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EXHIBIT 10.15
***Text Omitted and Filed Separately
Confidential Treatment Requested
Under 17 C.F.R. Sections 200.80(b)(4),
200.83 and 240.24b-2
8 Oktober 1997
CONTRACT RESEARCH AND DEVELOPMENT AGREEMENT
THIS CONTRACT RESEARCH AND DEVELOPMENT AGREEMENT ("Agreement") is made effective
as of October 22, 1997 ("Effective Date"), by and among Xxxxxxx Pharmaceutical,
Inc. ("XXXXXXX"), a Delaware corporation having a place of business at 000
Xxxxxxxxxx Xxxxxx, Xxxx Xxxx, Xxxxxxxxxx 00000-000X, U.S.A., and Xx. Xxxx XXXXXX
GmbH ("XXXXXX") a German corporation having its principal place of business at
Xxxxxxxxxxxx Xxxxxx 00, 00000 Xxxxxxxx an der Riss, Federal Republic of Germany.
BACKGROUND
XXXXXXX is the proprietor of a [...***...] cell line known as B1 which produces
[...***...] monoclonal antibody ANTI B1.
XXXXXX owns specialized [...***...] facilities that may be suitable for
production of ANTI lB1, and employs personnel who have experience in [...***...]
processes as well as in CMC registration of biopharmaceuticals.
XXXXXXX desires to have XXXXXX personnel evaluate the XXXXXX generic
manufacturing process for the XXXXXXX B1 Cell Line and sterile liquid filling of
the resulting product in XXXXXX'x facilities.
XXXXXXX and XXXXXX have previously entered into a Material Transfer Agreement
dated December 3/5, 1996 to evaluate the Cell Line with XXXXXX'x serum free
medium.
The parties have already entered into a Feasibility Agreement, signed by Xxxxxxx
May 9, 1997, covering the evaluation of a generic manufacturing process
developed by Xxxxxx, applied to the Anti-B1 Antibody and equivalence testing of
the resulting product, and the Amendment No. 1 dated June 2, 1997 covering
period from April 1, 1997 to December 31, 1997 for the scale up to the
[...***...].
AGREEMENT
IN CONSIDERATION OF the mutual covenants set forth in this Agreement, XXXXXX,
and XXXXXXX hereby agree as follows:
1. DEFINITIONS.
1.1 "XXXXXXX" shall mean Xxxxxxx Pharmaceutical Inc. as laid down first
above.
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1.2 "XXXXXXX Confidential Information" shall mean the Cell Line, Process,
Product and all technical and other information relating thereto,
excluding the XXXXXX Confidential Information that is disclosed or
supplied to XXXXXX by XXXXXXX pursuant to this Agreement whether
patented or unpatented, including, without limitation, trade secrets,
know-how, processes, concepts, experimental methods and results and
business and scientific plans.
1.3 "ANTI B1" shall mean the [...***...] antibody directed against B-cells,
[...***...].
1.4 "Cell Line" shall mean the novel and proprietary cell line [...***...]
developed by XXXXXXX and provided to XXXXXX pursuant to the terms of
this Agreement, including, without limitation, all modifications,
analogs, progeny, other improvements and derivatives of such cell line.
1.5 "Certificate of Analysis" shall mean a document describing testing
methods and results, the accuracy of which has been certified by the
issuing party.
1.6 "Effective Date" shall mean the date first above written, which shall be
the effective date of this Agreement.
1.7 "GMP" shall mean the regulatory requirements for good manufacturing
practices promulgated by the FDA under the United States Federal Food,
Drug and Cosmetic Act, as amended, 21 C.F.R. Section 210 et seq and 21
C.F.R. Sections 600-610, as applicable.
1.8 "Master Cell Bank" shall mean XXXXXXX'x reference deposit or collection
of vials of the Cell Line, from which XXXXXX'x cell banks (Master Cell
Bank and Working Cell Bank) is derived.
1.9 "Process" shall refer to a generic XXXXXX process for using the Cell
Line, including defined procedures, equipment and analytical
methodologies for in-process control, release testing and Product
characterization, that has been developed by XXXXXX to the [...***...]
fermentation scale. The present Process is laid down in APPENDIX 8.
1.10 "Product" shall mean the ANTI B1 produced by XXXXXX using the Cell Line
in accordance with the Process.
1.11 "Project" shall mean the activities and work to be performed as laid
down in the respective chapter of the Master Project plan attached
hereto as APPENDIX 1. The primary objectives, which will be to
establish, to adapt and scale up the Process in the XXXXXX facility,
successfully demonstrate that equivalent Product can be reproducibly
manufactured in XXXXXX'x facilities, and generate a comprehensive report
compiling all relevant data generated hereunder. A proposed timeline for
the Project is included in Appendix 1.
1.12 "Project Fee" shall have the meaning specified in Section 6 hereof.
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1.13 "Project Manager" shall have the meaning specified in Section 2.1
hereof.
1.14 "Project Team" shall have the meaning specified in Section 2.2 hereof.
1.15 "Start Date" shall mean [...***...].
1.16 "XXXXXX Confidential Information" shall mean all technical and other
information relating to XXXXXX'x facilities and associated technologies,
excluding the XXXXXXX Confidential Information that is disclosed or
supplied to, or used on behalf of, XXXXXXX by XXXXXX pursuant to this
Agreement, whether patented or unpatented, including, without
limitation, trade secrets, know-how, processes, concepts, experimental
methods and results and business and scientific plans.
1.17 "Working Cell Bank" shall mean XXXXXX'x vialed collection serially
subcultivated cells that is derived from the XXXXXXX Master Cell Bank.
The Working Cell Bank is used to establish seed cultures of the Cell
Line to initiate the Process.
1.18 "Specifications" shall mean the specifications for the Product and the
respective test methods attached hereto as APPENDIX 5 on the basis of
the specifications provided by XXXXXXX and as such specifications may be
amended from time to time by mutual agreement of XXXXXXX and XXXXXX
according to further development of the Process and Product.
2. COOPERATION BETWEEN THE PARTIES IN THE COURSE OF THE PROJECT.
2.1 Designation of Project Manager.
XXXXXX and XXXXXXX shall each identify a Project Manager who will be
responsible for communicating all instructions and information
concerning the Project to the other party. Each Project Manager will be
available on an agreed upon bi-monthly basis for consultation at
pre-arranged times during the course of the Project. In the absence of
the Project Manager, a substitute shall be appointed. Additional modes
or methods of communication and decision making may be implemented with
the mutual consent of each party.
