materials and/or solvents unless approved
procedures and specifications are in place.

 

 

 

 

 

X

9.

 

Laboratory Controls

 

 

 

 

 

 

9.01

 

Have written procedures for sample management, testing, approval, disposition,
recording, storage, retention and disposal of laboratory data.

 

 

 

 

 

X

9.02

 

Retain samples as required by regulatory agencies.

 

 

 

 

 

X

9.03

 

Have written procedures and appropriately document the preparation, use and
management of reagents, solutions, and

 

 

 

 

 

X

 

16

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

 

 

 

standards.

 

 

 

 

 

 

9.04

 

Have appropriate specifications and test procedures for the Product which are
consistent with the applicable approved  filing and/or compendia) monograph.

 

 

 

X

 

X

9.05

 

Test Product in accordance with approved validated or qualified methods and
specifications using calibrated equipment.

 

 

 

 

 

X

9.06

 

Have a program for qualification, calibration, and preventive maintenance of all
analytical equipment.

 

 

 

 

 

X

9.07

 

Responsible for analytical method development, qualification and or validation
as appropriate.

 

 

 

X

 

X

9.08

 

Responsible for transferring any developed methods to Supplier.

 

 

 

X

 

 

9.09

 

Providing development reports, test procedures, validation documents, etc and
other source documents

 

 

 

X

 

X

9.10

 

If commercially available reference standards are not’- available, reference
standards for the Product ‘will be provided.

 

 

 

X

 

X

10.

 

Storage and Distribution

 

 

 

 

 

 

10.01

 

Maintain storage facilities appropriate for conditions specified on the Product
label. Maintain records of any critical storage conditions.

 

 

 

 

 

X

10.02

 

Have systems for controlling quarantined, rejected or recalled materials.

 

 

 

 

 

X

10.03

 

Provide Material Safety Data Sheets or equivalent.

 

 

 

X

 

 

10.04

 

Notify Client in a timely manner if Supplier finds a quality issue post Supplier
release/shipment.

 

 

 

 

 

X

10.05

 

Storing API under labelled conditions

 

 

 

 

 

X

10.06

 

Qualifying of carrier

 

 

 

X

 

X

10.07

 

Preparing API for dispatch and loading of vehicles

 

 

 

 

 

X

10.08

 

Maintaining storage conditions during transportation until agreed transition
point

 

 

 

X

 

X

11.

 

Complaints

 

 

 

 

 

 

11.01

 

Have written procedures in place to document, investigate, and respond to all
quality related complaints.

 

 

 

 

 

X

11.02

 

Assist in investigations as reasonably requested by Client for complaints
associated with Product.

 

 

 

X

 

X

11.03

 

Retain complaint investigation records and evaluate trends and severity.
Implement corrective and preventive actions as necessary.

 

 

 

 

 

X

11.04

 

Implementing corrective actions, if necessary

 

 

 

 

 

X

11.05

 

Responding to external customers

 

 

 

X

 

 

11.06

 

Clarifying root cause

 

 

 

X

 

X

11.07

 

Storing or disposing returned product

 

 

 

 

 

X

12.

 

Recalls

 

 

 

 

 

 

12.01

 

In the event that either Client or Supplier determines that an event or
circumstance has occurred relating to the manufacture or stability of the
Product which may result in the need for a recall, stock recovery or market
withdrawal of Client’s finished drug product, Supplier and Client shall consult
with each other in a timely manner. The final decision to recall any of the
Client’s drug products shall be made by

 

 

 

X

 

 

 

17

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

 

 

 

Client.

 

 

 

 

 

 

12.02

 

Notification of the recall or similar action to the authorities, distributors
and customers of the finished drug product shall be made by Client

 

 

 

X

 

X

12.03

 

Supplier will have procedures in place to facilitate the recall of an API as
necessary. Supplier will provide assistance to the Client for the recall of drug
product incorporating the Supplier’s API.

 

 

 

 

 

X

13.

 

Annual Product Reviews

 

 

 

 

 

 

13.01

 

Have procedures to conduct and document annual product reviews, if applicable.

 

 

 

 

 

X

13.02

 

Allow viewing of the Annual Product Review APR) for  the Product during an
on-site audit.

 

 

 

 

 

X

14.

 

Stability

 

 

 

 

 

 

14.01

 

Maintain a documented, ongoing stability program to monitor the stability of the
Product using stability indicating procedures.

 

 

 

 

 

X

14.02

 

Data analysis and trending reporting will be performed.

 

 

 

 

 

X

14.03

 

OOS notification to Client will be provided in a timely manner.

 

 

 

 

 

X

14.04

 

Use data to confirm appropriateness of storage conditions and retest or expiry
date:,

 

 

 

 

 

X

14.05

 

Store stability samples in commercial size and/or simulated market containers
under ICH storage conditions.

 

 

 

 

 

X

14.06

 

Place the first three commercial production batches and at least one batch per
year (if a batch is produced in the year) on stability or as required by
applicable regulatory agencies.

 

 

 

 

 

X

14.07

 

Preparing stability protocols

 

 

 

 

 

X

14.08

 

Approving stability protocols

 

 

 

X

 

X

15.

 

Validation/Qualification

 

 

 

 

 

 

15.01

 

Determine according to Product lifecycle and guidance documents when process
validation is required.

 

 

 

 

 

X

15.02

 

Have a written master validation/qualification plan for the facilities,
equipment/instruments, manufacturing process, cleaning procedures, analytical
procedures, in process control tests and computerized systems as appropriate.
These to be approved by the quality unit.

 

 

 

 

 

X

15.03

 

Responsible for developing, preparing and maintaining validation documentation
approved by the quality unit, including protocols, reports and associated
documentation.

 

 

 

 

 

X

15.04

 

Qualify as necessary all critical systems and equipment used for the manufacture
and control of Product (Installation Qualification (IQ), Operational
Qualification (OQ), and/or Performance Qualification (PQ)).

 

 

 

 

 

X

15.04

 

Allow viewing of the validation documentation for the Product during an onsite
audit.

 

 

 

X

 

X

16.

 

Right to Audit

 

 

 

 

 

 

16.01

 

Client has the right to audit Supplier’s facilities and systems and review
documents as they relate to the manufacture of Product. Such inspections and
document review shall be conducted by Client at a time, date and duration
mutually agreeable to the Supplier and Client and subject to Client

 

 

 

X

 

 

 

18

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

 

 

 

signature of a separate confidentiality agreement with the Supplier entity
owning the production site.

 

 

 

 

 

 

16.02

 

Client retains the right to conduct reasonable “for cause” audits.  Specific
goals/scope of the audit, proposed dates and names of the auditors will be
agreed upon mutually by the Client and the Supplier.

 

 

 

X

 

 

16.03

 

Issue Supplier a confidential audit report summarizing audit observations within
30 days of audit.

 

 

 

X

 

 

16.04

 

Issue responses to all observations documented in the issued audit report in
writing to Client Quality Assurance within 30 days of receipt of the report.

 

 

 

 

 

X

16.05

 

Maintain internal GMP audit program.

 

 

 

X

 

X

16.06

 

Maintain external GMP audit program for Suppliers of raw materials and
components, or other suitable qualification program.

 

 

 

X

 

X

17.

 

Regulatory Inspections and Exchanges

 

 

 

 

 

 

17.01

 

Notify Client within three business days of the receipt of a Regulatory
Authority inspection report, deficiency letter or written regulatory  compliance
observation, which contains any significant adverse findings that relate to the
Product or the facilities used to produce, test or warehouse the Product sold to
Client. A significant adverse finding is herein defined as the following:
conditions, practices, or processes that adversely affect or may potentially
adversely affect product or service quality and/or the rights, safety or well
being of subjects/patients and/or the quality and integrity of data,
documentation, or other materials or information addressed in the inspection.

 

 

 

 

 

X

17.02

 

Provide copies of the inspection report, deficiency letter or written regulatory
compliance observation that relate to the Product or the facilities used to
produce, test or warehouse the Product sold to Client. This shall be edited to
exclude

Supplier or other Client’s proprietary information or a complete summary report
containing the description of the adverse finding as stated in the inspection
report, deficiency letter or regulatory compliance observation to Client by
facsimile or electronically within five (5) business days of the receipt of the
inspection report.

 

 

 

 

 

X

18.

 

Regulatory Filings and Regulatory Status

 

 

 

 

 

 

18.01

 

Responsible for submission, maintenance, approvals and updates/amendments to
regulatory filings for Product (including API DMF). Client will be notified as
per FDA or EU requirements.

 

 

 

 

 

X

18.02

 

Responsible for providing to the agencies all requested documentation/data
required for regulatory filings.

 

 

 

X

 

X

18.03

 

Responsible for communicating to the other party approvals, deficiencies or
rejections by agencies regarding submissions, amendments or updates.

 

 

 

X

 

X

18.04

 

Responsible for submission and maintenance of drug product registration and
current site registration and obtaining labeler code as required by regulatory
agencies.

 

 

 

 

 

X

18.05

 

Client shall provide Supplier with the following information regarding the use
of the product:

 

 

 

X

 

 

 

19

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

 

 

 

Clinical phase of development of the drug product that Product is used in and
any change regarding this status Intended use of the drug product in which that
Product is used Regulatory agencies with which the drug product is filed and if
Product is included in the filing.

 

 

 

 

 

 

18.06

 

Notify Supplier if Supplier will be name in any governmental filing prior to
such filing being made.

 

 

 

X

 

 

18.07

 

Coordinate the activities necessary to ensure readiness prior to Regulatory
Agency Pre-Approval Inspection (PAI).

 

 

 

X

 

X

18.08

 

Provide Letter of Authorization for Client to permit reference to Supplier
submissions in the registration of the Client’s drug product.

 

 

 

 

 

X

19.

 

Animal Derived Materials:

 

 

 

 

 

 

19.01

 

Evaluate and control the risk of Transmissible Spongiform Encephalopathy (TSE)
for raw Materials and components. Maintain appropriate records for each lot of
animal derived material to ensure traceability. Where required by local
regulations, Supplier will assure that the country of origin or slaughtering
information (either or both, which ever can be obtained from the manufacturer)
will be documented and provided to Client.

 

 

 

 

 

X

 

20

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Glossary

 

Active Pharmaceutical Ingredient (API) — Any API or mixture of APIs, intended to
be used in the manufacture of a drug (or: medicinal) product and that, when used
in the production of a drug, becomes an active ingredient of the drug product.
Such APIs are intended to furnish pharmacological activity or other direct
effect in the diagnosis, cure, mitigation, treatment or prevention of disease or
to affect the structure or any function of the body of man or animals.

 

Business day — Any day of the week, other than Saturday, Sunday, or day on which
the party required to take action is regularly closed for business, i.e., Monday
to Friday (European working hours) except any official national or regional bank
holidays or shut down of the plant.

 

CEP — A certificate issued by the European Directorate for the Quality of
Medicines which demonstrates that the Product complies with the requirements of
the European Pharmacopoeia monograph and / or Transmissible Spongiform
Encephalopathy (TSE) requirements. Also known as “CoS” = Certificate of
Suitability.

 

Certificate of Analysis — A document identified as such, provided by the
Supplier signed by its Responsible Person, or produced by a computer system
which provides a degree of control equivalent to that given by a signature,
which sets forth the analytical test results, obtained from testing of a
representative sample, against the specifications for the batch to be delivered.

 

Certificate of Conformance  — A document identified as such, provided by the
Supplier and signed by a nominated representative of its Quality Unit; or
produced by a computer system which provides a degree of control equivalent to
that given by a signature, which certifies that each batch of Product was
produced and -tested in compliance with the agreed specifications, cGMP, and the
relevant pharmacopoeial monographs, as applicable.

 

Contract — Business agreement for supply of goods or performance of work at a
specified price.

 

Contract Manufacture — Performance of some aspect of manufacture, under a
contract, on behalf of the original manufacturer.

 

Client — The company or organisation receiving the product (API or intermediate)
once it has left the control of the Supplier; includes users and distributors.

 

Critical Deviation — Departure from an approved process step, process condition,
test requirement, or other relevant parameter or item that must be controlled
within predetermined criteria to ensure that the API meets its specification or
established standard and has an adverse impact on the final Product quality
and/or stability and/or physical characteristics.

 

Distributor — Any party in the distribution/supply chain starting from the point
at which an API or intermediate is transferred outside the control of the
original manufacturer’s material management system including parties involved in
trade and distribution, such as (re)processors,

 

21

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

 

(re)packagers, transport and warehousing companies, forwarding agents, brokers,
traders, and Suppliers other than the original manufacturer.

 

DMF — Drug Master File. The Supplier’s dossier for providing confidential
information to a regulatory authority about facilities, processes, or articles
relating to product used in the manufacturing, processing, packaging, and
storing of one or more drug (or: medicinal) products.

 

GMP — Good Manufacturing Practice. Requirements for the Quality System under
which drug (or: medicinal) products and their (active) ingredients are
manufactured. Current Good Manufacturing Practice (cGMP) is the applicable term
in the United States. For the purposes of this guideline, the terms GMP and cGMP
are equivalent.

 

Immediately — Generally no more than twenty-four (24) business hours. This
period may be exceeded due to events or circumstances beyond the reasonable
control of the responsible party.

 

Laws — All laws, statutes, rules, regulations (including, without limitation,
cGMPs, NDA regulations, and other relevant provisions enforced by any applicable
governmental authority), ordinances and other pronouncements having the binding
effect of law of any governmental authority.

 

Major Changes — Changes to a process step, process condition, test requirement,
or other relevant parameter or item that must be controlled within predetermined
criteria to ensure that the API meets its specification or established standard
that could impact the identity, strength, safety, potency, stability, purity,
and/or regulatory status.

 

Manufacturing License — With respect to a country, any regulatory authorisation
required to manufacture one or more products or classes of product as granted by
the relevant governmental authority.

 

Non-conformance — Departure of a quality characteristic from its intended level
or state such as to cause an associated material or activity not to comply with
its specification, cGMP, marketing authorisation or applicable law.

 

Original Manufacturer — Person or company manufacturing a material to the stage
at which it is designated as a pharmaceutical starting material.

 

Product Quality Review — The PQR is an assessment to verify the operational
consistency of a process based on results trending and non-conformances.

 

Promptly — Generally no more than three (3) -business days. This period may be
exceeded due to events or circumstances beyond the reasonable control of the
responsible party.

