KBI BIOPHARMA, INC. SERVICES AGREEMENT
This Services Agreement ("Agreement") dated March 28, 2006 between DNAprint
Pharmaceuticals, Inc., a Utah company ("Client") having its principal place of
business at ▇▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇, ▇▇▇▇▇▇▇▇, ▇▇ ▇▇▇▇▇ and KBI BioPharma, Inc., a
Delaware company ("KBI BioPharma") having its principal place of business at
▇▇▇▇ ▇▇▇▇▇▇ ▇▇▇▇, ▇▇▇▇▇▇, ▇▇▇▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇▇ (each a "Party", collectively the
"Parties").
Whereas:
Client desires KBI BioPharma to perform services in accordance with the terms of
the Agreement and KBI BioPharma desires to perform such services.
In consideration of the above statements, which form part of the Agreement, and
other good and valuable consideration, the sufficiency and receipt of which are
hereby acknowledged, the Parties hereto agree as follows:
1. Performance
KBI BioPharma will perform the services (the "Services")detailed in the proposal
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set forth in Attachment One (the "Proposal") on behalf of Client in accordance
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with the Agreement herein incorporating the Proposal and incorporating the
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Quality Agreement (applicableonlyfor projectswith cGMP activities) attached
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hereto as Attachment Two. In the event of any conflict between the Agreement
and the proposal and/or scope-of-work, the Agreement shall control. In the
event of any conflict between the Proposal and/or scope-of-work and any
applicable Quality Agreement, the Quality Agreement shall control.
Client shall support and cooperate with the execution of the services and shall
not engage in any act or omission, which may reasonably be expected to prevent
or delay the successful execution of the Services. Such support and cooperation
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shall include, but not be limited to, informing KBI BioPharma of global
regulatory strategy for development and approval of the product(s) to the extent
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relevant to the Proposal, prompt review and approval of documents requiring
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Client's signature, timely delivery of methods and materialsand prompt response
to other similar issues.
2. Compliance with Applicable Government Regulations
KBI BioPharma will undertake the services in compliance in all material respects
with applicable U.S. Food and Drug Administration (FDA) current Good
Manufacturing Practice (cGMP) and all statutory and applicable international
regulatory requirements.
3. Client Obligations
Unless otherwise agreed to by the Parties in writing, Client is solely
responsible for, in each case as required for the Proposal and set forth in
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Attachment One: (a) provision of complete and accurate scientific data regarding
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the Proposal; (b) provision of all information necessary to effect the reliable
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transfer of methods to KBI BioPharma; (c) provision of specific reagents,
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reference standards or other materials necessary for execution of the Proposal;
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(d) if applicable, review and approve in-process and finished product test
results to ensure conformity of such results with product specifications,
regardless of which party is responsible for finished product release; (e)
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preparation of all submissions to regulatory authorities; and (f) performance of
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other obligations of Client set forth in the Proposal.
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4. Hazardous Materials
Client warrants to KBI BioPharma that no specific safe handling instructions are
applicable to any substance or material provided by Client to KBI BioPharma,
except as disclosed to KBI BioPharma in sufficient time for review and training
by KBI BioPharma prior to delivery. Where appropriate or required by law Client
shall provide a Material Safety Data Sheet and instructions for proper storage
for all Client-provided materials, finished product and reference standards.
5. Facility Visits and Audits
Client's representatives may visit KBI BioPharma's facilities during normal
business hours and with prior written notice to observe the progress of the
Proposal, provided that such access does not compromise cGMP compliance or
safety. KBI BioPharma will assist Client in scheduling such visits, which will
be conducted in a manner reasonably required to protect confidentiality of other
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clients.
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Client may conduct one quality assurance audit per calendar year at no cost in
accordance with the provisions of the Quality Agreement (if applicable).
Additional audits will be invoiced separately on a time and materials basis at
the then current rate for such services.
6. Regulatory Inspections
KBI BioPharma will promptly notify Client of any regulatory inspections directly
relating to the Proposal in accordance with the terms of the Quality Agreement
(if applicable) incorporated herein. Client accepts reasonable and documented
costs charged by a regulatory authority for inspections directly related to the
Proposal.
7. Compensation
KBI BioPharma will invoice Client as set forth in the Proposal. Payments are
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due thirty (30) days from date of invoice. Late payments are subject to an
interest charge of one and one half percent (1 %) per month. Failure to ▇▇▇▇
for interest due shall not be a waiver of KBI BioPharma's right to charge
interest.