2.2 Project Team.
XXXXXX and XXXXXXX shall each name representatives to a Project Team,
which shall consist of knowledgeable specialists in appropriate
disciplines who shall be responsible for planning and executing the
Project and any subsequent interactions between the parties. At regular
intervals, the Project Managers shall schedule meetings between each
company's representatives for the purpose of communicating project
updates and providing a forum for strategic decision making and rapid
resolution of issues. Joint project meetings shall be conducted by
telephoneconference, video conference and face to face meetings. Meeting
minutes shall be prepared jointly by the Project Managers to record all
issues discussed and decisions made. The present list of the members of
the Project Team is attached hereto as Appendix 6. The members of the
Project Team may be changed from time to time as appropriate.
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2.3 Cooperation.
In the course of the Project, XXXXXX will at all times take into
consideration and implement the recommendations of XXXXXXX as long as
they do not adversely affect XXXXXX'x ability to perform other XXXXXX
biotech operations and are agreed upon by the Project Team; in the
absence of explicit instructions from XXXXXXX, XXXXXX shall be entitled
to employ its reasonable judgment in carrying out the Project consistent
with XXXXXX'x overall obligations under this Agreement. XXXXXX shall be
entitled to rely upon any written instructions or oral directives
confirmed in writing provided by any XXXXXXX representative and shall
not be responsible for failure to achieve any objective or the inability
to adhere to any guideline due to causes beyond the control of XXXXXX
including, but not limited to technical failures, incomplete direction
or documentation of Process variables.
2.4 Disputes.
In the event that a disagreement, dispute, controversy or claim should
arise relating to scientific or technical issues, the parties will
attempt in good faith to resolve their differences. If the parties are
unable to resolve such dispute, XXXXXXX shall have the final decision.
XXXXXX then shall follow the decision of XXXXXXX at the sole risk of
XXXXXXX if and as long as such decision doesn't affect the Master
Projectplan attached hereto as APPENDIX 1 with regard to costs and/or
time. If the latter is the case the parties shall have to agree as laid
down in paragraph 4.4 below.
2.5 FDA Interaction.
XXXXXX has the express right to send representatives to any meeting of
or on behalf of XXXXXXX with the FDA for discussions (regarding the
CMC-part of BLA) involving the Product. XXXXXX shall have advance notice
of at least thirty (30) days before any meeting scheduled with the FDA.
2.6 Access to Facilities.
XXXXXX shall permit XXXXXXX, upon reasonable prior notice to XXXXXX, to
review the originals of all batch records and other primary documents at
its facilities. XXXXXX shall allow XXXXXXX personnel to be present in
its facilities at appropriate times for audits or observance in critical
parts of the development as agreed upon by the Project Team. While at
any facility, personnel shall comply with all security and' safety
policies and procedures of the facility owner.
3. XXXXXXX RESPONSIBILITIES.
3.1 License to Use of XXXXXXX Cell Line and Intellectual Property.
XXXXXXX hereby grants to XXXXXX [...***...] to use the Cell Line,
Process and XXXXXXX Confidential Information solely for the purpose of
conducting the Project.
3.2 Materials and Information to be Provided.
To enable XXXXXX to begin and continue the Project, XXXXXXX shall
perform the work and tasks as laid down and detailed in APPENDIX 9
hereto and shall provide all materials and information as laid down
therein.
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4. XXXXXX RESPONSIBILITIES.
4.1 General.
In the course of this Agreement XXXXXX shall perform the work and tasks
as laid down and detailed in APPENDIX 10 hereto.
4.2 Documentation.
As soon as reasonably available XXXXXX shall provide XXXXXXX with the
CMC-part of the BLA (all other parts of registration and the
registration itself being the task and responsibility of XXXXXXX), in
formats to be mutually agreed upon. Such CMC-part shall be in English
and shall contain all required portions of the respective filing as laid
down in APPENDIX 2 hereto. All information provided under this section
shall be deemed to be XXXXXXX Confidential Information, except for
XXXXXX Confidential Information.
4.3 Stability Program.
The Stability Program shall be performed by XXXXXX as laid down in
APPENDIX 4 hereto. The timeline for this work is laid down in the Master
Projectplan including Project Timeline (Appendix 1).
4.4 Additional Work.
On request of XXXXXXX, XXXXXX shall perform additional work to sustain
the progress of the Project on conditions in terms of money, time and
scope to be subject to mutual agreement of the parties hereto
4.5 Reference to XXXXXX'x XXX.
XXXXXXX will be authorized by XXXXXX to reference XXXXXX'x XXX with
respect to the manufacture of the Product in support of XXXXXXX'x XXX.
4.6 BLA Timelines.
XXXXXXX will determine the filing date for the BLA. The current timeline
is listed in Appendix 1 and may be changed from time to time in writing
by XXXXXXX. XXXXXX will make reasonable efforts to meet the current
timeline. If XXXXXX is unable to meet the deadline, XXXXXX expressly
agrees that XXXXXXX may file as planned and XXXXXX data will be filed in
an amendment to the BLA.
5. PROJECT TO BE CONDUCTED ON [...***...] BASIS.
The Project shall be conducted by XXXXXX for XXXXXXX on [...***...]
basis, in consideration of payment by XXXXXXX of the Project Fee.
XXXXXXX acknowledges that the Project is experimental in nature and that
no favorable or useful result can be assured by XXXXXX. Accordingly
provided XXXXXX has complied with the terms of this Agreement, XXXXXX
shall not be responsible to XXXXXXX for any failure of fermentations or
inability to obtain useful yields of Product, and the Project Fee shall
be payable in full regardless of result unless the Project is terminated
prior to its scheduled completion pursuant to Section 12 hereof.
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6. PROJECT FEE.
XXXXXXX shall pay XXXXXX a Project Fee of [...***...] for the services
provided in carrying out the Project. This fee includes XXXXXX'x work
according to Article(degree)4 hereof. Disposal of organic and hazardous
waste is included in the Project Fee. The Project Fee shall be payable
in [...***...] as provided for in the Master Projectplan (APPENDIX 1).
XXXXXX shall have the right to receive adequate installments according
to the progress of the Project, in accordance with APPENDIX 1.