 

Quality Agreement — A legally binding agreement that is mutually negotiated and
concluded between (the Quality Departments of) API manufacturers and their
customers. It is intended to define, in a formalised manner responsibilities
relative to quality tasks to assure the manufacture, supply and use of safe in
aerials acceptable for pharmaceutical use It may also include

 

22

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

 

commitments between the parties regarding (a) the provision of information,
documents, or samples, and (b) communication and notification rules including
contacts.

 

Quality Incident — An incident relating to an issue or defect which is not
necessarily detected by the specification parameters but which potentially could
result in a non-conformance. A “critical” quality incident is relating to a
defect or fault that makes a product unsuitable for use and which could
potentially result in a recall, retrieval or withdrawal.

 

Record — Document stating results obtained and/or providing evidence of
activities performed. The medium may be paper, magnetic, electronic or optical,
photography etc. or a combination thereof.

 

Responsible Person — The person(s) within the Quality Unit at the Supplier who
is accountable for the release of batches of product.

 

Sample — A part or parts of the product taken to show the quality of the whole.

 

Site — A location where the API or intermediate manufactured. This may be any
operational area within the Supplier’s facility referred to in the section
“Parties to the agreement” of the Quality Agreement (see chapter 5.2, I.1 of
this guideline), or at a remote facility that may be the facility of an
affiliate of the Supplier or a sub-contractor.

 

Sub-Contractor — A third party contractor, engaged and qualified by the Supplier
to perform any part of the Supplier’s cGMP obligations under the License, Supply
or Quality Agreements.

 

Supplier — Person or company providing APIs or intermediates on request.
Suppliers may be (original) manufacturers or distributors.

 

Supply chain — For the purpose of this guideline, supply chain is defined as all
steps in the entire chain of distribution starting from the point at which an
API or intermediate is transferred outside the control of the original
manufacturer’s material a management system downstream to the final user(s).

 

Timely manner — As soon as can be expected considering the typical operations
and processes at manufacturers, the defined responsibilities and the agreed
communication pathways. A “reasonable period of time” is considered as
practically synonymous. The exact period of time depends on the respective
subject.

 

User — A party who utilises an API in the manufacture of a drug product or an
intermediate in the manufacture of an API.

 

23

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

 

Appendices:

 

1.                                      List of Products manufactured by
Supplier for Client

 

2.                                      List of Key Contacts

 

3.                                      Product Specifications

 

4.                                      Examples of Changes that do not require
notification

 

5.                                      Examples of OOS/Critical Deviations

 

24

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

 

Appendix 1:

 

List of Products manufactured by Supplier for Client:

 

BA058 API

 

25

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

 

Appendix 2:

 

List of Key Contacts:

 

Client

 

Supplier

 

 

 

J. Guerriero

 

F. Mutterer

 

 

 

L. O’Dea

 

P. Loosen

 

26

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

 

Appendix 4:

 

Examples of Changes that Do Not Require Notification (not intended to be all
inclusive)

 

Editorial changes to procedures, batch records, or manufacturing/testing
procedures, which are of a typographical, grammatical/presentation updates or
which provide additional detail/clarity in describing an existing established
practice.

 

Environmental control changes, which do not affect the processes, product or
service (e.g., changes in sample frequency or locations)

 

Safety changes, which do not affect the process, product or services.

 

Like-for-like changes to equipment or parts. Like-for-like changes are those
that use the same replacement part from the same Supplier or parts from a
different Supplier, but which are deemed and documented by the user to be
identical in functionality and performance.

 

New procedures that are created to document an existing established practice,
provided that the new details are in accordance with the process as described in
the master batch record.

 

Routine and preventative maintenance updates that do not have an associated
change to an operating parameter.

 

27

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

 

Appendix 5:

 

Examples of Examples of OOS/ Critical Deviations that Require Notification (not
intended to be all inclusive)

 

Any manufacturing, holding, packaging, labelling, sampling or testing
OOS/deviation that may affect the quality, safety, purity, or integrity of the
product.

 

Any reprocessing, reworking or process amendments.

 

Any aberrant result, including yields and analytical test results.

 

Any physical contamination, cross-contamination, chemicalor microbiological
contamination of the product or processes.

 

Critical departures from the master batch record, validation, analytical
methods, or stability.

 

Equipment failure / calibration failure only if impact or the product quality.

 

28

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

 

Done in two (2) original copies, each party having received its copy.

 

 

Company Approval

 

It has been approved by:

 

RADIUS

 

 

Signed:

 

Date:

 

 

 

 

 

 

/s/ Nick Harvey

 

 

Dec. 13, 2010

 

Nick Harvey

 

 

 

CFO

 

 

 

 

 

 

 

 

 

 

 

Signed:

 

Date:

 

 

 

 

 

 

/s/ Louis O’Dea

 

 

Dec. 15, 2010

 

Louis O’Dea

 

 

 

CMO

 

 

 

 

 

 

 

 

 

 

LONZA

 

 

 

 

 

 

Signed:

 

Date:

 

 

 

 

 

 

/s/ Frederique Mutterer

 

 

Dec. 21, 2010

 

Frederique Mutterer

 

 

 

Head of Quality Assurance and Regulatory Affairs

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Signed:

 

Date:

 

 

 

 

 

 

/s/ Patrick Loosen

 

 

Dec. 21, 2010

 

Patrick Loosen

 

 

 

General Manager Head of Operations

 

 

 

29

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

 

AMENDMENT NO. 1

 

to

 

DEVELOPMENT AND MANUFACTURING SERVICES AGREEMENT

 

This Amendment No. 1 to the DEVELOPMENT AND MANUFACTURING SERVICES AGREEMENT is
entered into on May 19, 2011 by and between Radius Health Inc., a Delaware
Corporation, with its principal office at 201 Broadway — 6th floor, Cambridge,
MA 02139, United States of America (“RADIUS”), and LONZA Sales Ltd, a Swiss
company having an address at Muenchensteinertrasse 38, CH-4002 Basel,
Switzerland (together with its Affiliates, “Manufacturer”), and upon execution
will be incorporated into the Development and Manufacturing Services Agreement
between RADIUS and Manufacturer dated October 16, 2007 (the “Agreement”). 
Capitalized terms in this Amendment will have the same meanings as set forth in
the Agreement, as amended to date.

 

WHEREAS

 

RADIUS and Manufacturer have agreed to amend the Agreement with respect to its
term.

 

NOW, THEREFORE, IT IS AGREED AS FOLLOWS:

 

According to Article 14.1 of the Agreement, RADIUS wishes to extend the term of
the Agreement for an additional two (2) year period effective April 4, 2011.

 

All other terms and conditions of the Agreement will apply to this Amendment and
shall remain in full force and effect.

 

AMENDMENT AGREED TO AND ACCEPTED BY:

 

 

RADIUS HEALTH, INC.

 

LONZA SALES LTD

 

 

 

 

 

 

 

 

 

 

 

 

By

/s/ B.N. Harvey

 

By

/s/ John Eley

 

/s/ Oliv Brunner

Print Name

B.N. Harvey

 

Print Name

John Eley

 

Oliv Brunner

Title

CFO

 

Title

Legal Counsel

 

Legal Counsel

Date

 

 

Date

20 May 11

 

 

 

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

 

AMENDMENT NO. 2

TO

DEVELOPMENT AND MANUFACTURING SERVICES AGREEMENT

 

This Amendment No. 2 (the “Amendment”) to the DEVELOPMENT AND MANUFACTURING
SERVICES AGREEMENT is entered into on January 30, 2014 by and between Radius
Health Inc., a Delaware corporation, with its principal office at 201 Broadway —
6th floor, Cambridge, MA 02139, United States of America (“RADIUS”), and LONZA
Sales Ltd, a Swiss company having an address at Muenchensteinerstrasse 38,
CH-4002 Basel, Switzerland (together with its Affiliates, “Manufacturer”), and
upon execution will be incorporated into the Development and Manufacturing
Services Agreement between RADIUS and Manufacturer dated October 16, 2007 (the
“Original Agreement”), as amended to date.  Capitalized terms in this Amendment
will have the same meanings as set forth in the Agreement, as amended to date.

 

WHEREAS, RADIUS and Manufacturer are parties to the Original Agreement; and

 

WHEREAS, RADIUS and Manufacturer are parties to Amendment No. 1, entered into on
May 19, 2011, to the Original Agreement (such Amendment No. 1 together with the
Original Agreement, the “Agreement”); and

 

WHEREAS, the Parties desire to further amend the Agreement as set forth herein.

 

NOW THEREFORE, in consideration of the above premises and the mutual covenants
herein set forth, and for other good and valuable consideration, the receipt and
sufficiency of which are hereby acknowledged, the Parties hereto agree as
follows:

 

1.                                      Amendment to Section 14.1.  The Parties
hereby agree to extend the term of the Agreement to December 31, 2015, unless
earlier terminated pursuant to Section 14 of the Agreement.  Any further
extensions of the term shall be mutually agreed by the Parties.

 

2.                                      Ratification.  All lawful actions taken
by RADIUS and Manufacturer which are consistent with the terms of the Agreement
are hereby authorized, approved and ratified, regardless of whether any such
actions were taken prior to the date of this Amendment.

 

3.                                      Remainder of Agreement.  Except as
modified by this Amendment, all other terms and provisions of the Agreement
shall remain in full force and effect in accordance with their terms.

 

4.                                      Entire Agreement.  This Amendment and
the Agreement supersede all other prior agreements, understandings,
representations and warranties, oral or written between the parties hereto in
respect of the subject matter hereof.

 

5.                                      Governing Law; Jurisdiction.  This
Amendment shall be construed, interpreted and enforced in accordance with the
internal substantive laws of the State of New York, without reference to the
choice of law doctrine of such state.

 

1

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

 

6.                                      Counterparts; Delivery.  This Amendment
may be executed in any number of counterparts, each of which shall for all
purposes be deemed an original and all of which shall constitute the same
instrument.  Delivery of an executed signature page of this Amendment by
facsimile or other electronic transmission shall be as effective as delivery of
an original executed counterpart of this Amendment.

 

[Remainder of Page Intentionally Left Blank]

 

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

 

IN WITNESS WHEREOF, the parties hereto have caused this Amendment to be executed
by their respective authorized representatives effective as of the date first
above written.

 

 

LONZA SALES LTD

RADIUS HEALTH, INC.

 

 

 

 

 

By:

/s/ Sven Frie

 

By:

/s/ B.N. Harvey

 

 

 

 

 

Name:

Sven Frie

 

Name:

B.N. Harvey

 

 

 

 

 

Title:

Head of Business Dev.

 

Title:

CFO

 

 

 

 

 

 

 

 

 

 

By:

/s/ Nadia Zieger

 

 

 

 

 

 

 

 

Name:

Nadi Zieger

 

 

 

 

 

 

 

 

Title:

Legal Counsel

 

 

 

 

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

 

WORK ORDER NO. 2*

 

THIS WORK ORDER NO. 2 is by and between RADIUS HEALTH, INC. (“RADIUS”) and LONZA
Sales Ltd, a Swiss company having an address at Muenchensteinerstrasse 38,
CH-4002 Basel, Switzerland (together with its Affiliates, “Manufacturer”), and
upon execution will be incorporated into the Development and Manufacturing
Services Agreement between RADIUS and Manufacturer dated October 16, 2007 (the
“Agreement”).  Capitalized terms in this Work Order will have the same meanings
as set forth in the Agreement.

 

RADIUS hereby engages Manufacturer to provide Services, as follows:

 

1.             API/Drug Substance and Product.

 

BA058

 

Nomenclature:   Chemical Name: 
Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-GlyLys-Ser-IIc-GIn-Asp-Leu-Arg-Arg-GIu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2 [Glu22,25,
Leu23,28,31, Aib29, Lys26,30] hPTHrP(1-34) NH2; The active pharmaceutical
ingredient (API), BA058 API, is isolated with associated water and acetate.

 

2.             Services.  Manufacturer will render to RADIUS the following
Services:

 

Manufacturer will produce Product hereunder for use by Radius in a Phase III
clinical study.  Such work shall be performed in accordance with Exhibits A-C
plus such additional requirements as discussed below.

 

Production:  Manufacturer will perform a solid-phase-peptide-synthesis process
(SPPS) characterized by the stepwise addition of Fmoc-amino acids using Fmoc-Aas
and coupling agents, followed by cleavage I deprotection and work-up in
accordance with the “Proposal for the Manufacture of 50g and 100g, 150g and 200g
of BA058 and upgrading of analytical methods to NDA filing levels for Radius
Health, Inc.” attached hereto as Exhibit A).  Production will be performed in a
20L reactor.  Two purification steps will be performed by reverse phase HPLC,
which is followed by isolation by means of lyophilization.  The purification
will be monitored using the Manufacturer’s methods FG1 and VG1.

 

Analytical development:  As a first step, method comparability between TG1, VG1
and FG1 will be established in accordance with the “Analytical Development
Proposal for BA058, API Project (Lonza RDS-001)” attached here as Exhibit B). 
If needed, additional method development may be performed to identify the method
of choice.  Once identified, the methods of choice (probably two) that are
suitable for quantification of process impurities and supportive of
ICH-stability studies will identified and agreed by the parties.  Resulting
product will be greater than 97% pure as measured by the Manufacturer’s method
FG1.  Release will be performed using the TG1 method, originally developed by
Ipsen, unless otherwise agreed upon in advance based upon the outcome of the
analytical method qualification.

 

Stability:  an ICH-stability study will be performed according to the
requirements in “SP-RDS-001 Stability Protocol for BA058 API, an Analog of Human
Parathyroid-related Peptide (PTHrP)” (Exhibit C).

 

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

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed
Separately with the Commission

 

CONFIDENTIAL

 

1

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

 

The above requirements, and any additional requirements that are agreed by the
parties as contemplated above, shall be deemed part of the Specifications for
the Product for purposes of the Agreement.

 

a)            Production will be initiated by the week of January 25, 2010. 
Analytical development will commence in the week of January 18, 2010.  The
deliverables will include regular updates (status reports, conference calls), as
requested by Radius.  Release specifications are listed in Exhibit D, which for
clarity shall be deemed part of the Specifications for the Product for purposes
of the Agreement.  Modifications may be required, as the development status
changes, and shall be agreed by the parties in writing.

 

b)            In the activities outlined in (a) and (b), which may include
Manufacturer Processes, Manufacturer Technology may be incorporated with the
prior consent of RADIUS.

 

c)             RADIUS will specify the number and size of aliquots to be
produced and notify the Manufacturer.  The material can be stored at the
Manufacturer’s site for up to three (3) months after release free of charge.  It
will be shipped after notification of RADIUS by Manufacturer.  Amber glass
packaging is assumed.  Upon request by RADIUS, Manufacturer will provide
additional dispensing at additional charge to be communicated to RADIUS
beforehand.