8. Taxes
Client will pay any sales, use, gross receipts, compensating or other taxes,
licenses or fees (excluding KBI BioPharma's net income and franchise taxes) to
be paid by KBI BioPharma to any tax jurisdiction arising from the Proposal.
9. Change Orders
KBI BioPharma may revise the price for the Services as set forth in the Proposal
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if (a) Client revises KBI BioPharma's responsibilities, the specifications, the
Proposal instructions, procedures, assumptions, processes, test protocols, test
methods, analytical requirements or otherwise requests a modification to the
Proposal, (b) Client's requirements or any Client-provided information is
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inaccurate or incomplete and such inaccuracy or incompleteness results ina
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materialincrease incosts to KBI BioPharma,(c) necessitated by changes to
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applicable laws, rules or regulations (d) if necessitated by an event outside
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the control of KBI BioPharma, including , without limitation, the events
described in section 16 (Force Majeure) or(e) for other such reasons set out in
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the Proposal. Client will be notified of such revision via issuance of a Change
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Order detailing the reasons for the price revision and subject to Client's
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written consent.
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10. Shipment
Unless otherwise agreed in writing by the parties, all products, raw materials,
samples components or other materials shipped by KBI BioPharma are delivered
F.O.B. KBI BioPharma's facilities. KBI BioPharma shall package for shipment
such product, raw materials, samples, components or other materials at Client's
expense (including insurance) and in accordance with Client's full written and
reasonable instructions.
11. Limitations of Liability
Notwithstanding any other provision in the Proposal, KBI BioPharma's liability
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under the Proposal, regardless of the cause of action, shall not exceed the
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total fees paid and/or due hereunder. Notwithstanding the foregoing, KBI
BioPharma's liability for losses to Active Pharmaceutical Ingredient, bulk drug
product, intermediates, samples, reagents or other materials provided by Client,
whether or not incorporated into finished product, shall not exceed the
undisputed fair market value thereof, taking into consideration any delay to the
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Proposal caused by such loss.
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Notwithstanding anything herein to the contrary, UNDER NO CIRCUMSTANCES SHALL
EITHER PARTY BE ENTITLED TO INCIDENTAL, INDIRECT, CONSEQUENTIAL, EXEMPLARY OR
SPECIAL DAMAGES, WHETHER OR NOT FORESEEABLE, ARISING IN CONNECTION WITH THE
DEFAULT OR BREACH OF ANY OBLIGATION OF THE OTHER PARTY UNDER THIS AGREEMENT, THE
PROPOSAL, THE QUALITY AGREEMENT OR ANY APPENDICES OR DOCUMENTS RELATED THERETO,
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SUBJECT TO SECTION 15 HEREOF.
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12. Warranties
The warranties set forth in the Proposal and the terms and conditions of the
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Agreement herein are the sole and exclusive warranties made by KBI BioPharma to
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the Client and there are no other warranties, representations or guarantees.
EXCEPT AS EXPRESSLY STATED HEREIN, NEITHER PARTY PROVIDES TO THE OTHER PARTY
HERETO ANY WARRANTIES, EXPRESS OR IMPLIED WITH RESPECT TO THE MATERIALS AND
SERVICES PROVIDED HEREUNDER, AND ALL SUCH WARRANTIES, EXPRESS OR IMPLIED,
INCLUDING WITHOUT LIMITATION ANY IMPLIED WARRANTIES OF MERCHANTABILITY,
NONINFRINGEMENT OR FITNESS FOR A PARTICULAR PURPOSE ARE WAIVED.
13. Confidentiality
All information disclosed by a party in connection with the Proposal shall be
considered confidential information. For the duration of the Proposal and for a
period of five (5) years thereafter, neither Party shall disclose confidential
information disclosed by the other Party without prior written permission unless
such disclosure is (i) to an affiliate that is under similar obligation to keep
such information confidential; (ii) is or becomes publicly available through no
fault of the receiving Party; (iii) is disclosed by a third party entitled to
disclose it; (iv) is already known to the receiving Party as shown by its prior
written records; or (v) is required to be disclosed by any law, rule,
regulation, order, decision, decree, subpoena or other legal process provided
that the receiving Party shall give prompt notice thereof to the disclosing
Party and shall cooperate with the disclosing Party to obtain a confidentiality
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order or other similar protection.