Each invoice shall be payable within 60 clays following of the
respective due date as laid down in the Master Projectplan (APPENDIX 1)
and upon receipt by XXXXXXX of the report for each section of the
workplan which result in an invoice, whatever is later.
7. ORDERING START-UP MATERIAL FOR [...***...] HARVEST.
XXXXXXX and XXXXXX expect that a raw material purchase for Phase III
will be necessary prior to the signment of this Agreement. This is
already covered by the Amendment No. 1 to the Feasibility Agreement as
of June 2, 1997 for the amount of [...***...].
8. OWNERSHIP OF PROJECT DATA / FUTURE ACTIVITIES / COMMERCIAL PRODUCTION.
8.1 Ownership of Project Data.
In consideration of the Project Fee, XXXXXX shall carry out the Project
and transfer all relevant information and materials obtained in the
course of the Project to XXXXXXX. However, this shall not apply to
information regarding XXXXXX'x facility and technical equipment. All
transferred information including but not limited to inventions,
know-how, data, trade secrets and materials - with the exception of
XXXXXX Confidential Information - shall be the sole and exclusive
property of XXXXXXX and XXXXXXX shall have the right to use such
information for any purpose without further obligation to XXXXXX.
XXXXXXX shall have a [...***...] license to use XXXXXX Confidential
Information that is used in carrying out the process to file for
regulatory approval, market, and sell the Product.
8.2 Further Future Activities regarding Research and Development.
If the results of the Project are favorable, XXXXXX and XXXXXXX may
confer to determine if additional work should be undertaken pursuant to
subsequent agreement between XXXXXX and XXXXXXX. Neither party shall be
obligated to conduct any further undertakings on behalf of the other
except as provided for herein or as may be mutually agreed and set forth
in a subsequent written agreement.
XXXXXXX shall not assert any right to use XXXXXX facilities at any
future date as a result of its use of XXXXXX facilities pursuant to this
Agreement.
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8.3 XXXXXX'x Right for Commercial Production and Supply.
The parties acknowledge and agree that, in case XXXXXXX decides to
commercialize the Product, and provided the Product is held biologically
equivalent by the respective regulatory authorities of the USA and EU,
XXXXXX has [...***...] to produce and supply commercial quantities of
the Product (in bulk drug, final product and/or finished product form)
to XXXXXXX within its respective capacity not exceeding the present
forecast estimation of XXXXXXX as laid down in APPENDIX 11.
Promptly upon the execution of this Agreement the parties shall
negotiate in good faith and consummate a multi-year commercial supply
agreement at the earliest opportunity for the supply by XXXXXX of
commercial quantities of the respective Product for the period as of
first commercial marketing until [...***...] any prolongation to be
subject to separate agreement of the parties. This commercial supply
agreement shall be [...***...].
8.4 Terms and Conditions of Supply Agreement.
Such agreement shall contain terms and conditions customary for such a
supply agreement.
In particular, the parties hereby agree that the pricing from XXXXXX for
the Product under such supply agreement shall be in accordance with a
volume discount pricing matrix as set forth in Appendix 7 attached
hereto, which pricing matrix will establish an absolute initial price
ceiling for the Product under the supply agreement and will provide a
framework to establish the Product costs for variable length production
campaigns.
In APPENDIX 11 XXXXXXX has laid down its present forecast estimation of
its total requirements of Product. This forecast is non-binding however,
XXXXXX'x capacity planning for commercial supply is based on and ceiled
by XXXXXXX'x forecast.
XXXXXX will make reasonable efforts to provide additional material as
requested by XXXXXXX and the Parties shall negotiate the terms and
conditions (e.g. in time and money) thereof in good faith..
9. REPRESENTATIONS, WARRANTIES AND INDEMNIFICATION.
9.1 XXXXXXX.
XXXXXXX hereby represent, warrant and agree that:
(a) XXXXXXX is free to supply the Cell Line and XXXXXXX Confidential
Information to XXXXXX;
(b) XXXXXXX is not aware of any special or unusual hazards involved
in handling the Cell Line or Product;
(c) XXXXXXX has full corporate authority, subject to Board of
Directors approval to enter into this Agreement and this
Agreement is binding upon XXXXXXX in accordance with its terms;
and
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(d) XXXXXXX shall indemnify, defend and hold XXXXXX, its affiliates,
and their respective officers, employees and agents harmless from
and against all losses, damages, costs and expenses (including,
without limitation, reasonable attorneys' fees), including injury
to persons or damage to property resulting from (i) any breach of
the representations and warranties made by XXXXXXX under this
Section, or (ii) as a result of any claim of infringement of the
intellectual property rights of a third party based upon XXXXXX'x
activities in implementing the Process or producing the Product
in accordance with the instructions and documentation provided by
XXXXXXX or developed in the course of the Project, or (iii) as a
result of the use by XXXXXXX of the results of the Project or the
use of any Product by XXXXXXX or any third party.
[...***...]
9.2 XXXXXX.
XXXXXX hereby represents, warrants and agrees that:
(a) XXXXXX is the owner of the facilities and XXXXXX Confidential
Information to be used for purposes set forth in this Agreement;
(b) XXXXXX is not aware of any special or unusual hazards that would
arise as a result of its carrying out of the Project as planned;
(c) XXXXXX has full corporate authority, subject to Board of
Directors approval to enter into this Agreement and this
Agreement is binding upon XXXXXX in accordance with its terms;
and
(d) XXXXXX shall indemnify, defend and hold XXXXXXX and its officers,
employees and agents harmless from and against all losses,
damages, costs and expenses (including, without limitation,
reasonable attorneys' fees), including injury to persons or
damage to property, resulting (i) from any breach of the
representations and warranties made by XXXXXX under this Section,
or (ii) of any claim that XXXXXX has violated any local law or
ordinance in carrying out its biotechnical manufacturing
responsibilities under this Agreement, or (iii) of any claim of
infringement of the intellectual property rights of a third party
based upon XXXXXX'x use of XXXXXX Confidential Information.
[...***...]
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10. LIABILITY.
10.1 No Warranty of Merchantability or Fitness.
XXXXXX shall provide the results of the Project to XXXXXXX without any
warranty of any kind, express or implied, including, without limitation,
any warranties of merchantability or fitness for a particular purpose.
XXXXXX warrants solely that the Project shall be conducted as described
to XXXXXXX and in accordance with this Agreement and all applicable
laws, and that any documentation of Project results or procedures
provided to XXXXXXX by XXXXXX shall be accurate in all material
respects.