 

d)            A project team will be formed which will work closely with the
team at RADIUS.  The project team will include technical project leaders as well
as the appropriate QC, QA, and Regulatory personnel.  Communications with RADIUS
will include weekly teleconferences as needed.  Audits of the manufacturing
plants and general customer visits may be scheduled as needed.

 

e)             For further details, please refer to Exhibits A, B and C attached
hereto.

 

f)             All Services hereunder will be conducted in compliance with
analytical standards suitable for NDA filing and in compliance with cGMP for
Phase III product.

 

3.             Completion:

 

Production will be completed by week of 26th April 2010 and API will be shipped
to RADIUS by week of 3rd of May 2010.

 

Preparation:

 

week of December 11, 2009

Start of Upstream:

 

week of January 25, 2010 (week 4)

Global deprotection:

 

week of February 15, 2010 (week 7)

Start of Downstream:

 

week of February 22, 2010 (week 8)

Lyophilisation step:

 

week of March 15, 2010 (week 11)

API QC/QA release:

 

week of April 26, 2010 (week 17)

Shipment of API:

 

week of May 3, 2010 (week 18)

 

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

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed
Separately with the Commission

 

2

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

 

4.             Facilities.  The Services described above will be rendered at the
Facility unless another facility of Manufacturer is indicated below:

 

Lonza S.A., Chausée de Tubize 297, B-1420 Braine l’Alleud, Belgium

 

5.             RADIUS Materials.  RADIUS will provide to Manufacturer the
following materials to be used by Manufacturer to perform the Services:

 

None

 

6.             RADIUS Equipment.

 

None

 

7.             Manufacturer Representative.

 

Raimund Miller, Director, Sales and Business Development, Lonza Custom
Manufacturing

 

8.             RADIUS Representative.

 

Louis O’Dea, Senior Vice President and Chief Medical Officer

 

9.             Compensation.  The total compensation due Manufacturer for
Services under this Work Order is €341,500.

 

 

 

Gram

 

€/gram

 

 

 

 

 

[*]g

 

$[*]

 

€

 

Raw Materials

 

 

 

 

 

[*]

 

Production (incl. SPPS, IPC, DSP)

 

 

 

 

 

[*]

 

QC, QA release

 

 

 

 

 

[*]

 

HPLC methods comparability

 

 

 

 

 

[*]

 

Additional method development (optional)

 

 

 

 

 

[*]

 

HPLC method qualification

 

 

 

 

 

[*]

 

ICH-stability

 

 

 

 

 

[*]

 

TOTAL cost

 

 

 

 

 

341,500

 

 

Such compensation will be paid in installments.  20% of the costs listed above
are due upon, signing of this Work Order.  The remaining payments are due upon
completion of the Services and delivery of the resulting material.  RADIUS and
Manufacturer must agree in advance of either party making any change in the
compensation due hereunder.  Manufacturer will invoice RADIUS to the attention
of Nick Harvey, SVP and CFO, for Services rendered under this Agreement. 
Manufacturer will invoice RADIUS for all amounts due under this Work Order.  All
undisputed payments will be made by RADIUS within thirty (30) days of receipt of
invoice.

 

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

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed
Separately with the Commission

 

3

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

 

10.          Insurance will be provided as required by the Agreement.

 

 

All other terms and conditions of the Agreement will apply to this Work Order.

 

WORK ORDER AGREED TO AND ACCEPTED BY:

 

RADIUS HEALTH, INC.

 

LONZA SALES LTD

 

 

 

By

/s/ B. N. Harvey

 

By

/s/ Raimund Miller

 

 

 

 

 

Print Name

Nick Harvey

 

Print Name

Raimund Miller, PhD.

 

 

 

 

 

Title

CPO

 

Title

Director, Sales & BD

 

 

 

 

 

Date

Jan 15, 2010

 

Date

Jan. 15, 2010

 

4

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

 

Exhibit A

 

Proposal for the Manufacture of 50g and 100g, 150g and 200g of BA058 and
upgrading of analytical methods to NDA filing levels for Radius Health, Inc.

 

5

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

 

[g17732lm019i001.gif]

 

PROPOSAL for the MANUFACTURE of 50g and 100g, 150g and 200g

of BA058 (Lonza Designation:  RDS-001)

and upgrading of analytical methods to NDA filing levels

for RADIUS Health, Inc.

(As per the March 19 and April 06, ‘09 RFPs)

1st Amendment dated April 28, ‘09

(all new text in blue)

2nd Amendment dated April 30, ‘09

(all new text in dark yellow)

3rd Amendment dated Nov. 30, ‘09 and Dec. 01, ‘09, and Dec. 3, ‘09

(for 50g and 100g; all new text in red)

 

 

Prepared for:

Maria Grunwald, Ph.D., MBA

Director, Business Development

Radius

300 Technology Square, 5th Floor

Cambridge, MA 02139

 

 

Prepared by:

Raimund J. Miller, PhD.

Director, Sales & Business Development

Lonza Custom Manufacturing

25 Commerce Drive

Allendale, NJ 07401

 

 

Date:

April 20, 2009

April 28, 2009

April 30, 2009

Nov. 30, 2009, Dec. 01, ‘09, Dec. 3, ‘09

 

DISCLAIMER

 

THIS DOCUMENT IS ISSUED BY LONZA FOR DISCUSSION PURPOSES ONLY.  IT IS NOT
INTENDED TO CONSTITUTE ANY SORT OF OFFER OR TO CREATE ANY LEGAL RELATIONS
BETWEEN LONZA AND ANY OTHER PARTY.

 

THE SUPPLY OF THIS DOCUMENT IN ELECTRONIC FORM IS STRICTLY ON THE UNDERSTANDING
THAT NO AMENDMENTS WILL BE MADE TO IT WHICH ARE NOT EXPLICITLY DRAWN TO LONZA’S
ATTENTION EITHER BY MARKING THE CHANGES IN THE TEXT ITSELF OR OTHERWISE IN
WRITING.  LONZA DOES NOT AGREE TO ANY AMENDMENT

 

CONFIDENTIAL

 

1

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

 

WHICH IS NOT SO EXPLICITLY BROUGHT TO OUR ATTENTION.

 

1)            Background

 

On March 19, ‘09 Dr. Maria Grunwald asked for a cost proposal + timelines for
upgrading the analytical methods, which were employed in the 1st BA-058
campaign, to NDA filing levels.  This was followed by a request for proposal on
April 6, ‘09 for pricing for a 150g Ph III / cGMP campaign.  On April 29, ‘09
Radius placed a request to include pricing for a 200g as well.  The 04/30/09
2nd proposal amendment provides pricing for the 200g. On Nov. 23, ‘09 Radius
requested a proposal for a 50g batch for Phase 3 (requiring manufacture to GMP
standards).  On Nov. 30, ‘09 Radius requested that pricing be added for a 100g
campaign as well.  On Dec. 3, ‘09, Radius requested a “break” on the 100g price
which Lonza is willing to give in support of Radius’ program.

 

In mid 2008 Lonza Braine performed the 1st BA-058 campaign (C1 campaign) which
yielded [*]g peptide corresponding to [*]g net peptide.  An extra quantity of
[*]g powder weight was generated during this first campaign.

 

Campaign summaries were provided in Process Analytical reports which were sent
to Radius on March 2, ‘09 (PAR-S-RDS-001-103 C1, concerning upstream process
description) and on March 9, ‘09 (PAR-P-RDS-001-Campaign 1-Lot 8AG1, concerning
downstream process description).

 

To date (April 20, ‘09) the following shipments were made out of this C1
campaign:

 

1) In February ‘09, 40.0g (8 x 5.0g powder weight) were sent to Vetter Pharma
(Germany).

 

2) In March ‘09, 4.0g (1 x 1.5g + 1 x 2.5g powder weight) were sent to Charles
River Laboratories (Canada)

 

2)            BA058—the Product

 

The BA058 (RDS-001) Peptide is an amide 34 mer with one non natural AA:
H-Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2

 

General Information

 

Nomenclature

 

Chemical Name:

 

Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-ALa-NH2 [GIU22,25,
Leu23,28,21, Aib29, Lys26,30] hPTHrP(1-34)-NH2

 

 

 

USAN Name:

 

Not assigned

 

 

 

Research Names:

 

BA058

(Radius Code)

 

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

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed
Separately with the Commission

 

2

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

 

CAS Registry

 

247062-33-5, 512206-66-5, 506422-98-6

Numbers:

 

 

 

Structure

 

The structure of BA058 peptide is depicted in Figure 1.

 

Figure 1:               Structure of BA058 Peptide

 

[g17732lm019i002.gif]

 

The active pharmaceutical ingredient (API), BA058 API, is isolated with
associated water and acetate.

 

3)            Process:

 

The manufacturing process which Radius asked Lonza to quote on for the
1st campaign was outlined in the 4/17/07 RFP.  The process is a
solid-phase-peptidesynthesis process (SPPS) characterized by the [*] amino acids
[*] and coupling agents, followed by cleavage, deprotection and work-up; the
purification is performed by reverse phase HPLC which is followed by isolation
by means of lyophilization.

 

In the course of the feasibility study performed by Lonza Braine in early ‘08,
two different analytical methods were developed in order to properly monitor
purification of the peptide.  These two methods provide much better resolution
than the one received from Radius using a TFA based system.

 

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

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed
Separately with the Commission

 

3

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

 

During the C1 campaign, these methods were used for the monitoring of the
primary purification of the peptide.  This has resulted in an 00C (out of
criteria), as the min. of 97.0% purity was not reached at the end of this step
of purification.

 

In an internal meeting, it was decided to implement a second step of
purification using acetic acid medium in order to increase the purity of
fractions.  At the same time, Radius requested to use the TFA method for the QC
lot release.  Lonza proposed to add one of our methods for supportive data
during this release.

 

By using Lonza’s analytical method, it was possible to produce an extra pure lot
at 99.1% HPLC purity (Radius method).  This means also that recovery and
productivity were low due to a secondary step of purification and recycling to
reach the required purity.

 

The new pricing is based on yields and recoveries obtained during the C1
campaign, which should not be considered as a representative campaign.

 

For the future C2 campaign, norms to reach will be performed in TFA method
(using the Radius HPLC method).

 

Concerning change of equipment, assembly of the peptide on the resin during C1
campaign has been performed in a 20 L-Pepsynloop reactor.  For a batch size of
150g NPW API, a bigger reactor will be used, such as a 50L-Pepsynloop reactor. 
The upstream process will not be changed as the same technology is used in
either reactor.

 

For the sake of this 1st amendment of the April 20th proposal all quantities to
be produced have been revised, and the entire campaign has been recalculated. 
The final quantity to be produced is 150g net peptide weight at 97.0% HPLC
purity (by the Radius method) which is unchanged.  The upstream will be
performed in two small-scale SPPS reactors (2 x 20 L) in parallel vs. a single
50 L reactor in the initial proposal.

 

For the sake of the 2nd amendment a totally new production concept has been
worked up and costed.  In this case we can use mid-scale equipment:  one run in
50 L SPPS reactor and LC200 for downstream; considerably less manpower is
required in this production scenario resulting in considerable cost savings vs.
a 150g campaign.

 

For the sake of the 3rd amendment and as the request concerns the same batch
size as for C1 campaign, we can use the same size equipment.  This means,
small-scale SPPS reactor (20 L) and LC150 for downstream.  All improvements
needed, coming from know-how acquired during C1 campaign, will be implemented in
this new campaign.

 

4

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

 

4)            Price Proposal and Assumptions for new 50q and 100q cGMP
campaigns.  The Quotation is in Euros (pro memoriam:  the 11/30/09 US$ / Euro
exchange rate is 1.5035):

 

 

 

50g

 

100g

 

Raw Materials

 

[*]

 

[*]

 

Production (incl. SPPS, IPC, DSP)

 

[*]

 

[*]

 

QC, QA release

 

[*]

 

[*]

 

TOTAL cost of 50g campaign

 

Euros 210,000

 

Euros 275,700
Euros 257,750

 

 

A 50g campaign is not well suited to the smallest reactor which we will have to
use.  A 100g campaign is much better suited.

 

The target quality of the 50g and 100g campaigns (NPW, net peptide weight) will
be 97.0% (HPLC, Radius method).

 

In terms of timing, synthesis + purification + QA/QC release are estimated to
take 14 weeks for the 50g, 17 weeks for the 100g campaign.

 

5)            Price Proposal and Assumptions for a new 150q cGMP campaign.  The
Quotation is in Euros (pro memoriam:  the 04/28/09 US$ / Euro exchange rate is
1.3153):  [SECTION 4 AND PRICING OF 150G REMAINS UNCHANGED IN THE 2ND AMENDMENT]

 

Prior to the start of production, specific raw material purchasing and their
QC/QA release have to be scheduled.  These tasks are estimated to take six
weeks.

 

Production of 150g (NPW, net peptide weight) at 97.0% (HPLC, Radius method),
including upstream, downstream, QC and QA release of the GMP lot.

 

Price :  €350,000 (all inclusive of raw materials, production, and margin)

 

This cost does NOT include Reference Standard qualification on this lot.  New
internal QA guideline is a separate RS from the batch (extra pure one, which
means:  two separate lyophilisation steps, 2 distinct QC releases and so on). 
Associated costs have been calculated as follows:

 

Assumptions :

 

·

[ Extra pure API (part of the purification lot)

·

Lyophilisation

·

QC release ]

 

[*] €

·

5g net peptide weight

 

[*] €

 

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

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed
Separately with the Commission

 

5

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

 

Total costs for a new reference standard:  €32,500

 

6)            Price Proposal and Assumptions for a new 200q cGMP campaign.  The
Quotation is in Euros (pro memoriam:  the 04/30/09 Euro / US$ exchange rate is
1.3205):

 

Prior to the start of production, specific raw material purchasing and their
QC/QA release have to be scheduled.  These tasks are estimated to take six
weeks.

 

Production of 200g (NPW, net peptide weight) at 97.0% (HPLC, Radius method),
including upstream, downstream, QC and QA release of the GMP lot.