10.2 Limitation of Liability.
XXXXXX has no knowledge or awareness of or control over the manner in
which XXXXXXX intends to use any Product or results obtained in the
Project, and in particular does not know whether XXXXXXX intends to use
such Product or results for a therapeutic or other pharmaceutical
purpose, whether in preclinical or clinical studies or otherwise. XXXXXX
shall not be liable to XXXXXXX for any losses, damages, costs or
expenses of any nature incurred or suffered by XXXXXXX or by a third
party, arising out of any dispute or other claims or proceedings made by
or brought against XXXXXXX in respect of the results of the Project, or
the use of any Product by XXXXXXX or by a third party (including,
without limitation, product liability claims and claims by a third party
alleging infringement of its intellectual property rights), nor shall
XXXXXX be responsible in any way for dealing with any such disputes,
claims or proceedings.
XXXXXXX shall indemnify, defend and hold XXXXXX, its affiliates and
their respective officers, employees and agents harmless from and
against all such losses, damages, costs and expenses (including, without
limitation, reasonable attorneys' fees).
10.3 Maximum Amount.
XXXXXX undertakes to use its best efforts to perform the Project under
the Master Project plan and to meet the target dates set forth in
Appendix 1 hereto. However, due to the biological nature of the work to
be performed hereunder XXXXXX'x liability under this Agreement shall in
no event amount to more than the cost for the replacement of
[...***...].
10.4 Product and/or Materials destroyed at XXXXXX facilities.
XXXXXX shall be liable for Product and/or Materials destroyed at XXXXXX
facilities.
11. CONFIDENTIALITY.
11.1 XXXXXX shall not disclose XXXXXXX Confidential Information to any person
other than its employees or employees of affiliated companies of the
Boehringer Ingelheim group who have a need to know such information in
order to perform their duties in carrying out the Project hereunder.
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11.2 XXXXXXX shall not disclose any XXXXXX Confidential Information to any
person other than
(a) its employees or consultants who are bound by similar obligations
of confidentiality and who have a need to know such information
in order to provide direction to XXXXXX or evaluate the results
of the Project, or
(b) regulatory authorities, for example, the FDA, that require such
information in order to review an IND or other regulatory filing.
11.3 The obligations of confidentiality applicable to XXXXXXX Confidential
Information and XXXXXX Confidential Information shall not apply to any
information that is:
(a) known publicly or becomes known publicly through no fault of the
recipient;
(b) learned by the recipient from a third party entitled to disclose
it;
(c) developed by the recipient independently of information or
materials obtained from the disclosing party;
(d) already known to the recipient before receipt from the disclosing
party, as shown by its prior written records;
(e) required to be disclosed by law, regulation or the order of a
judicial or administrative authority; or
(f) released with the prior written consent of the disclosing party.
11.4 No right or license, either express or implied, under any patent or
proprietary right is granted hereunder by virtue of the disclosure of
XXXXXXX Confidential Information or XXXXXX Confidential Information.
Either party shall be entitled to injunctive relief in the event of a
breach of this Agreement by. the other party. The obligations of both
parties under this Section 11 shall survive the expiration or
termination of this Agreement. Both XXXXXXX and XXXXXX shall use
reasonable and customary precautions to safeguard XXXXXXX Confidential
Information and XXXXXX Confidential Information, including ensuring that
all employees or consultants who are provided access to such information
are informed of the confidential and proprietary nature of such
information and understand that all such information is required to be
maintained confidential.
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12. TERM AND TERMINATION.
12.1 Term.
This Agreement shall, unless terminated earlier, commence as of the
Effective Date and shall terminate upon the date of payment of the last
sum due hereunder, or upon the date when the last services required to
be performed hereunder are performed, whichever date shall last occur.
12.2 Right to Terminate.
If it becomes apparent to either party at any stage of the Project that
it will not be possible to carry out the Project for material scientific
or technical reasons or as a result of Force Majeure, the parties shall
permit thirty (30)) business days or as mutually agreed by the parties
for discussion to resolve, if possible, the scientific or technical
issue giving rise to the problem. If the parties fail to resolve the
problem, either party shall have the right to terminate this Agreement
effective upon written notice to the other or to identify a mutually
agreed upon way to work around the Force Majeure. In the event of such
termination, the amount due to XXXXXX hereunder shall include
[...***...] and [...***...].
Either party may terminate this Agreement effective upon written notice
if either of the following events occurs.
(a) The other party commits a material breach of this Agreement and
the material breach is not remedied within 30 days after the
receipt of written notice identifying the material breach and
requiring its remedy; or
(b) The other party (I) becomes unable to pay its debts as they
become due, (II) suspends payment of its debts, (III) enters into
or becomes subject to corporate rehabilitation or bankruptcy
proceedings or liquidation or dissolution, (IV) makes an
assignment for the benefit of its creditors or (V) seeks relief
under any similar laws for debtor's relief.
12.3 Effect of Termination.
Upon the expiration or termination of this Agreement:
(a) At the request of XXXXXXX, XXXXXX shall either destroy the Cell
Line as well as the material derived from its culture or deliver
the same to XXXXXXX or a party nominated by XXXXXXX at XXXXXXX'x
cost and shall promptly return all XXXXXXX Confidential
Information to XXXXXXX; except for a single copy and/or sample of
each material for documentation purposes only. [...***...] and
(b) XXXXXXX shall promptly return all XXXXXX Confidential Information
to XXXXXX, except for a single copy and/or sample for
documentation purposes only.
The respective rights of XXXXXX and XXXXXXX to indemnification as
set forth in Section 9 hereof shall survive termination of this
Agreement with respect to any claims that relate to or derive
from the Project, or any acts or failures to act,
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of either XXXXXX or XXXXXXX in connection with the Project that
occur prior to termination.
Section 8.1 shall survive termination of this Agreement; paragraphs
11.1, 11.2, 11.3 and 11.4 shall survive termination of this Agreement
for a period of [...***...] from the Start Date.
13. FORCE MAJEURE.
Neither party shall be in breach of this Agreement if there is any
failure of performance under this Agreement (except for payment of any
amounts due hereunder) occasioned by any act of God, fire, act of
government or state, war, civil commotion, insurrection, embargo,
prevention from or hindrance in obtaining energy or other utilities,
labor disputes of whatever nature or any other reason beyond the control
of either party.
14. PUBLICITY.
No press release or other form of publicity regarding the Project or
this Agreement shall be permitted by either party to be published unless
both parties have indicated their consent to the form of the release in
writing.
15. NOTICES.
Any notice required or permitted to be given hereunder by either party
shall be in writing and shall be (a) delivered personally, (b) sent by
registered mail, return receipt requested, postage prepaid or (c)
delivered by facsimile with immediate telephonic confirmation of
receipt, to the addresses or facsimile numbers set forth below:
If to XXXXXX: Xx. Xxxx Xxxxxx GmbH
Xxxxxxxxxxxx Xxxxxxx 00
D-88397 Biberach an der Riss
Federal Republic of Germany
Attention: Prof. Dr. Roll X. Xxxxxx
(cc. Xx. Xxxxxxxx Xxx)
Fax: 0 73 51/54-51 31
Phone 0 73 51/54-48 00
If to XXXXXXX:Xxxxxxx Pharmaceutical Inc.
000 Xxxxxxxxxx Xxxxxx, Xxxxx 000
Xxxx Xxxx
Xxxxxxxxxx, XXX, 00000-0000
Attention: Xx. Xxxx Xxxxxxx (cc. Xxxxxxx X. Xxxxxx)
Fax: 000-000-0000
Phone 000-000-0000
Each notice shall be deemed given (a) on the date it is received if it
is delivered personally, (b) 1 day after the date it is postmarked if it
is sent by certified United States
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mail, return receipt requested, postage prepaid or (c) on the date it is
received if it is sent by facsimile with immediate telephonic
confirmation of receipt.
16. APPLICABLE LAW.
This Agreement shall be governed by and construed in accordance with the
laws of the place of domicile of the party sued and the courts of the
place of domicile of the party sued shall have exclusive jurisdiction
over all legal matters and proceedings hereunder.
17. COMPLIANCE WITH LAWS.
XXXXXX shall perform the work hereunder in conformance with GMP, as
applicable, and all German and/or EEC laws, ordinances and governmental
rules or regulations pertaining thereto.
18. INDEPENDENT CONTRACTORS.
Each of the parties hereto is an independent contractor and nothing
herein contained shall be deemed to constitute the relationship of
partners, joint ventures, nor of principal and agent between the parties
hereto. Neither party shall hold itself out to third persons as
purporting to act on behalf of, or serving as the agent of, the other
party.
19. WAIVER.
No waiver of any term, provision or condition of this Agreement whether
by conduct or otherwise in any one or more instances shall be deemed to
be or construed as a further or continuing waiver of any such term,
provision or condition or of any other term, provision or condition of
this Agreement.
20. SEVERABILITY.
If any provision of this Agreement is held to be invalid or
unenforceable by a court of competent jurisdiction all other provisions
shall continue in full force and effect.
The parties hereby agree to attempt to substitute for any invalid or
unenforceable provision a valid or enforceable provision which achieves
to the greatest extent possible the economic legal and commercial
objectives of the invalid or unenforceable provision.
21. ENTIRETY.
This Agreement, including any exhibits and appendices attached hereto
and referenced herein, constitutes the full understanding of the parties
and a complete and exclusive statement of the terms of their agreement,
and no terms, conditions, understandings or agreements purporting to
modify or vary the terms thereof shall be binding unless it is hereafter
made in writing and signed by both parties. This Agreement has been
prepared in English language and the English language shall control its
interpretation.
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22. ASSIGNMENT.
This Agreement shall be binding upon the successors and assigns of the
Parties and the name of a party appearing herein shall be deemed to
include the names of its successors and assigns, provided always that
nothing herein shall permit any assignment by either party, except as
XXXXXX may assign this Agreement to an affiliated company taking over
the operative biotech business of XXXXXX, and XXXXXXX may assign in the
case of a merger or acquisition or transfer of list assets related to
the Agreement.
IN WITNESS WHEREOF, the parties have caused this Agreement to be executed as of
the Effective Date.
XXXXXXX PHARMACEUTICAL INC. XX. XXXX XXXXXX GmbH
By /s/ Xxxxxxx X. Xxxxxx /s/ Xx. Xxxxx /s/ Dr. Micheberger
--------------------------- ---------------------------------------------
Title Vice President and CFO Xx. Xxxxx Xx. Xxxxxxxxxxxx
------------------------ ---------------------------------------------
(Member of the Board) (Head of Legal Dept.)
Date October 30, 1997 22 October 1997
------------------------- ---------------------------------------------
APPENDICES:
Appendix 1 Master Project plan including Project Timeline
Appendix 2 Tasks of the parties with respect to Documentation and XXXXXX'x
Documentation Work regarding CMC-part of BLA
Appendix 3 Present cost estimate for initial material (see Appendix 1 to the
Amendment No. 1 to the Feasibility Agreement)
Appendix 4 Stability Program
Appendix 5 Specifications and Test Methods for the Product
Appendix 6 Project Managers and Project Team Members
Appendix 7 Basic Production Assumptions and Pricing System for Commercial
Supply
Appendix 8 Flow Chart on Fermentation, Purification and Filling Process
Appendix 9 XXXXXXX'x Responsibilities
Appendix 10 XXXXXX'x Tasks in Detail
Appendix 11 Forecast Estimation of XXXXXXX'x total Requirements of Product
14
15
APPENDIX 1
--------------------------------------------------------------------------------
MASTER PROJECTPLAN : ANTI-B1
XXXXXXX PHARMACEUTICAL / XXXXXX
Forecast of proposed Workscope and Cost Estimate
Scale up to Commercial Scale [...***...]
--------------------------------------------------------------------------------
TIME TOTAL DATE OF
LINE WORKSCOPE COST INVOICE
[...***...]
--------------------------------------------------------------------------------
[...***...] [...***...] [...***...] [...***...]
--------------------------------------------------------------------------------
APPENDIX 1
MASTER PROJECT PLAN: ANTI-B1
XXXXXXX PHARMACEUTICALS/XXXXXX
Premises:
Fermentation / Purification Process
[...***...]
Filing Process
[...***...]
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APPENDIX 1
TIMELINE XXXXXXX ANTI-B1 MANUFACTURING H84
[...***...]