 

Price :  €285,000 (all inclusive of raw materials, production, and margin;
excluding the €[*] cost for the new stationary phase for the larger column)

 

This cost does NOT include Reference Standard qualification on this lot.  New
internal QA guideline is a separate RS from the batch (extra pure one, which
means:  two separate lyophilisation steps, 2 distinct QC releases and so on). 
Associated costs have been calculated as follows:

 

Assumptions :

 

·

[ Extra pure API (part of the purification lot)

·

Lyophilisation

·

QC release ]

 

[*] €

·

5g net peptide weight

 

[*] €

 

Total costs for a new reference standard:  €26,335

 

7)            Price Proposal for Upgrading of Analytical Methods to NDA filing
levels.  The Quotation is in Euros (pro memoriam:  the 04/17/09 Euro /
US$ exchange rate is 1.3043):

 

1.             Analytical activities (this should be performed in parallel of
the GMP campaign, concerning validation methods.  For additional testing 3 extra
weeks are needed after the release of the lot).

 

·      Validation of analytical methods :  Price €100,000

 

·      HPLC / M-009-RDS-001TG1 (QC release method)

·      HPLC / M-009-RDS-001 FG1 (QC release method)

·      Acetate and Trifluoroacetate content in API

·      Water content

·      GC-Headspace (complement to general method)

·      Direct GC (complement to general method)

·      Specific rotation

·      Peptide content (Nitrogen)

·      HPLC for in-process control upstream and downstream (3 methods).

 

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

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed
Separately with the Commission

 

6

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

 

·      Additional testing requested for NDA filling :  Price:  €25,000

 

·      LC-MS profiles of one lot + one lot in stability study (study of
degradation of API:  impurity profile).

·      Comparability study for lots coming from different suppliers

·      Heavy metals

·      General properties:  polymorphism, solubility, pH (isoelectric point),
appearance, etc...

 

For all this analytical work, [*] g powder weight of API is needed.  We still
have [*] g powder weight of lot 8AG1 in stock.  We will be able to use this
material if Radius so decides.  Otherwise, we will have to use an extra quantity
to be made available from this lot (this one has not been paid yet by Radius). 
This will be discussed with Radius when necessary.

 

Total price:  €125,000

 

2.             Regulatory activities

 

NDA filing.  Price:  €57,500

 

15 weeks will be needed to finalize the NDA writing and associated corrections.

 

8)            Terms and Conditions

 

·      Proposal Validity:  May 31, ‘09.  After the expiry of the validity Lonza
reserves the right to revisit all assumptions taken and outlined in this
proposal.

·      Proposal Validity for 3rd Amendment:  May 31, ‘10.

·      Payment Terms:  a min. 30% upfront payment is required upon commencement
of project related lab activities.

·      Packaging:  Lonza standard packaging is assumed.  Should any non-standard
packaging be required, additional costs associated with this change will be
charged separately.

·      INCO-terms:  FCA Lonza Braine.

 

KB / RJM

04 / 20 / 09

04 / 28 /09

04 /30 / 09

11 / 30 /09; 12/01/09; 12/03/09

 

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

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed
Separately with the Commission

 

7

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

 

Grunwald, Maria

 

From:

 

Miller Raimund - Allendale [raimund.miller@Ionza.com]

Sent:

 

Thursday, December 17, 2009 10:07 AM

To:

 

Grunwald, Maria

Cc:

 

Bouget Karine - Braine

Subject:

 

New Price offer for 75g

 

Hello Maria,

 

Per our telecon on Tuesday, Dec. 15, we are herewith re-quoting for a new 75g
campaign which will produce 97% material by the FG1 method.  The 10% which were
added to our Dec. 8, ‘09 quote for the same quantity, are to cover raw material
supply and recycling steps during purification to reach the targeted purity.

 

Price Proposal and Assumptions for new 75q cGMP campaign.

 

The Quotation is in Euros (pro memoriam:  the 12/17/09 US$ / Euro exchange rate
is 1.437):

 

 

 

75g

 

Raw Materials

 

[*]

 

Production (incl. SPPS, IPC, DSP)

 

[*]

 

QC, QA release

 

[*]

 

TOTAL cost of 75g campaign

 

Euros 258,500

 

 

Assumptions:  same as in the most recent proposal dated Dec. 3, ‘09.

 

Thanks,

Raimund

 

Raimund J. Miller, PhD.

Lonza Custom Manufacturing

Lonza Inc.

25 Commerce Drive

Allendale, NJ 07401

Tel+1-201-316-9322

Cell +1-201-233-2006

Fax+1-201-696-3530

 

Lonza

raimund.miller@lonza.com

www.lonza.com

 

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

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed
Separately with the Commission

 

1

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

 

Exhibit B

 

Analytical Development Proposal for BA058, API project (Lonza RDS-001)

 

6

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

 

[g17732lm021i001.gif]

 

Analytical Development Proposal For BA058, API Project
(Lonza RDS-001)

 

Development proposal

 

The development proposal is divided into 3 steps that should be conducted prior
to the next API batch release.

 

1.             HPLC methods comparability

 

A first step will be to establish method comparability between TG1, VG1 and FG1
HPLC methods, in order to understand the capabilities and pitfalls of these
methods for true process impurities, including [3-34] and [4-34] truncated
peptides.  The HPLC data will be backed up by LC/MS data to support
identification of impurities and methods comparability in case of co-elution of
impurities (either with the main peak or with other impurities).

 

This will also allow building a rationale for method change in future API
release specifications.

 

This method comparability would be based on Lonza samples (including previously
manufactured lots 5AG1R and 8AG1, [3-34] and [4-34] impurity markers, as well as
DSP side fractions containing process impurities).  Should it be of interest to
Radius, samples of BA058, API from other sources could also be added to this
study in order to bridge these materials with the current Lonza material (8AG1).

 

Requirement:  Samples from Radius (if needed)

Timeline:  4 weeks

Deliverable:  Comparability report between 3 HPLC methods, including LC/MS
identification of impurities.

Price:  €15,000

 

2.             Additional method development

 

Based on the above assessment, additional HPLC method development may have to be
performed, in order to identify the method of choice (separate the critical
[3-34] and [4-34] from the other process impurities), in addition to the
identified HPLC method that will be used to assess overall purity and individual
impurities.

 

For this, we could use alternative stationary phases (eg HILIC) or even move to
UPLC (more resolution power than HPLC)

 

Timeline:  4 weeks

Deliverable:  HPLC method Development report

Price:  €15,000

 

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

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed
Separately with the Commission

 

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

 

 

3.                                      HPLC methods qualification

 

Once identified, the methods of choice (probably two) found suitable for their
intended purposes (quantitation of process impurities, and stability-indicating
to support ICH stability studies of API and DP) will be qualified.  One of these
methods could also be used to determine the API content in the powder (against
an external reference standard), should this be a requirement from Radius.  This
method qualification work will have to be completed before initiation of the
next campaign release.

 

Timeline:  5 weeks (assuming 2 methods qualified in parallel)

Deliverable:  HPLC method Qualification protocol and report

Price:  €18,000 per method (in line with any previous proposal for method
qualification)

 

JMP / KB / RJM

01/08/10

 

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

 

Exhibit C

 

SP-RDS-001 Stability Protocol for BA058 API, an Analog of Human
Parathyroid-related Peptide (PTHrP)

 

7

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

 

SP-RDS-001-8AG1

 

BA058 API, an Analog of Human Parathyroid-related Peptide
(PTHRP)/RDS-001

 

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

 

Table of Contents

 

1.

OBJECTIVE

3

2.

INTRODUCTION

3

3.

STABILITY STUDY DESCRIPTION

3

3.1

Equipment description

3

3.2

Containers for stability samples

3

3.3

Analytical tests to be performed

4

3.4

Acceptance criteria

4

3.5

Testing schedule

4

3.5.1

Material required for each test per station and storage condition

4

3.5.2

Material sampling per station and storage condition

4

3.5.3

Material inventory

5

 

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

 

1.                                      OBJECTIVE

 

This protocol describes the experiments to be performed in order to assess the
stability of batch 8AG1 of BA058 Active Pharmaceutical Ingredient (API), as
produced in the current manufacturing process.

 

2.                                      INTRODUCTION

 

This study will be performed in different storage conditions up to 36 months.

 

The conditions meet the requirements of the International Conference for
Harmonization, as described in Q1A(R2) “Stability Testing of New Drug Substances
and Products”.

 

3.                                      STABILITY STUDY DESCRIPTION

 

3.1                               Equipment description

 

·                                         Freezer at - 78°C ± 8°C
Such as THERMO (Forma -86C ULT freezer)

 

Temperature records in Freezer at - 78°C ± 8°C :

·                                          Digital thermometer for permanent
record

·                                          Manual record of temperature
twice-weekly

·                                          The temperature uniformity is checked
at least annually

 

·                                         Freezer at - 20°C ± 5°C
Such as Elbanton LTV650.

 

·                                         Cold room at + 5°C ± 3°C
Such as refrigerator WEISS

 

Temperature records in Freezer at - 20°C ± 5°C and in the cold room :

·                                          GTO monitoring for continuous
monitoring and permanent record.

·                                          Manual record of temperature every
day.

 

3.2                               Containers for stability samples

 

Stability samples will be stored in 8 mL HDPE bottle with suitable closure of
the same quality as those used for bulk storage.

 

Two samples will be stored at below - 25°C as witness samples

 

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

 

3.3                               Analytical tests to be performed

 

Tests

 

Methods

Powder appearance by visual examination

 

M-001

Water content by coulometric KF

 

M-048

Overall purity and related substances

 

M-009-RDS-001TG1

Overall purity and related substances

 

M-009-RDS-001FG1

Peptide content

 

M-022

 

3.4                               Acceptance criteria

 

The norms set in the current specifications are applied to the stability results
obtained at the recommended storage temperature (- 20°C ± 5°C).

 

3.5                               Testing schedule

 

Months

 

0

 

1

 

3

 

6

 

9

 

12

 

18

 

24

 

36

 

+ 5°C ± 3°C

 

—

 

A

 

A

 

A

 

 

 

 

 

 

 

 

 

 

 

- 20°C ± 5°C

 

A

 

—

 

A

 

A

 

A

 

A

 

A

 

A

 

A

 

 

3.5.1                     Material required for each test per station and
storage condition

 

Tests & Methods

 

Quantity by test

·

 

Powder appearance by visual examination

 

 

 

 

(M-001)

 

10 mg

·

 

Water content by coulometric KF

 

 

 

 

(M-048)

 

30 mg

·

 

Peptide content, overall purity and related substances

 

 

 

 

(M-009-RDS-001TG1)

 

20 mg

·

 

Overall purity and related substances by SEC-HPLC

 

 

 

 

(M-009-RDS-001FG1)

 

20 mg

·

 

M-022 by nitrogen analysis

 

 

 

 

(M-022)

 

20 mg

 

3.5.2                     Material sampling per station and storage condition

 

One HDPE bottle container containing 200 mg (all tests in duplicate analyses).

 

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

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed
Separately with the Commission

 

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

 

3.5.3                     Material inventory

 

The following table displays the material inventory required for this stability
study :

 

 

 

Storage
condition

 

Control time
points

 

Reserve sample

 

Total number

Short term

 

+ 5°C

 

3

 

2

 

5

Long term

 

- 20°C

 

7

 

4

 

11

Witness sample

 

Below - 25°C

 

—

 

2

 

2

Initial

 

NA

 

1

 

—

 

1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

19

 

This study will require 19 HDPE bottles containing 200 mg of powder.

 

A total quantity of 4.1g of peptide powder is requested for this stability study

 

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

 

Exhibit D

 

Batch Analysis of BA058 API

 

Test

 

Specification

Appearance

 

White to off-white powder

Identification:  HPLC

 

Co-Elutes with reference

Identification:  TLC

 

Single spot with Rf similar to reference

Assay Peptide content (HPLC) Peptide content (HPLC, anhydrous, free base basis)

 

> [*] (w/w) [*] to [*]%

Purity BA058 (HPLC) Total related impurities Individual related impurities

 

> 97.0%, area %

< 3.0%

< 1.0% area %

Purity by Mass Spectrometry 44117D(3-34 analog) 44116D (4-34 analog)

 

Not detected**

Not detected

Acetate Content

 

< [*]% (w/w)

Water Content

 

< [*] % (w/w)

TFA Content

 

Report

Specific Optical Rotation (anhydrous free base corrected)

 

Report

Residual Solvents

 

Methanol <[*]% w/w

Acetonitrile <[*]% w/w

Ethyl Acetate <[*]% w/w

Triisopropylsilane <[*]% w/w

Dimethylformamid <[*]% w/w

Microbial content Bacteria Yeasts and Molds LAL

 

Report (cfu/g)

Report (cfu/g)

< [*]UI/mg

 

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

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed
Separately with the Commission

 

8

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

 

 

AMENDMENT NO.3 to WORK ORDER NO.2*

 

This Amendment No. 3 to Work Order No.2 is entered into on December 15, 2010 by
and between Radius Health Inc., a Delaware Corporation, with its principal
office at 300 Technology Square - 5th floor, Cambridge, MA 02139, United States
of America (“RADIUS”), and LONZA Sales Ltd, a Swiss company having an address at
Muenchensteinerstrasse 38, CH-4002 Basel, Switzerland (together with its
Affiliates, “Manufacturer”), and upon execution will be incorporated into
Development and Manufacturing Services Agreement between RADIUS and Manufacturer
dated October 16, 2007 (the “Agreement”). Capitalized terms in this Amendment
will have the same meanings as set forth in the Agreement.

 

WHEREAS

 

RADIUS and Manufacturer are parties to Work Order No.2 executed January 15, 2010
under which Manufacturer had agreed to produce Product for use by Radius in a
Phase III clinical study.

 

Manufacturer has produced excess product, which RADIUS wishes Manufacturer to
purify to yield 100 grams of product (“Purified Product”) under this amendment.

 

Purified Product will be released, dispensed and packaged separately from
Product.

 

NOW, THEREFORE, IT IS AGREED AS FOLLOWS:

 

1.                     Services.  Manufacturer will render to RADIUS the
following Services:

 

Manufacturer will purify Product and release, dispense and package Purified
Product hereunder suitable for use by RADIUS in a Phase III clinical study. Such
work shall be performed in accordance with Exhibit A plus such additional
requirements as discussed below. Prior to purification of Product, Manufacturer
will (i) perform analytical testing of Product as identified in the first three
bullet points of Section 5 of Exhibit A, (ii) provide Radius with (a) a report
identifying the results of such testing and (b) Batch Documentation for the
Product (collectively, (a) and (b) are the “Analytical Test Reports”) and
(iii) obtain RADIUS’ written consent for Manufacturer to proceed with the
remaining activities in this Amendment (“Consent to Purify”). The decision as to
whether the analytical testing yielded satisfactory results and the Analytical
Test Reports are acceptable will be at RADIUS’ sole and absolute discretion and
RADIUS is under no obligation to provide any Consent to Purify.  Unless and
until Consent to Purify is provided by RADIUS, no further Services under this
Amendment shall be performed by Manufacturer.  The above requirements, and any
additional requirements that are agreed by the parties as contemplated above,
shall be deemed part of the Specifications for the Product for purposes of the
Agreement.