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APPENDIX 2:
TASKS OF THE PARTIES WITH RESPECT TO DOCUMENTATION AND XXXXXX'X
DOCUMENTATION WORK REGARDING CMC-PART OF BLA
BIOLOGICS LICENSE APPLICATION
--------------------------------------------------------------------------------
Table of Content Data Source
--------------------------------------------------------------------------------
I. INTRODUCTION
--------------------------------------------------------------------------------
II. DRUG SUBSTANCE
A. DESCRIPTION AND CHARACTERIZATION
1. Description
2. Characterization / Proof of Structure
a. Physicochemcial Characterization of [...***...]
Reference Standard and Qualifing Lots
--------------------------------------------------------------------------------
b. Biological Activity
[...***...]
--------------------------------------------------------------------------------
B. MANUFACTURER(S)
1. Identification
2. Floor Diagram
3. Other Products [...***...]
C. METHOD(S) OF MANUFACTURE
1. Raw Material
2. Flow Charts
-------------------------------------------------------------------------------
3. Detailed Description
a. Animals Sources
b. Cellular Sources
i. Cell Substrate Monoclonal Antibodies [...***...]
ii. Cell Seed Lot System
A. Master Cell Bank [...***...]
--------------------------------------------------------------------------------
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--------------------------------------------------------------------------------
Table of Content Data Source
--------------------------------------------------------------------------------
B. Working Cell Bank [...***...]
--------------------------------------------------------------------------------
C. End of Production Cells (EPC)
iii. Cell Growth and Harvesting [...***...]
c. Purification and Downstream Processing
4. Batch Record
--------------------------------------------------------------------------------
D. PROCESS CONTROL
1. In-Process Controls
-------------------------------------------------------------------
2. Process Validation
a. Validation Studies for the Cell Growth and
Harvesting Process
b. Validation Studies for the Purification [...***...]
Process
-------------------------------------------------------------------
c. Microbiology
--------------------------------------------------------------------------------
E. REFERENCE STANDARD(S)
1. Primary Reference Standard [...***...]
-------------------------------------------------------------------
2. Working Reference Standard (is Used)
--------------------------------------------------------------------------------
F. SPECIFICATION / ANALYTICAL METHODS
1. Drug Substance Specification and Tests
a. Specifications and Analytical Methods
b. Certificates of Analysis and Analytical
Results
-------------------------------------------------------------------
2. Impurities Profile
-------------------------------------------------------------------
G. CONTAINER / CLOSURES SYSTEM [...***...]
--------------------------------------------------------------------------------
H. DRUG SUBSTANCE STABILITY [...***...]
--------------------------------------------------------------------------------
III. DRUG PRODUCT [...***...]
A. COMPOSITION
B. SPECIFICATIONS & METHODS DRUG INGREDIENTS
1. Drug Substance Including all active Ingredients
--------------------------------------------------------------------------------
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--------------------------------------------------------------------------------
Table of Content Data Source
--------------------------------------------------------------------------------
2. Excipients
a. Compendial Excipient(s)
b. Non-Compendial Excipient(s)
--------------------------------------------------------------------------------
C. MANUFACTURER(S)
D. METHODS OF MANUFACTURE AND PACKAGING [...***...]
E. SPECIFICATION & TEST METHODS FOR DRUG PRODUCT
1. Sampling Procedures [...***...]
2. Specification & Methods [...***...]
F. CONTAINER / CLOSURE SYSTEM [...***...]
G. MICROBIOLOGY [...***...]
--------------------------------------------------------------------------------
H. DRUG PRODUCT STABILITY [...***...]
--------------------------------------------------------------------------------
IV. INVESTIGATIONAL PRODCUT/FORMULATION [...***...]
--------------------------------------------------------------------------------
V. ENVIRONMENTAL ASSESSMENT
VI. METHOD VALIDATION [...***...]
VII.REFERENCES
--------------------------------------------------------------------------------
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APPENDIX 3 THE START-UP MATERIAL IS ALREADY COVERED BY THE AMENDMENT NO. 1 TO
THE FEASIBILITY AGREEMENT OF JUNE 2, 1997
--------------------------------------------------------------------------------
START-UP MATERIAL COMMERCIAL SCALE [...***...]
MASTER PROJECTPLAN : ANTI-B1
--------------------------------------------------------------------------------
Quantity Price/Unit Total Amount
[...***...] [...***...]
--------------------------------------------------------------------------------
Start-up Material Commercial Scale
[...***...]
--------------------------------------------------------------------------------
Fermentation
[...***...] [...***...] [...***...] [...***...]
--------------------------------------------------------------------------------
Purification
[...***...] [...***...] [...***...] [...***...]
--------------------------------------------------------------------------------
Total Start-up Material [...***...]
--------------------------------------------------------------------------------
[...***...]
*Confidential Treatment Requested
21
APPENDIX 4
STABILITY STUDIES
------------------------------------------------------------------------------------------------
DESCRIPTION CONDITIONS TIME POINTS
------------------------------------------------------------------------------------------------
[...***...] L Lot No. 1 - Intermediate [...***...] To be defined once process
and hold steps
------------------------------------------------------------------------------------------------
[...***...] are finalized
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
[...***...] X Xxx Xxx. 0, 0 & 0 - XXX [...***...] [...***...] months
------------------------------------- -------------------------- -------------------------------
[...***...] [...***...] months
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
[...***...] X Xxx Xxx. 0, 0 & 0 - Xxxx [...***...] [...***...] months
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
[...***...] [...***...] months
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
[...***...] [...***...] days
------------------------------------------------------------------------------------------------
------------------------------------- -------------------------- -------------------------------
TEST METHOD BULK FINAL CONTAINER
================================================================================================
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
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22
APPENDIX 5 a
------------------------------------------------------------------------------------------------
Product Specification Doc. Number: PSP/PCP XXXXX
ANTI-B1 ANTIBODY BULK Effective Date: DRAFT
Manufactured by Xx. Xxxx Xxxxxx GmbH Page Number: 1 of 3
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
PRODUCT DESCRIPTION
------------------------------------------------------------------------------------------------
Purified Monoclonal Antibody Bulk directed against [...***...] formulated in
[...***...].
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
PART NUMBER: LOT NUMBER: STORAGE CONDITIONS [...***...]
------------------------------------------------------------------------------------------------
MANUFACTURER: XXXXXX MANUFACTURE DATE EXPIRATION DATE [...***...]