 

a)                Analytical testing will commence in the week of January 17,
2011. Purification will be initiated by the week of February 7, 2011.  The
deliverables will include regular updates (status reports, conference calls), as
requested by Radius, and Batch Documentation for the Purified Product.  Release
specifications for Purified Product are listed in Exhibit B, which for clarity
shall be deemed part of the Specifications for the Product for purposes of the
Agreement. Modifications may be required, as the development status changes, and
shall be agreed by the parties in writing.

 

b)                In the activities outlined in (a), which may include
Manufacturer Processes, Manufacturer Technology may be incorporated with the
prior consent of RADIUS.

 

c)                 Upon completion of the purification activities described
herein, Manufacturer will provide RADIUS with the Batch Documentation for the
Purified Product for

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

CONFIDENTIAL

 

1

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

 

RADIUS’ review.  No Purified Product will be shipped to RADIUS or its designee
until it has received written approval to ship from RADIUS.

 

d)                RADIUS will specify the number and size of aliquots to be
produced and notify the Manufacturer.  The material can be stored at the
Manufacturer’s site for up to three (3) months after release free of charge. It
will be shipped after notification of RADIUS by Manufacturer.  HDPE packaging is
assumed. Upon request by RADIUS, Manufacturer will provide additional dispensing
at additional charge to be communicated to RADIUS beforehand.

 

e)                 A project team will be formed which will work closely with
the team at RADIUS. The project team will include technical project leaders as
well as the appropriate QC, QA, and Regulatory personnel. Communications with
RADIUS will include weekly teleconferences as needed.  Audits of the
manufacturing plants and general customer visits may be scheduled as needed.

 

f)                 For further details, please refer to Exhibits A and B
attached hereto.

 

g)                 All Services hereunder will be conducted in compliance with
analytical standards suitable for NDA filing and in compliance with cGMP for
Phase III product.

 

2.                     Completion:

 

Analytical testing will be completed by January 21st, 2011. The Analytical Test
Reports will be provided to RADIUS by January 21st, 2011.  Purification will be
completed by week of 21st of March 2011 and API will be shipped to RADIUS by
week of 4th of April 2011.

 

3.                     Facilities.  The Services described above will be
rendered at the Facility unless another facility of Manufacturer is indicated
below:

 

Lonza S.A., Chausée de Tubize 297, B-1420 Braine l’Alleud, Belgium

 

4.                     RADIUS Materials.  RADIUS will provide to Manufacturer
the following materials to be used by Manufacturer to perform the Services:

 

None

 

5.             RADIUS Equipment.

 

None

 

6.             Manufacturer Representative.

 

Raimund Miller, Director, Sales and Business Development, Lonza Custom
Manufacturing

 

7.                     RADIUS Representative.

 

Louis O’Dea, Senior Vice President and Chief Medical Officer

 

8.                     Compensation.  The total compensation due Manufacturer
for proper performance of Services under this Amendment is €107,500. Such
compensation will be paid in installments as follows: 20% of the fee listed
above is due upon RADIUS providing Consent to Purify. The remaining amount will
be invoiced to RADIUS upon acceptance of the Services and delivery of 100 grams
of the Purified Product to RADIUS. For the

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

2

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

 

avoidance of doubt, no compensation will be due Manufacturer for any Services
performed under this Statement of Work if RADIUS elects not to provide the
Consent to Purify.  RADIUS and Manufacturer must agree in advance of either
party making any change in the compensation due hereunder. Manufacturer will
invoice RADIUS to the attention of Nick Harvey, SVP and CFO, for Services
rendered under this Agreement.  Manufacturer will invoice RADIUS for all amounts
due under this Amendment.  All undisputed payments will be made by RADIUS within
thirty (30) days of receipt of invoice.

 

9.             Insurance will be provided as required by the Agreement.

 

All other terms and conditions of the Agreement and Work Oder No. 2 will apply
to this Amendment No.3.

 

 

AMENDMENT AGREED TO AND ACCEPTED BY:

 

 

 

 

 

 

 

 

RADIUS HEALTH, INC.

 

LONZA SALES LTD

 

 

 

 

 

 

 

 

 

 

By

/s/ B.N. Harvey

 

By

/s/ Syed T. Husain

 

 

 

 

 

Print Name

Nick Harvey

 

Print Name

Syed T. Husain

 

 

 

 

 

Title

CFO

 

Title

Head of Sales & BD

 

 

 

 

 

Date

Dec. 14, 2010

 

Date

15-Dec-10

 

3

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

 

Exhibit A

 

Radius

 

Page 1 of 3

 

LONZA

BA-058 (RDS-D01)

 

Version 1.1a

 

 

 

PROPOSAL

 

RADIUS

 

Product: BA-058

 

(Lonza Code: RDS-001)

 

Proposal for purification and Release of Overage ex C2 Campaign

 

([*] g NPW)

 

Version 1.1a

 

November 8, 2010

 

December 13, 2010

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission

 

4

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

 

Radius

 

Page 2 of 3

 

LONZA

BA-058 (RDS-D01)

 

Version 1.1a

 

 

 

1) Introduction

 

The quotation provided herewith covers all activities which are required to
purify and release the overage which resulted out of the C2 BA-058 campaign. 
The target amount is [*] g NPW.

 

2) Peptide Sequence

 

H-Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-

Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2

 

3) Assumptions / Remarks

 

·      This quotation is based on the yields and results obtained in the [*]g
NPW campaign produced in 2010.

·      The same purification process will be used as the one used for C2
campaign: two HPLC purifications (primary and secondary purifications) in order
to meet the expected customer specifications.  As a consequence, a final HPLC
purity of the API > 97% is expected to be obtained (FG1 method).

·      Raw material prices: standard 2010 raw material prices were used in the
cost calculation.  Only purification related raw materials are included in this
quotation.

·      We expect a min. of [*] g peptide (NPW) to result out of this
purification campaign.

 

4) Purification of C2 crude overage at 100g NPW scale

 

Raw materials (€)

 

[*]

Manpower Downstream (€)

 

[*]

Manufacturing facilities downstream (€)

 

[*]

 

 

 

Total Production (€)

 

[*]

 

 

 

QA/QC release (€)

 

[*]

 

 

 

TOTAL (€)

 

107,500

Prices per gram (€)

 

[*]

 

Timelines: 7 weeks; 1st purification line to become available in week 6 of 2011.

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

5

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

 

RADIUS

 

Page 3 of 3

 

Lonza

BA-058 (RDS-001)

 

Version 1.1a

 

 

 

5) Activities to be performed prior to Purification (are all included in the
quotation):

 

·      Analysis of the crude in IPC upstream HPLC release method, in order to
check global purity.

·      LC-MS analysis in the same analytical method; comparison with the one
available for the crude at t=0.

·      Assess potency of the crude by VG1 HPLC method before purification
process.

·      Report of results as part of the purification batch record and review by
Production and QA before purification.

·      Include decision point: apply C2 purification process, if there is no
degradation. If there is degradation, include discussions to define a new
process.

 

BK / RJM

11/08/10

12/13/10

 

6

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

 

Exhibit B

 

7

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

 

Test

 

Specification

 

 

 

Appearance

 

White to off-white powder

 

 

 

Identification: HPLC

 

Co-Elutes with reference

 

 

 

Identification: TLC

 

Single spot with Rf similar to reference

 

 

 

Assay
Peptide content (HPLC)
Peptide content (HPLC, anhydrous, free base basis)

 

 

> [*] % (w/w)
[*] to [*] %

 

 

 

Purity BA058 (HPLC)
Total related impurities
Individual related impurities

 

> 97% ,area %
£ 3.0%
£ 1.0% area %

 

 

 

Purity by Mass Spectrometry
44117D(3-34 analog)
44116D (4-34 analog)

 

 

Not detected**
Not detected

 

 

 

Acetate Content

 

£ [*]% (w/w)

 

 

 

Water Content

 

£ [*] % (w/w)

 

 

 

TFA Content

 

Report

 

 

 

Specific Optical Rotation (anhydrous free base corrected)

 

Report

 

 

 

Residual Solvents

 

Methanol <[*]% w/w
Acetonitrile <[*]% w/w
Ethyl Acetate <[*]% w/w
Triisopropylsilane <[*]% w/w
Dimethylformamid <[*]% w/w

 

 

 

Microbial content
Bacteria
Yeasts and Molds
LAL

 

 

Report (cfu/g)
Report (cfu/g)
< [*] UI/mg

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

8

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

 

 

Confidential Treatment Requested

 

Under 17 C.F.R. §§ 200.80(b)(4) and 240.24b-2

 

WORK ORDER NO. 4

 

THIS WORK ORDER NO. 4 is by and between RADIUS HEALTH, INC. (“RADIUS”) and LONZA
Sales Ltd, a Swiss company having an address at Muenchensteinerstrasse 38,
CH-4002 Basel, Switzerland (together with its Affiliates, “Manufacturer”), and
upon execution will be incorporated into the Development and Manufacturing
Services Agreement between RADIUS and Manufacturer dated October 16, 2007 (the
“Agreement”). Capitalized terms in this Work Order will have the same meanings
as set forth in the Agreement.

 

RADIUS hereby engages Manufacturer to provide Services, as follows:

 

1.                                      API/Drug Substance and Product.

 

BA058

 

Peptide Sequence: 
H-Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2

 

2.                                      Services.  Manufacturer will render to
RADIUS the following Services:

 

Manufacturer will perform activities required for RADIUS’ filing of a new drug
application (“NDA”) in the United States with the FDA and similar applications
required by the European Medicines Agency (EMEA) and other
Authorities, excluding authorities in Japan, for BA058 including, but not
limited to, production of three (3) validation Batches.  These activities will
provide for full process qualification and process validation and all required
documentation necessary for regulatory submissions of the NDA to the FDA and the
NDA equivalents to other Authorities.

 

Such work will be performed in accordance with Exhibits A and B of this Work
Order plus such additional requirements as discussed below.  The Services are
identified in terms of a particular numbered activity (each, an “Activity”). 
All Services under this Work Order, including Manufacture of any Batches, will
be conducted in compliance with standards suitable for an NDA filing by RADIUS. 
All Batches will be Manufactured in compliance with cGMP, will conform to
Specifications provided to Manufacturer prior to commencement of the applicable
Batch, and the other requirements of the Agreement and this Work Order.  Except
for Activities 1 and 6, Manufacturer will not proceed to a subsequent numbered
Activity until it provides a report to RADIUS with the status of and results of
the prior numbered Activity and RADIUS provides Manufacturer with written
authorization to proceed to the next Activity.

 

Activity 1: Development Work: The objective for this Activity is to define the
best conditions for the preparation of the BA058 peptide.  As a first step,
Manufacturer will identify which parameters have influenced the unexpected high
yield in the C2 campaign.  In addition, Manufacturer will investigate the
chemistry to ensure repeatability/reproducibility of such results. The criteria
to be evaluated and the deliverables to be provided are as set forth in
Section 4 of Exhibit B.

 

Activity 2: Pre-qualification activities: Manufacturer will challenge the
parameters identified as critical as a result of the performance of Activity 1
and identify working ranges for the parameters to ensure a robust process for
upstream and downstream activities.  In addition, the studies identified in
Section 5 of Exhibit B will have to be conducted on different steps of the
process in order to define “holding points”.  If conducted on any intermediate
products, all stability studies conducted by Manufacturer will be

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

1

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

 

conducted in accordance with the Manufacturer generated stability protocol to be
approved by RADIUS in writing.

 

Activity 3: Qualification Campaign:  Manufacturer will not commence this
Activity without the prior written consent of RADIUS.  Manufacturer will
Manufacture a qualification Batch at a purification scale of NPW (net peptide
weight) selected by RADIUS from the table in Exhibit A; however, the assembly
and cleavage reaction that will lead to the crude will be performed at a scale
of 180g NPW equivalent. The Batch will be Manufactured in a 20L SPPS reactor. An
amount identified by RADIUS out of the crude that was Manufactured will be
purified on an LC150 HPLC column and lyophilized in a GT10 lyophilizer. The
excess of crude will be stored and will be purified by Manufacturer, if so
requested by RADIUS in writing (“Additional Purification”). These activities are
further described in Section 6 of Exhibit B.

 

Activity 4: Qualification Stability : Manufacturer will perform a stability
study from samples of the Product Manufactured pursuant to Activity 3 in
accordance with ICH requirements and the time points required by ICH
requirements (at a minimum, the following time points:  0, 3, 6, 9, 12, 18, 24,
36 months). The study will be performed according to a stability protocol to be
generated by Manufacturer and approved by RADIUS in writing.

 

Activity 5: Pre-validation activities: Based on pre-qualification Batches (C1
and C2 which were previously Manufactured) and the qualification Batch (C3 —
still to be produced), Manufacturer will prepare and deliver the reports and
protocols identified in Section 8 of Exhibit B.

 

Activity 6: Analytical Methods Validation: Manufacturer will validate the
analytical methods identified in Section 9 of Exhibit B and provide reports on
the analytical methods. These Services described in this Activity will commence
immediately. Completion dates are planned to allow the qualification Batch
described in Activity 3 to be tested with the required methods validated in this
Activity.  In any event, all methods will be validated before the commencement
of Activity 7.

 

Activity 7: Validation Campaign:

 

Manufacturer will Manufacture and release three (3) Batches of Product at a
scale of NPW (net peptide weight) selected by RADIUS from the table in
Exhibit A; however, the assembly and cleavage reaction that will lead to the
crude will be performed at a scale of 180g API equivalent. Manufacturer will
commence Manufacture of a Batch only with the prior written consent of RADIUS.
The excess of crude will be stored and Additional Purification will be performed
by Manufacturer, if so requested by RADIUS in writing. These activities are
further described in Section 10 of Exhibit B.

 

Activity 8: Validation Reports:   Manufacturer will provide the following
reports:

 

·                                          Upstream process validation reports

·                                          Downstream process validation report

 

Activity 9: Validation Stability: Manufacturer will perform a stability study
from samples of the Product Manufactured pursuant to Activity 7 in accordance
with ICH QIA requirements and the time points required by ICH requirements (at a
minimum, the following time points:  0, 3, 6, 9, 12, 18, 24, 36 months). The
study will be performed in according to a stability protocol to be generated by
Manufacturer and approved by RADIUS in writing.

 

Activity 10: DMF Filing:  Manufacturer will prepare, submit to applicable
Authorities identified by Radius, or to Radius for submission, and manage the
Drug Master File (DMF) using information about processes, equipment, facilities,
qualifications, controls and as needed.  Manufacturer will provide the DMF to
Radius for review and approval prior to submission.

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

2

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

 

For each Batch of Product Manufactured under this Work Order, Manufacturer shall
Manufacture, in accordance with cGMP and the Manufacturing Process, enough crude
to yield 180 grams (or such other amount specified by Radius in writing) of
Product.

 

The above requirements, including the yield requirements, and any additional
requirements that are agreed by the parties as contemplated above, shall be
deemed part of the Specifications for the Product for purposes of the Agreement.

 

a)                                                 Manufacturer will commence
performance of this Work Order by the week of January 2, 2012. The deliverables
will include regular updates (status reports, conference calls), as requested by
RADIUS.   Release specifications will be provided by Radius, which for clarity
shall be deemed part of the Specifications for the Product for purposes of the
Agreement. Modifications may be required, as the development status changes, and
shall be agreed by the parties in writing.

 

b)                                                 In the activities identified
above, which may include Manufacturing Processes, Manufacturer Technology may be
incorporated with the prior written consent of RADIUS.

 

c)                                                  A project team will be
formed which will work closely with the team at RADIUS. The project team will
include technical project leaders as well as the appropriate QC, QA, and
Regulatory personnel. Communications with RADIUS will include teleconferences as
needed.  Audits of the manufacturing plants and general customer visits may be
scheduled as needed.

 

d)                                                 For further details, please
refer to Exhibits A and B attached hereto.

 

3.                                      Completion:  Manufacturer will use
commercially reasonable efforts to complete the Services no later than the
following:

 

Activity 1: Development Work

 

Week of March 19, 2012

Activity 2: Pre-qualification activities

 

Week of May 28, 2012

Activity 3: Qualification Campaign

 

Week of June 29, 2012

Activity 4: Qualification Stability

 

Stability study to start by July 31, 2012 and continue according to protocol

Activity 5: Pre-validation activities

 

Week of Sept 24, 2012

Activity 6: Analytical Methods Validation

 

Week of May 30, 2012

Activity 7: Validation Campaign (Batch #1-3)

 

Batch #1 and #2: Week of Dec 26, 2012. Batch #3: Week of Feb 11, 2013 (or 2
weeks earlier, if small quantity has been requested).

Activity 8: Validation Reports

 

20 working days after completion of Validation Batch #3, or 20 days from date
requested by RADIUS

Activity 9: Validation Stability

 

Stability study to start within one month of batch purification and continue
according to protocol

Activity 10: DMF Filing

 

Within 40 working days of date requested by RADIUS, but not earlier than 3.5
months after the end of the Validation Campaign.

 

4.                                      Facilities.  The Services described
above will be rendered at the Facility unless another facility of Manufacturer
is indicated below:

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

3

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

 

Lonza S.A., Chausée de Tubize 297, B-1420 Braine l’Alleud, Belgium

 

5.                                      RADIUS Materials.  RADIUS will provide
to Manufacturer the following materials to be used by Manufacturer to perform
the Services:

 

None

 

6.                                      RADIUS Equipment.

 

None

 

7.                                      Manufacturer Representative.

 

Raimund Miller, Director, Sales and Business Development, Lonza Custom
Manufacturing

 

8.                                      RADIUS Representative.

 

Louis Brenner, Senior Vice President and Chief Medical Officer

 

9.                                      Compensation.  The total compensation
due Manufacturer for Services under this Work Order will not exceed €363,500
plus the applicable charges for Activities 3 and 7, as shown in Exhibit A.  The
reduced prices for validation Batch #2 and #3 will apply, if validation Batches
can be Manufactured simultaneously. The fees for the performance of the
Activities described above are set forth below.

 

 

 

€

Activity 1: Development Work

 

[*]

Activity 2: Pre-qualification activities

 

[*]

Activity 3: Qualification Campaign

 

See Exhibit A

Activity 4: Qualification Stability

 

[*]

Activity 5: Pre-validation activities

 

[*]

Activity 6: Analytical Methods Validation

 

[*]*

Activity 7: Validation Campaign, Batch #1-3

 

See Exhibit A

Activity 8: Validation Reports

 

[*]

Activity 9: Validation Stability

 

[*]

Activity 10: DMF Filing

 

[*]

 

In addition, the prices for the Additional Purification, as described in
Activity 3 and 7, are identified in Exhibit A.

 

To the extent that a regulatory approval process is substantially different from
FDA or EMEA and requires additional effort as part of Activity 10, an additional
fee may apply as may be agreed to in writing by the parties.

 

Invoicing: Compensation will be paid in installments as follows: Twenty percent
(20%) of the fee listed above for an Activity (or in the case of Activity 3 and
7, the applicable Batch or Additional Purification) will be invoiced upon
commencement of such Activity; the remaining fee for the Activity will be
invoiced upon completion of all Services for such Activity including, but not
limited, delivery to RADIUS of the resulting material, if applicable.

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

4

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

 

Expenses: Radius will be invoiced €22,500 for a stationary phase of an HPLC
column used by Manufacturer in the Manufacture of the Product. This stationary
phase will become the property of Radius upon payment to Manufacturer of the
applicable invoice.

 

General: RADIUS and Manufacturer must agree in advance of either party making
any change in the compensation due hereunder. Manufacturer will invoice RADIUS
to the attention of Nick Harvey, SVP and CFO, for Services rendered under this
Agreement.  Manufacturer will invoice RADIUS for all amounts due under this Work
Order.  All undisputed payments will be made by RADIUS within thirty (30) days
of receipt of invoice.

 

10.                               Insurance will be provided as required by the
Agreement.

 

All other terms and conditions of the Agreement will apply to this Work Order.

 

WORK ORDER AGREED TO AND ACCEPTED BY:

 

RADIUS HEALTH, INC.

 

LONZA SALES LTD

 

 

 

 

 

 

By

/s/ Nick Harvey

 

By

/s/ Rachel Corder

 

 

 

 

 

 

Print Name

Nick Harvey

 

Print Name

Rachel Corder

Title

CFO

 

Title

Senior Legal Counsel

Date

December 22, 2011

 

Date

December 23, 2011

 

 

 

 

 

 

 

 

By

/s/ John Eley

 

 

 

 

 

 

 

 

Print Name

John Eley

 

 

Title

Legal Counsel

 

 

Date

December 23, 2011

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

5

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

 

Exhibit A

 

Pricing for Activity 3 and Activity 7

 

Pricing is identified below for several options which Radius may elect for the
Activities identified below.

 

Activity 3, Qualification Campaign

 

 

 

First Purification (after synthesis at a scale of
180g NPW equivalent)

 

Additional
Purification

 

 

 

50g

 

100g

 

150g

 

180g

 

50g

 

Qualification Batch

 

€

[*

]

€

[*

]

€

[*

]

€

[*

]

€

[*

]

per gram

 

€

[*

]

€

[*

]

€

[*

]

€

[*

]

€

[*

]

 

Activity 7, Validation Campaign

 

 

 

First Purification (after synthesis at a scale of 180g NPW
 equivalent)

 

Additional
Purification

 

 

 

50g

 

100g

 

150g

 

180g

 

50g

 

Validation Batch #1

 

€

[*

]

 

€

[*

]

 

€

[*

]

 

€

[*

]

 

€

[*

]

per gram

 

€

[*

]

 

€

[*

]

 

€

[*

]

 

€

[*

]

 

€

[*

]

Validation Batch #2

 

€

[*

]

 

€

[*

]

 

€

[*

]

 

€

[*

]

 

€

[*

]

per gram

 

€

[*

]

 

€

[*

]

 

€

[*

]

 

€

[*

]

 

€

[*

]

Validation Batch #3

 

€

[*

]

 

€

[*

]

 

€

[*

]

 

€

[*

]

 

€

[*

]

per gram

 

€

[*

]

 

€

[*

]

 

€

[*

]

 

€

[*

]

 

€

[*

]

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

6

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

 

Exhibit B

 

Proposal

RADIUS

Product: BA-058

(Lonza Code: RDS-001)

Proposal for Pre-Validation and Validation Activities (Regulatory Roadmap)

(Version 1.7)

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

7

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

 

[g17732lm029i001.jpg]

 

PROPOSAL

 

RADIUS

 

Product: BA-058

 

(Lonza Code: RDS-001)

 

Proposal for Pre-Validation and Validation Activities

 

[Regulatory Roadmap]

 

Version 1.5

 

July 20, 2010

 

September 29, 2010

 

October 6, 2010

 

October 13, 2010

 

October 18, 2010

 

October 25, 2010

 

October 18, 2011 (version 1.5)

 

October 21, 2011 (version 1.6)

 

December 05, 2011 (version 1.7)

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

8

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

 

CONFIDENTIAL

 

CONFIDENTIAL

 

This proposal contains information proprietary to Lonza Sales AG, and must not
be copied or otherwise distributed other than for the purpose of review by
RADIUS in accordance with the terms of our existing CDA.

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

9

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

 

Company: RADIUS

 

 

 

From:

 

Raimund Miller

 

 

 

 

 

 

Paul Tastenhoye

To:  

 

 

 

Date: Oct.18, 2011

 

 

Maria Grunwald, PhD

 

 

 

 

 

 

E-mail:

 

 

 

Page(s): 10

 

 

mgrunwald@radiuspharm.com

 

 

 

 

 

 

Subject: Regulatory Roadmap

 

 

 

Copy:

 

 

 

Dear Maria,

 

On behalf of Lonza, we are pleased to provide you with our proposal for
Pre-Validation and Validation Activities [Regulatory Roadmap] for your BA-058
(Lonza Code: RDS-001).

 

We would like to thank you for giving us the opportunity to quote for these
activities. We sincerely hope that this proposal will win your confidence, as
Lonza is highly committed to meet your requirements to the fullest extent.

 

Kind regards,

 

[g17732lm029i002.gif]

 

[g17732lm029i003.jpg]

 

 

 

Raimund Miller

 

Eric Bironneau

Director, Sales & BD

 

Head of Business Development - Peptides

Lonza Inc.

 

Lonza Sales Ltd.

Lonza Custom Manufacturing

 

Lonza Custom Manufacturing

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

10

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

 

1) Introduction

 

The quotation provided herewith covers all activities which are required prior
to NDA filing of the BA-058 peptide; these activities are in addition to the two
development campaigns, C1 and C2 (50 g and 300 g respectively), which were
already run and which supported Radius’ product requirements for Ph II and Ph
III clinical trials. These regulatory road-map activities comprise the following
steps:

 

·                  Development work

·                  Pre-qualification activities

·                  Qualification campaign at 50g NPW scale

·                  Pre-validation documentation

·                  Analytical methods validation

·                  Validation campaigns - 3 batches at 50g NPW scale

·                  Post-validation documentation

·                  Master validation report

·                  DMF Filing

 

2)  Peptide Sequence

 

H-Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2

 

3)  Assumptions / Remarks

 

·                  The prices quoted are based on the yields and results
obtained in the C2 campaign produced in 2010.

·                  The full SPPS strategy is the only strategy considered.

·                  The chemical assembly/cleavage process will be followed by
two HPLC purifications (primary and secondary purifications) in order to meet
the customer specifications. As a consequence, an expected final HPLC purity of
the API > 97% will be obtained (by the FG1 method).

·                  Raw material prices: standard 2012 raw material prices were
used in the cost calculations.

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

11

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

 

4)  Development Work (all quotations are in Euros €; (pro memoriam, as of
Oct.14, ’11, the US $ / € exchange rate was 1.38)

 

·                  Objective: Define the best conditions for the preparation of
BA-058 peptide.

 

First of all, Lonza will have to define clearly which parameters have influenced
the unexpected high yield in the C2 campaign. Moreover, Lonza needs to
investigate the chemistry to ensure repeatability / reproducibility of such
results for future campaigns. Various criteria will have to be evaluated.

 

1.              Concerning raw materials:

 

·                  In order to achieve the same quality for future campaigns,
Lonza will have to test different resin suppliers and qualify at least two of
them.

·                  Specifications of the starting resin should then be modified
in order to fit the defined parameters.

 

2.              Concerning process, Lonza will have to challenge the different
steps.

 

·                  Loading:

 

a)            use of preloaded resin or in-house loading?

b)            working range of loading. It has to be defined in terms of
productivity and quality of the resulting crude material.

 

·                  Assembly:

 

a)            Identification of critical impurities in the crude coming from
mono deletion or double addition. This analysis will be performed based on
impurities present in C1 and C2 materials.

 

·                  Cleavage:

 

a)            Define the best conditions of cleavage in order to minimize
impurities linked to this step (almost 15% HPLC area for two impurities formed
during this cleavage step).

 

·                  Purification:

 

a)             Assessment of the potential impact of upstream development work
on the purification process.

b)             Development of UPLC method for in process control corresponding
to FG1 method (analysis time reduction).

 

·                  Deliverables:

 

Upstream (7 to 8 weeks)

 

·                  Development work - experimental part     € [*]

·                  Process development report — Compilation of the process
knowledge (C1, C2, and development work)   € [*]

 

Downstream (2 to 3 weeks)

 

·                  Development work - experimental part   € [*]

·                  Process development report — Compilation of the process
knowledge (C1, C2, and development work) € [*]

 

In order to reach Radius target in terms of price and timing, it has been
decided to reduce tests performed during this development work.

 

Quotation for development activities (in Euros €):  € 50,000 (Breakdown: see
quotation for each activity; duration: almost 2.5 months with activities
performed in parallel).

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

12

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

 

5) Pre-qualification Activities

 

·                  Objective: ensure we have a robust process by challenging
parameters defined as critical for both upstream and downstream.

 

In order to ensure we have a robust process before running the qualification
campaign, parameters defined as critical will have to be “challenged” in order
to obtain a suitable working range for these parameters. Moreover, some
stability studies will have to be conducted on different steps of the process in
order to define “holding points”, such as:

 

For upstream part (2 weeks)     price € [*]

 

a)             stability of the peptide resin

b)             stability of the crude in neat TFA

c)              stability of the crude during evaporation step

d)             stability of the crude after precipitation

e)              stability of the crude during drying step

f)               stability of the crude upon storage, etc…

 

For downstream part (3 weeks)   price € [*].