------------------------------------------------------------------------------------------------
ATTRIBUTE TEST METHOD SPECIFICATION
------------------------------------------------------------------------------------------------
QUALITY
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
IDENTITY
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] Comparable to Reference;
Report pl range of bands
present
------------------------------------------------------------------------------------------------
[...***...] [...***...] Comparable to Reference
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
COMPOSITION
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
-------------------------------- ------------------------------- -------------------------------
------------------------------------------------------------------------------------------------
PURITY
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
Comparable to Reference
Reduced:
Comparable to Reference
[...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
Comparable to Reference
Report Results
------------------------------------------------------------------------------------------------
*Confidential Treatment Requested
23
APPENDIX 5 a
------------------------------------------------------------------------------------------------
POTENCY
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
SAFETY
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
FOR INFORMATION ONLY
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
ATTRIBUTE TEST METHOD SPECIFICATION
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
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APPENDIX 5 b
------------------------------------------------------------------------------------------------
Product Specification Doc. Number: PSP/PCA XXXXX
ANTI-B1 FINAL BAGGED PRODUCT Effective Date: DRAFT
for further manufacturing Page Number: 1 of 3
Manufactured by Xx. Xxxx Xxxxxx GmbH
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
PRODUCT DESCRIPTION
------------------------------------------------------------------------------------------------
Purified Monoclonal Antibody directed against [...***...] formulated in
[...***...].
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
PART NUMBER: LOT NUMBER: STORAGE CONDITIONS [...***...]
------------------------------------------------------------------------------------------------
MANUFACTURER: XXXXXX MANUFACTURE DATE EXPIRATION DATE [...***...]
------------------------------------------------------------------------------------------------
ATTRIBUTE TEST METHOD SPECIFICATION
------------------------------------------------------------------------------------------------
QUALITY
------------------------------------------------------------------------------------------------
Label [...***...] Identical to file copy
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
IDENTITY
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] Comparable to Reference;
Report pl range of bands
present
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
COMPOSITION
------------------------------------------------------------------------------------------------
[...***...] Mass [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
PURITY
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
Comparable to Reference
Reduced:
Comparable to Reference
[...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
Comparable to Reference;
Report Results
------------------------------------------------------------------------------------------------
*Confidential Treatment Requested
25
APPENDIX 5 b
------------------------------------------------------------------------------------------------
POTENCY
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
SAFETY
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...]
[...***...]
------------------------------------------------------------------------------------------------
FOR INFORMATION ONLY
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
ATTRIBUTE TEST METHOD SPECIFICATION
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
*Confidential Treatment Requested
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APPENDIX 5 c
------------------------------------------------------------------------------------------------
Product Specification Doc. Number: PSP/PCA XXXXX
ANTI-B1 ANTIBODY FINAL VIALED PRODUCT Effective Date: DRAFT
Manufactured by Xx. Xxxx Xxxxxx GmbH Page Number: 1 of 2
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
PRODUCT DESCRIPTION
------------------------------------------------------------------------------------------------
Purified Monoclonal Antibody directed against [...***...] formulated in
[...***...]
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
ATTRIBUTE TEST METHOD SPECIFICATION
------------------------------------------------------------------------------------------------
QUALITY
------------------------------------------------------------------------------------------------
[...***...] [...***...] Identical to file copy
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
[...***...]
[...***...]
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
IDENTITY
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] Comparable to Reference;
Report pl range of bands
present
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
COMPOSITION
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
PURITY
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
[...***...] Comparable to Reference
Reduced:
Comparable to Reference
[...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
[...***...] Comparable to Reference;
Report Results
------------------------------------------------------------------------------------------------
*Confidential Treatment Requested
27
APPENDIX 5 c
------------------------------------------------------------------------------------------------
POTENCY
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
SAFETY
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...]
[...***...]
------------------------------------------------------------------------------------------------
FOR INFORMATION ONLY
------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------
ATTRIBUTE TEST METHOD SPECIFICATION
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
[...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
*Confidential Treatment Requested
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APPENDIX 6
MASTER-PROJECTPLAN: ANTI - B1
XXXXXXX PHARMACEUTICALS INC. XXXXXX
PROJECT MANAGERS AND PROJECT TEAMS MEMBERS
------------------------------------------------------------------------------------------------------------------------------------
ACTIVITY XXXXXX XXXXXXX
------------------------------------------------------------------------------------------------------------------------------------
STEERING COMMITTEE [...***...] [...***...]
------------------------------------------------------------------------------------------------------------------------------------
COMMUNICATIONS [...***...] [...***...]
------------------------------------------------------------------------------------------------------------------------------------
CONTRACTS [...***...] [...***...]
------------------------------------------------------------------------------------------------------------------------------------
QUALITY CONTROL, ANALYTICAL CHEMISTRY [...***...] [...***...]
------------------------------------------------------------------------------------------------------------------------------------
QUALITY ASSURANCE [...***...] [...***...]
------------------------------------------------------------------------------------------------------------------------------------
REGULATORY [...***...] [...***...]
------------------------------------------------------------------------------------------------------------------------------------
PROJECT MANAGEMENT [...***...] [...***...]
------------------------------------------------------------------------------------------------------------------------------------
DEVELOPMENT [...***...] [...***...]
------------------------------------------------------------------------------------------------------------------------------------
MANUFACTURING [...***...] [...***...]
------------------------------------------------------------------------------------------------------------------------------------
*Confidential Treatment Requested
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APPENDIX 7
------------------------------------------------------------------------------------------------
MASTER PROJECTPLAN : ANTI B1
XXXXXXX PHARMACEUTICAL / XXXXXX
------------------------------------------------------------------------------------------------
Basic Production Assumptions and Pricing System for Commercial Supply
------------------------------------------------------------------------------------------------
MANUFACTURING PROCESS PARAMETERS BULK PRODUCT
Scale [...***...] [...***...] [...***...]
Titer [...***...] [...***...] [...***...]
Overall Yield [...***...] [...***...] [...***...]
Total amount per run [...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
PRICE PER GRAM RELEASED PURIFIED BULK MATERIAL
Quantity per year Price per gram Price per gram Price per gram
[...***...] [...***...] [...***...] [...***...]
[...***...] [...***...] [...***...] [...***...]
[...***...] [...***...] [...***...] [...***...]
[...***...] [...***...] [...***...] [...***...]
------------------------------------------------------------------------------------------------
STERILE LIQUID FILLING [...***...] VIAL
Batch Size [...***...]