Potential critical parameters such as column loading, gradient, chemical
stability of fractions in purification and peptide concentration, tray volume,
powder homogeneity in lyophilization will have to be assessed and challenged.

 

·                  Deliverables (4 weeks):

 

Upstream   € [*]

 

·                  Qualification parameter protocols

·                  Qualification parameter - experimental part

·                  Qualification parameter reports

·                  Definition of critical parameters Upstream

·                  Parameter List

·                  Robustness Testing

 

Downstream € [*]

 

·                  Qualification parameter protocols

·                  Qualification parameter experimental

·                  Qualification parameter reports

·                  Definition of critical parameters Downstream

·                  Parameter List

·                  Robustness Testing

 

Quotation for pre-qualification activities (in Euros €):  € 80,000 (Breakdown:
37.5% upstream, 62.5% downstream; duration: 9 weeks with activities performed in
parallel).

 

By reducing development work, less experiment needed for this part of the
roadmap.

Costs have been decreased accordingly.

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

13

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

 

6) Quotation for Qualification Campaign at 50g NPW scale (in Euros)

 

·                  Objective: Qualify the parameters defined as critical for
both upstream and downstream for the preparation of BA-058 peptide.

 

Lonza will run the qualification campaign at a scale of 50g NPW; however, the
assembly and cleavage reaction that will lead to the crude will be performed at
a scale of 180g API equivalent, since this is the minimum scale at which the
process can be validated later. The assembly will be performed in a 20L SPPS
reactor. Only part of the crude (50g NPW out of 180g NPW) will be purified on an
LC150 HPLC column and lyophilized in a GT10 lyophilizer. The excess of crude
will be stored and can be purified later. Excellent 18M stability data of the
crude are currently available.

 

The price is given for the first 50g NPW production (including the full cost of
the crude at a scale of 180g NPW  API equivalent), as well is for the later
processing of the excess crude (without crude processing cost and per 50g NPW
API):

 

Quotation

 

First 50 g
NPW

 

50 g Price
without cost
of crude

 

First
100 g
NPW

 

First 150g
NPW

 

Full 180g
NPW

Raw Materials

 

[*

]

[*

]

[*

]

[*

]

[*]

Production:

 

 

 

 

 

 

 

 

 

 

·      Crude (at scale of 180 g API equivalent)

 

[*

]

[*

]

[*

]

[*

]

[*]

·      Purification and Lyophilisation

 

[*

]

[*

]

[*

]

[*

]

[*]

QC/QA Release

 

[*

]

[*

]

[*

]

[*

]

[*]

Total Quote

 

217,000

 

99,500

 

243,000

 

264,000

 

274,500

Price / g

 

[*

]

[*

]

[*

]

[*

]

[*]

 

·                  Lead time: 14 weeks

·                  Deliverables: see point 8

·                  Following Lonza SOP a Development Manufacturing Report will
be issued after qualification, considered as engineering batch. In case of no
change between this batch and validation batches, this is possible after an
equivalency report to use this batch as commercial supply. Moreover, this batch
may be use for clinical trials as far as API specifications are met, as for C1
and C2 campaigns material.

 

7) Qualification stability: 0, 6, 12, 24, 36 months

 

€ 21,600

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

14

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

 

8) Pre-validation Activities

 

·                  Objective: prepare validation campaigns

 

·                  Deliverables:

 

·                  Update Process development report — Compilation of the
process knowledge (pre-qualification and qualification batch)

·                  Master validation protocol

·                  Upstream and Downstream process validation protocols

 

·                  Cost:

 

·                  Process development report upstream

·                  Master validation protocol

·                  Upstream process validation protocol

 

·                  Process development report downstream

·                  Downstream process validation protocol

 

Quotation for pre-validation activities (in Euros €):  € 30,000

 

·                  Expected time needed: ± 20 working days (upstream and
downstream activities in parallel).

 

9) Analytical Methods Validation

 

·                  These activities should start at least 6 months before the
first batch of validation.

·                  Validation of analytical methods :

 

·                  Acetate and Trifluoroacetate content in API € [*]

·                  Water content € [*]

·                  GC-Headspace (complement to general method) € [*]

·                  Direct GC (complement to general method)  € [*]*

·                  Specific rotation  € [*]

·                  Peptide content (Nitrogen) € [*]

·                  HPLC for in-process control upstream and downstream (3
methods). Need for HPLC methods will be discussed with Radius.

·                  HPLC for in-process control downstream : 2 methods (FG1 and
VG1) € [*] each method

·                  HPLC for in-process control upstream : 3 methods: loading €
[*], short method cleavage € [*], long method cleavage € [*]

 

Quotation for analytical methods validation (in Euros €):  € 71,000

 

Additional testing (if needed):

 

· LCMS comparability:

 

LC-MS analysis by TG1 method: € [*] per sample

Comparability report: € [*]

 

· reference standard [assuming 2 lots and 250mg of each minimum]

 

Sequencing by ES/MS/CAD/MS: € [*] for 2 samples

Amino acid analysis: € [*] for 2 samples

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

15

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

 

Limit test for residual amino acids: € [*] for 2 samples

Secondary counter ions: € [*] for 2 samples

 

· Heavy metals (USP/EP level)

 

€ [900]* per test sample (same method as for lot 4AI1) + $ [*] for specific
method validation (Sn, Cr, Hg, Pb, As, Cd per ICH guidelines)

 

· General properties:

 

Solubility: € [*] per test sample

pH: € [*] per test sample

isoelectric point: € [*] per test sample

 

10) Quotation for Validation Campaign at 50 g NPW scales (in Euros)

 

Lonza will  run do the validation campaign at a scale of 50g NPW; however, as
for the qualification campaign, the assembly and cleavage reaction that will
lead to the crude, will be performed at a scale of 180g API equivalent, since
this is the minimum scale at which the process can be validated.

 

In order to make use of potential efficiencies, Radius asked for scenarios
whereby validation batches V2 and V3 are performed in parallel. The quotes for
these scenarios are presented in the table below:

 

·                  Validation batch 1 (V1) performed alone, no change in price

·                  Validation batches V2 and V3 performed in parallel in
synthesis but not for purification

·                  2 releases in parallel for V2 and V3

 

The price is given for the first 50g NPW production (including the full cost of
the crude at a scale of 180g NPW  API equivalent), as well is for the later
processing of the excess crude (without crude processing cost and per 50g NPW
API):

 

Validation 1:

 

Quotation

 

First 50 g
NPW

 

50 g Price
without cost
of crude

 

First
100 g
NPW

 

First 150g
NPW

 

Full 180g
NPW

 

Raw Materials

 

[*

]

[*

]

[*

]

[*

]

[*

]

Production:

 

 

 

 

 

 

 

 

 

 

 

·  Crude (at scale of 180 g API equivalent)

 

[*

]

[*

]

[*

]

[*

]

[*

]

·  Purification and Lyophilisation

 

[*

]

[*

]

[*

]

[*

]

[*

]

QC/QA Release

 

[*

]

[*

]

[*

]

[*

]

[*

]

Homogeneity Study

 

[*

]

[*

]

[*

]

[*

]

[*

]

Total Quote

 

226,750

 

99,500

 

252,750

 

273,750

 

284,250

 

Price / g

 

[*

]

[*

]

[*

]

[*

]

[*

]

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

16

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

Validations 2 and 3:

 

Quotation

 

First 50 g
NPW

 

50 g Price
without cost
of crude

 

First
100 g
NPW

 

First 150g
NPW

 

Full 180g
NPW

 

Raw Materials

 

[*

]

[*

]

[*

]

[*

]

[*

]

Production:

 

 

 

 

 

 

 

 

 

 

 

·  Crude (at scale of 180 g API equivalent)

 

[*

]

[*

]

[*

]

[*

]

[*

]

·  Purification and Lyophilisation

 

[*

]

[*

]

[*

]

[*

]

[*

]

QC/QA Release

 

[*

]

[*

]

[*

]

[*

]

[*

]

Homogeneity Study

 

[*

]

[*

]

[*

]

[*

]

[*

]

Total Quote

 

209,000

 

97,750

 

235,000

 

256,000

 

266,500

 

Price / g

 

[*

]

[*

]

[*

]

[*

]

[*

]

 

Lead time: 17 weeks (3 validation campaigns)

 

Total price for the 3 validation campaigns at 50 g:  1 x €226,750 + 2 x €209,000
= €644,750

 

Concerning homogeneity, this study in plates is performed during
prequalification activities. In the case of the validation batches, defined as
the most representative material compared to commercial batches, the homogeneity
study is performed on bulk material during dispensing. This work will be done on
all validation batches and will assay water content, acetonitrile content and
acetate content (€9,750 per batch). This is the reason why validation batches
are a bit more expensive than qualification batches.

 

No experience gain is expected between qualification and validation batches at
that scale: same equipments, same scale.

 

11) Validation Reports

 

·                  Upstream process validation reports:              € [*] (20
working days)

·                  Downstream process validation report:          € [*] (20
working days)

 

Quotation for Validation reports:                 €22,500

 

12) Validation stability: ICH (0, 3, 6, 9, 12 etc. months)

 

€ 35,000 per batch

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

17

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

 

13) Stationary phase HPLC column

 

5kg of stationary phase of the HPLC column will be charged to Radius. This
stationary phase is fully dedicated to BA-058 and cannot be used anymore for
other products in case the RDS-001 project would stop for any reason. Therefore,
it is now common practice at Lonza to sell the full amount of the phase directly
to the customer at the start of a project. Once Radius has paid for it, it
becomes Radius property.

 

€ 22,500€.

 

14) DMF Filing

 

Quotation for DMF filing: €40,000

 

15) Validity of Proposal

 

The validity of this proposal expires on December 31, 2011.

 

BK / RJM

07/20/10; 09/29/10; 10/06/10; 10/13/10; 10/18/10; 10/25/10.

 

PT/RJM

10/18/11; 10/21/11; 12/05/11

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

18

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

 

Confidential Treatment Requested Under 17 C.F.R. §§ 200.80(b)(4) and 240-24b-2

 

WORK ORDER NO. 5

 

THIS WORK ORDER NO. 5 is by and between RADIUS HEALTH, INC. (“RADIUS”) and LONZA
Sales Ltd, a Swiss company having an address at Muenchensteinerstrasse 38,
CH-4002 Basel, Switzerland (together with its Affiliates, “Manufacturer”), and
upon execution will be incorporated into the Development and Manufacturing
Services Agreement between RADIUS and Manufacturer dated October 16, 2007, as
amended to date (the “Agreement”). Capitalized terms in this Work Order will
have the same meanings as set forth in the Agreement.

 

RADIUS hereby engages Manufacturer to provide Services, as follows:

 

1.                                      API/Drug Substance and Product.

 

BA058

 

Peptide Sequence: 
H-Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2

 

(collectively, “Product”)

 

2.                                      Services.  Manufacturer will render to
RADIUS the following Services:

 

Activity 1: Production: Manufacturer will use commercially reasonable efforts to
Manufacture a Batch of Product at a purification scale of approximately NPW (net
peptide weight) 230 g. The Batch of Product will be manufactured in a 20L SPPS
reactor and will be purified on an LC150 HPLC column and lyophilized in a GT10
lyophilizer.

 

Manufacturer shall use commercially reasonable efforts to manufacture, in
accordance with cGMP and the Manufacturing Process, enough crude to yield
approximately 230 grams NPW of Product to meet Specifications as agreed in
Appendix A and deliver the actual quantity prepared to Radius.

 

Manufacturer plans to commence performance of this Work Order the week of
January 5, 2015.

 

·                       Assembly: estimated week 2-5

·                       Purification: estimated week 9-10

·                       Lyophilisation: estimated week 11

·                       Release: estimated week 15 (April 13) — week 16
(April 20)

 

Radius shall place purchase orders with Manufacturer in accordance with Work
Order 5 and shall not be permitted to terminate prior to the completion of the
Services.

 

The deliverables will include regular updates (status reports, conference
calls), as reasonably requested by RADIUS.

 

3.                                      Facilities.  The Services described
above will be rendered at the Facility unless another facility of Manufacturer
is indicated below:

 

N/A

 

4.                                      RADIUS Materials.  RADIUS will provide
to Manufacturer the following materials to be used by Manufacturer to perform
the Services:

 

None

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

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

 

Confidential Treatment Requested Under 17 C.F.R. §§ 200.80(b)(4) and 240-24b-2

 

5.                                      RADIUS Equipment.

 

None

 

6.                                      Manufacturer Representative.

 

Debra Sponholtz, Director, Sales East Coast, Lonza

 

7.                                      RADIUS Representative.

 

David Hanley, Executive Director, Technical Operations

 

8.                                      Compensation.  Radius will be invoiced
1667 €/gram upon Manufacturer’s release of the Product. Radius shall purchase
all surplus quantities of the Product arising from the manufacture of the Batch
at a rate of 1667 €/gram. The total compensation due Manufacturer for Services
under this Work Order is not expected to exceed €400,000.

 

9.                          General: RADIUS and Manufacturer must agree in
advance of either party making any change in the compensation due hereunder.
Manufacturer will invoice RADIUS to the attention of David Hanley, for Services
rendered under this Agreement.  Manufacturer will invoice RADIUS for all amounts
due under this Work Order.  All undisputed payments will be made by RADIUS
within thirty (30) days of receipt of invoice.

 

All other terms and conditions of the Agreement will apply to this Work Order.

 

WORK ORDER AGREED TO AND ACCEPTED BY:

 

RADIUS HEALTH, INC.