Final Dosage [...***...]
Fill Volume [...***...]
Price per released Vial [...***...]
[...***...]
------------------------------------------------------------------------------------------------
*) S = SURCHARGE
If the annual Quantity falls below the Minimum Quantity of [...***...]
of anti-B1 Xxxxxx will charge Xxxxxxx an annual surcharge, calculated as
follows:
[...***...]-
[...***...]
[...***...]
------------------------------------------------------------------------------------------------
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APPENDIX 8A: FERMENTATION SCHEME
[...***...]
[...***...]
[...***...]
[...***...]
[...***...]
[...***...]
[...***...]
[...***...]
[...***...]
[...***...]
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APPENDIX 8B: RECOVERY SCHEME
[...***...]
[...***...]
[...***...]
[...***...]
[...***...]
[...***...]
[...***...]
[...***...]
[...***...]
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APPENDIX 8C: FINAL VIAL SCHEME
[...***...]
[...***...]
[...***...]
[...***...]
[...***...]
[...***...]
[...***...]
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APPENDIX 9
XXXXXXX'X RESPONSIBILITIES
1. Materials and Information to be Provided
(a) sufficient vials of the Master Cell Bank [...***...] to enable
Xxxxxx to begin quarantine testing of [...***...] Cell bank.
(b) a Certificate of Analysis specifying [...***...] for complete
testing of the original [...***...] Master Cell Bank.
2. ACTIVITIES TO BE PERFORMED
As the Project is carried out, Xxxxxxx shall:
(a) conduct and conclude its existing Master Cell Bank [...***...]
stability testing program and supply data and results to Xxxxxx
as needed to assist with documentation of [...***...]; and
(b) at the request of Xxxxxx, transfer to Xxxxxx on a continuous
basis any available additional information concerning the
Process, analytical test methods, reference materials and any
critical reagents that Xxxxxxx deem necessary to facilitate the
Project.
(c) provide Xxxxxx with following parts of the BLA: [...***...]
(d) CPI retains final responsibility for [...***...].
(e) CPI will [...***...].
(f) Xxxxxxx will be responsible for definition of a [...***...].
*Confidential Treatment Requested
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APPENDIX 10
1. XXXXXX RESPONSIBILITIES (PHASE I-III)
1.1 Control of Cell Line
Xxxxxx shall maintain the Cell Line in safe and secure storage under its
control in its facilities and shaft not permit the transfer of the Cell
Line to any third party that is not specifically authorized by Xxxxxxx.
Xxxxxx shall comply with all applicable regulatory requirements relating
to general safety and biosafety in handling the Cell Line and any raw
materials used in the Project.
1.2 Quarantine and Testing
Commencing as of the Start Date, Xxxxxx will quarantine and test the
Cell Line samples provided to it in order to verify that the Cell Line
is suitable for introduction into Xxxxxx'x facilities. The quarantine
and testing time is estimated to be about [...***...].
1.3 Fermentation
Following verification of the Cell Line, Xxxxxx will adapt the Xxxxxxx
cell line [...***...] in its pilot facility to a generic Xxxxxx process
as laid down in the Master Projectplan (Appendix 1 ).
Within the scope of the Process described by Xxxxxx. Xxxxxx will
[...***...] to adapt the Process and achieve success in establishing a
suitable process in its fermentors, followed by implementation of the
process as an applicable large-scale form, laid down in the Master
Projectplan (Appendix 1).
1.4 Downstream Processing
Upon completion of fermentation at the respective scale, Xxxxxx shall
adapt a suitable generic downstream process and adequate purification
steps of the process in its facilities. Xxxxxx will [...***...] to
establish and document, in its facilities, analytical methods for
inprocess control, release testing and characterization of the product
as laid down in the Master Projectplan (Appendix 1).
1.5 Contractor will be responsible for performing all testing according to
the bulk and final product specifications.
1.6 Contractor will be responsible for stability studies for the [...***...]
lots to establish shelf life according to a protocol reviewed and
approved by CPI.
1.7 Sterile Liquid Filling Process
If purification of the Product is successful, Xxxxxx will [...***...]
to establish a sterile liquid filling process for the Product in its
facility.
1.8 Cleaning Validation
Xxxxxx will establish cleaning validation protocols and reports that
have been employed on the Xxxxxxx process in Thomaes facilities. Based
upon this information and its own facility operating procedures. Xxxxxx
shall develop appropriate cleaning protocols.
*Confidential Treatment Requested
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1.9 Materials and Information to be Delivered
Xxxxxx will provide Xxxxxxx with the materials and information as
described in the Master Projectplan (Appendix 1 ) at the times indicated
therein.
1.10 Product to be Delivered
Based upon the premises (Appendix 1 ) attached, and if the basic process
parameters are met, Xxxxxx shall supply Product derived from the Project
as laid down in Appendix 1 to Xxxxxxx for clinical testing and market
supply. All product produced in the course of the Project shall be
retained by Xxxxxx, stored under conditions specified by Xxxxxxx not
longer than [...***...] as of production, and delivered to Xxxxxxx as
instructed by Xxxxxxx and at the cost and risk of Xxxxxxx.
1.11 Prior Approval
Prior to implementing any deviation from the Process, Xxxxxx shall
notify Xxxxxxx and obtain the approval of the Project Manager or other
responsible person at Xxxxxxx. Additional development work beyond the
Project activities shall be approved by Xxxxxxx and shall be charged
separately.
1.12 Retention Samples
Xxxxxx shall isolate, identify and retain samples of all raw materials
used in fermentations carried out in the course of the Project, obtain
retention samples of Process media at appropriate time points in each
fermentation, and retain samples of Product at each appropriate stage of
purification. Retention samples shall be provided to Xxxxxxx at its
request within [...***...]. Shipment shall be at the cost and risk of
Xxxxxxx.
*Confidential Treatment Requested
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APPENDIX 11
Manufacturing Forecast for Xxxxxxx B1 Therapy
Draft for Discussion Purposes only
YEARS
(IN GRAMS) [...***...] [...***...] [...***...] [...***...] [...***...]
US Demand [...***...] [...***...] [...***...] [...***...] [...***...]
European Demand [...***...] [...***...] [...***...] [...***...] [...***...]
Total Demand [...***...] [...***...] [...***...] [...***...] [...***...]
Assumes:
[...***...]
[...***...]
*Confidential Treatment Requested