 

LONZA SALES LTD

 

 

 

 

 

By

/s/ David C. Hanley

 

By

/s/ Fabrice Gachot

 

 

 

 

 

 

 

 

 

Print Name

David C. Hanley

 

Print Name

Fabrice Gachot

Title

Executive Director

 

Title

Head of Business Development

Date

4 Dec 2014

 

Date

 

 

 

 

/s/ Greg Williams

3 Dec. 2014

 

 

 

 

 

By

/s/ Nadia Zieger

/s/ David C. Hanley

3 Dec. 2014

 

 

(Bob Ward by email)

 

Print Name

Nadia Zieger

 

 

Title

Senior Legal Counsel

 

 

Date

10 Dec. 14

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

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

 

Confidential Treatment Requested Under 17 C.F.R. §§ 200.80(b)(4) and 240-24b-2

 

Exhibit A

 

Specifications

 

See attached

 

MLP ID

B0-40066PA

MLP Version

8

Modified on

12-May-2014 16:40

Modified by

AFRANCOIS

Description

180798 RDS-001 Abaloparatide

Product code

CR298021 Shell life : [*]

Product group

 

Version comment

 

Test schedule

B0-40066PA.08

Substance

180798

Document

 

Document Version

 

Modifiable

TRUE

Group

B0

 

Component

 

Type

 

 

 

Intern

 

Extern

 

Warning

 

Unit

 

DP

 

CoA

 

Pos

 

Short

 

Dyn
Lvl

 

Part
Samp

 

Std

B0VO11042A

 

T

 

Text

 

—

 

Powder

 

—

 

 

 

0

 

*

 

1

 

*

 

0

 

Y

 

Y

Appearance

 

 

 

Phrase

 

—

 

B0-40066PA

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0VO11042A

 

T

 

Text

 

—

 

White to off-white

 

—

 

 

 

0

 

*

 

2

 

*

 

0

 

Y

 

Y

Colour

 

 

 

Phrase

 

—

 

B0-40066PB

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0LO14864C

 

T

 

Text

 

—

 

Complies

 

—

 

 

 

0

 

*

 

3

 

*

 

0

 

Y

 

Y

Coelution with reference

 

 

 

Phrase

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

sample (HPLC)

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0LO14864C

 

N

 

Min

 

—

 

[*]

 

—

 

%

 

1

 

*

 

4

 

*

 

0

 

Y

 

Y

Total Impurities (HPLC)

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0LO14864C

 

N

 

Min

 

—

 

[*]

 

—

 

%

 

1

 

*

 

5

 

*

 

0

 

Y

 

Y

Impurity, main (HPLC)

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0LO14864C

 

N

 

Min

 

—

 

[*]

 

—

 

%

 

1

 

*

 

6

 

*

 

0

 

Y

 

Y

Purity (HPLC)

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0LO14864C

 

N

 

Min

 

—

 

[*]

 

—

 

%w/w

 

1

 

*

 

7

 

*

 

0

 

Y

 

Y

API content (HPLC)

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0LO14864E

 

N

 

Min

 

—

 

—

 

—

 

 

 

2

 

*

 

8

 

*

 

0

 

Y

 

Y

Imp. unknowm, RRT,

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

>0.1%area (HPLC)

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

1

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

 

Confidential Treatment Requested Under 17 C.F.R. §§ 200.80(b)(4) and 240-24b-2

 

Component

 

Type

 

 

 

Intern

 

Extern

 

Warning

 

Unit

 

DP

 

CoA

 

Pos

 

Short

 

Dyn
Lvl

 

Part
Samp

 

Std

B0L014864E

 

N

 

Min

 

—

 

—

 

—

 

%

 

1

 

*

 

9

 

*

 

0

 

Y

 

Y

Impurity unknowm,

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

>0.1%area (HPLC)

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0M024591A

 

N

 

Min

 

—

 

[*]

 

—

 

Da

 

1

 

*

 

10

 

*

 

0

 

Y

 

Y

Mass, average (MS)

 

 

 

Max

 

—

 

[*]

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0L015151A

 

N

 

Min

 

—

 

—

 

—

 

%

 

1

 

*

 

11

 

*

 

0

 

Y

 

Y

Total impurities (HPLC)

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0L015151A

 

N

 

Min

 

—

 

—

 

—

 

%

 

1

 

*

 

12

 

*

 

0

 

Y

 

Y

Impurity, main (HPLC)

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0L015151A

 

N

 

Min

 

—

 

—

 

—

 

%

 

1

 

*

 

13

 

*

 

0

 

Y

 

Y

Purity (HPLC)

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0M0007621

 

N

 

Min

 

—

 

—

 

—

 

%

 

1

 

*

 

14

 

*

 

0

 

Y

 

Y

[*]

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0M0007621

 

N

 

Min

 

—

 

—

 

—

 

%

 

1

 

*

 

15

 

*

 

0

 

Y

 

Y

[*]

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0L022057A

 

N

 

Min

 

—

 

[*]

 

—

 

%w/w

 

1

 

*

 

16

 

*

 

0

 

Y

 

Y

[*]

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0L022057B

 

N

 

Min

 

—

 

[*]

 

—

 

%w/w

 

1

 

*

 

17

 

*

 

0

 

Y

 

Y

[*]

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0N024072A

 

N

 

Min

 

—

 

[*]

 

—

 

%w/w

 

1

 

*

 

18

 

*

 

0

 

Y

 

Y

Water (KF, coulom.)

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0G024588A

 

N

 

Min

 

—

 

[*]

 

—

 

µg/g

 

0

 

*

 

19

 

*

 

0

 

Y

 

Y

[*]

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

2

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

 

Confidential Treatment Requested Under 17 C.F.R. §§ 200.80(b)(4) and 240-24b-2

 

Component

 

Type

 

 

 

Intern

 

Extern

 

Warning

 

Unit

 

DP

 

CoA

 

Pos

 

Short

 

Dyn
Lvl

 

Part
Samp

 

Std

B0G024588A

 

N

 

Min

 

—

 

[*]

 

—

 

µg/g

 

0

 

*

 

20

 

*

 

0

 

Y

 

Y

[*]

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0G024588A

 

N

 

Min

 

—

 

[*]

 

—

 

µg/g

 

0

 

*

 

21

 

*

 

0

 

Y

 

Y

[*]

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0G024588A

 

N

 

Min

 

—

 

[*]

 

—

 

µg/g

 

0

 

*

 

22

 

*

 

0

 

Y

 

Y

[*]

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0G024588A

 

N

 

Min

 

—

 

[*]

 

—

 

µg/g

 

0

 

*

 

23

 

*

 

0

 

Y

 

Y

[*]

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0G024635A

 

N

 

Min

 

—

 

[*]

 

—

 

µg/g

 

0

 

*

 

24

 

*

 

0

 

Y

 

Y

[*]

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0G012082A

 

N

 

Min

 

—

 

[*]

 

—

 

µg/g

 

0

 

*

 

25

 

*

 

0

 

Y

 

Y

Total residual solvents (GC)

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0O023196A

 

N

 

Min

 

—

 

[*]

 

—

 

*

 

1

 

*

 

26

 

*

 

0

 

Y

 

Y

Specific Optical Rotation

 

 

 

Max

 

—

 

[*]

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

(on AFB)

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0K011068W

 

N

 

Min

 

—

 

[*]

 

—

 

EU/mg

 

0

 

*

 

27

 

*

 

0

 

Y

 

Y

[*]

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0K011091J

 

N

 

Min

 

—

 

[*]

 

—

 

CFU/100mg

 

0

 

*

 

28

 

*

 

0

 

Y

 

Y

[*]

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0K011091J

 

N

 

Min

 

—

 

[*]

 

—

 

CFU/100mg

 

0

 

*

 

29

 

*

 

0

 

Y

 

Y

[*]

 

 

 

Max

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B0A022698A

 

N

 

Min

 

—

 

[*]

 

—

 

%w/w

 

0

 

*

 

30

 

*

 

0

 

Y

 

Y

Mass balance (calculated)

 

 

 

Max

 

—

 

[*]

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Calc

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AQL

 

—

 

—

 

—

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

3

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

 

WORK ORDER NO. 6

 

THIS WORK ORDER NO. 6 is by and between RADIUS HEALTH, INC. (“RADIUS”) and LONZA
Sales Ltd, a Swiss company having an address at Muenchensteinerstrasse 38,
CH-4002 Basel, Switzerland (together with its Affiliates, “Manufacturer”), and
upon execution will be incorporated into the Development and Manufacturing
Services Agreement between RADIUS and Manufacturer dated October 16, 2007 (the
“Agreement”). Capitalized terms in this Work Order will have the same meanings
as set forth in the Agreement.

 

RADIUS hereby engages Manufacturer to provide Services, as follows:

 

1.                                      API/Drug Substance and Product.

 

BA058

 

Peptide
Sequence: H-Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2

 

2.                                      Services.  Manufacturer will render to
RADIUS the following Services:

 

Activity 1: Transfer of method FG2 to Vetter, (report containing analytical
results).: 9,230€

Activity 2: Bridging study for API /DP. 12 batches or 120 samples to test: 
14,615€

Activity 3: Bridging reports TG2 with TG1 and FG2 with FG1: 2,770€

Activity 4: 3 registration stability batches

1.              Time point 0: 3 batches — 3 conditions:  (9 x 7h =63h)

2.              Time point 1M: 3 batches — 2 conditions: (6 x 7h =42h)

3.              Time point 3M: 3 batches — 3 conditions:  (9 x 7h =63h)

 

Total Price: =29,040€

 

Activity 5: Release testing of 3 Vetter batches with FG2:

·                  3 batches, or 30 samples: 4,710€

 

Radius shall place purchase orders with Manufacturer in accordance with Work
Order 6.

 

The deliverables will include regular updates (status reports, conference
calls), as requested by RADIUS.

 

3.                                      Facilities.  The Services described
above will be rendered at the Facility unless another facility of Manufacturer
is indicated below:

 

N/A

 

4.                                      RADIUS Materials.  RADIUS will provide
to Manufacturer the following materials to be used by Manufacturer to perform
the Services:

 

None

 

5.                                      RADIUS Equipment.

 

None

 

6.                                      Manufacturer Representative.

 

Debra Sponholtz, Director, Sales and Business Development, Lonza

 

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

 

7.                                      RADIUS Representative.

 

David Hanley, Executive Director, Technical Operations

 

8.                          Compensation.  Radius will be invoiced 50% upon
signature of this WO and 50% upon Completion of each Activity. The total
compensation due Manufacturer for Services under this Work Order is not expected
to exceed €60,365

 

9.                          General: RADIUS and Manufacturer must agree in
advance of either party making any change in the compensation due hereunder.
Manufacturer will invoice RADIUS to the attention of David Hanley, for Services
rendered under this Agreement.  Manufacturer will invoice RADIUS for all amounts
due under this Work Order.  All undisputed payments will be made by RADIUS
within thirty (30) days of receipt of invoice.

 

All other terms and conditions of the Agreement will apply to this Work Order.

 

WORK ORDER AGREED TO AND ACCEPTED BY:

 

RADIUS HEALTH, INC.

 

LONZA SALES LTD

 

 

 

 

 

By

/s/ Greg Williams

 

By

/s/ Fabrice Gachot

 

/s/ Nadia Zieger

 

 

 

 

 

 

 

 

 

 

Print Name

Greg Williams

 

Print Name

Fabrice Gachot

 

Nadia Zieger

Title

CDO

 

Title

Head of Business Development

 

Senior Legal Counsel

Date

22 Dec 2014

 

Date

 

 

 

 

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

 

WORK ORDER NO. 7

 

THIS WORK ORDER NO. 7 is by and between RADIUS HEALTH, INC. (“RADIUS”) and LONZA
Sales Ltd, a Swiss company having an address at Muenchensteinerstrasse 38,
CH-4002 Basel, Switzerland (together with its Affiliates, “Manufacturer”), and
upon execution will be incorporated into the Development and Manufacturing
Services Agreement between RADIUS and Manufacturer dated October 16, 2007 (the
“Agreement”). Capitalized terms in this Work Order will have the same meanings
as set forth in the Agreement.

 

RADIUS hereby engages Manufacturer to provide Services, as follows:

 

1.             API/Drug Substance and Product.

 

BA058

 

Peptide Sequence:
H-Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2

 

2.             Services.  Manufacturer will render to RADIUS the following
Services:

 

Activity 1: Regulatory activities necessary to support submission of RDS-001 NDA
by the customer Radius according to the defined timelines.

 

Scope of work will include full NDA module 3.2.S and corresponding 2.3.S section
written by Lonza on templates provided by customer, based on finalised source
documents available on site and/or provided by customer.

 

Estimation of regulatory activity:

 

Estimated cost includes familiarization with the project, internal review with
technical experts, one review round with customer followed by one document
update.

·        Writing of full NDA 3.2.S and corresponding 2.3.S sections for RDS-001
Drug Substance:

·        Estimated Time is 34-40 working days

 

Estimated price:

         68’000-80,000 Euro

 

Administrative charges and fees related to the legalization and/or issuing of
original documents by local Health Authorities will be charged at additional
cost to the customer.

 

Timelines

 

Expected submission date is 30th September 2015. Detailed timelines for review
and finalisation of 3.2.S sections to be agreed by both Parties.

 

Additional Services

 

Additional services can be provided at a manday-rate basis (2000 Euro/day),
examples provided here:

·        Support for Health Authority Questions

·        Support for follow-on submissions in additional regions

·        Maintenance of NDA throughout life cycle

 

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

 

In the event additional services are requested a separate work order will be
agreed by both Parties.

 

Activity 2: Training of Vetter technicians in Braine on the Lonza method that is
to be transferred to Vetter as outlined in WO6.

 

Price: 5270 Euro

 

Radius shall place purchase orders with Manufacturer in accordance with Work
Order 7.

 

The deliverables will include regular updates (status reports, conference
calls), as requested by RADIUS.

 

3.                                      Facilities.  The Services described
above will be rendered at the Facility unless another facility of Manufacturer
is indicated below:

 

N/A

 

4.                                      RADIUS Materials.  RADIUS will provide
to Manufacturer the following materials to be used by Manufacturer to perform
the Services:

 

None

 

5.                                      RADIUS Equipment.

 

None

 

6.                                      Manufacturer Representative.

 

Debra Sponholtz, Director, Sales and Business Development, Lonza

 

7.                                      RADIUS Representative.

 

David Hanley, Executive Director, Technical Operations

 

8.                          Compensation.  Radius will be invoiced 50% upon
signature of this WO (€36,635) and 50% upon Completion of each Activity. The
total compensation due Manufacturer for Services under this Work Order is not
expected to exceed €85,270

 

9.                           General: RADIUS and Manufacturer must agree in
advance of either party making any change in the compensation due hereunder.
Manufacturer will invoice RADIUS to the attention of David Hanley, for Services
rendered under this Agreement.  Manufacturer will invoice RADIUS for all amounts
due under this Work Order.  All undisputed payments will be made by RADIUS
within thirty (30) days of receipt of invoice.

 

All other terms and conditions of the Agreement will apply to this Work Order.

 

WORK ORDER AGREED TO AND ACCEPTED BY:

 

RADIUS HEALTH, INC.

 

LONZA SALES LTD

 

 

 

 

 

By

/s/ Gregory C. Williams

 

By

/s/ Marie Leblane

 

/s/ Nadia Ziegar

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Print Name

Gregory C. Williams

 

Print Name

Marie Leblane

 

Nadia Ziegar

 

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

 

Title

Chief Development Officer

 

Title

Associate Director

Key Account Management

Senior Legal Counsel

Date

2/18/15

 

Date

24 February 2015

 

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