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14. Intellectual Property
All KBI BioPharma Materials, including without limitation, all improvements,
development, derivatives or modifications to the KBI BioPharma Materials, shall
be owned exclusively by KBI BioPharma. For the purposes hereof, "KBI BioPharma
Materials" means all KBI BioPharma proprietary information, intellectual
property and developments, including without limitation, all patents, patent
applications, know-how, inventions, design, concepts, improvements, technical
information, manuals, instructions which are owned, licensed or used by KBI
BioPharma in developing, formulating, manufacturing, processing, packaging,
analysis or testing of pharmaceutical or diagnostic products.
All Client Materials, including without limitation, all improvements,
development, derivatives or modifications to the Client Materials, shall be
owned exclusively by the Client. For the purposes hereof, "Client Materials"
means all Client proprietary information, intellectual property and
developments, including without limitation, all patents, patent applications,
know-how, inventions, design, concepts, improvements, technical information,
manuals, instructions which are owned, licensed or used by Client relating to
pharmaceutical or diagnostic products or the development, formulation,
manufacture, processing, packaging, analysis or testing thereof.
15. Indemnification
Client will indemnify and hold harmless KBI BioPharma, its affiliates and their
officers, directors, agents, and employees against any loss, cost, damage or
expense (a "Loss") from any lawsuit, action, claim, demand, assessment or
proceeding brought by a third party(a "Claim") arising directly or indirectly
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from or related to the conduct of the Proposal as a result of Client's
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negligence, gross negligence or intentional misconduct or inaction (including
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violation or non-performance of this Agreement); provided that if such Loss or
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Claim arises in whole or part from KBI BioPharma's negligence, gross negligence
or intentional misconduct or inaction, then the amount of such loss that Client
shall indemnify KBI BioPharma for shall be reduced by an amount proportional to
KBI BioPharma's responsibilities for such Loss as determined by a court of
competent jurisdiction.
KBI BioPharma will indemnify and hold harmless Client, its affiliates and their
officers, directors, agents, and employees against any Loss or Claim arising
directly or indirectly from or related to the conduct of the Proposal as a
result of KBI BioPharma's negligence, gross negligence or intentional misconduct
or inaction (including violation or non-performance of this Agreement); provided
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that if such Loss or Claim arises in whole or part from Client's negligence,
gross negligence or intentional misconduct or inaction, then the amount of such
loss that KBI BioPharma shall indemnify Client for shall be reduced by an amount
proportional to Client's responsibilities for such Loss as determined by a court
of competent jurisdiction.
16. Force Majeure
Neither party will be liable for any failure to perform or for delay in
performance resulting from any cause beyond its reasonable control, including,
without limitation, acts of God, fires, floods, or weather, disease, strikes or
lockouts, factory shutdowns, embargoes, wars, hostilities or riots, acts of
terrorism, shortages in transportation, government action or power failure,
provided that such failure to perform shall be excused only to the extent of and
during such disability. Any time specified or estimated for completion of
performance of Servicesfalling due during or subsequent to the occurrence of any
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such events shall be automatically extended for a period of ninety (90) days to
recover from such disability. If any part of the Proposal is invalid as a
result of such disability, KBI BioPharma will, upon written request from Client,
and at Client's sole cost and expense, repeat that part of the Proposal affected
by the disability.
17. Use and Disposal
Client represents and warrants to KBI BioPharma that it has legal title and/or a
valid license to materials, process patents and other intellectual property
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necessary to conduct the Proposal and that KBI BioPharma's performance of the
Proposal will not violate or infringe on the patents, trademarks, service marks
or copyrights of any third party. Client further represents and warrants to KBI
BioPharma that it will hold, use and/or dispose of Product and materials
provided by KBI BioPharma in accordance with all applicable laws, rules and
regulations.
KBI BioPharma represents and warrants to Client that it has legal title and/or a
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valid license to materials, process patents and other intellectual property
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necessary to conduct the Services and that KBI BioPharma's performance of the
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Services will not violate or infringe on the patents, trademarks, service marks
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or copyrights of any third party. KBI BioPharma further represents and warrants
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to Client that it will hold, use and/or dispose of information and materials
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provided by Client in accordance with all applicable laws, rules and
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regulations.
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18. Independent Contractor
KBI BioPharma shall perform the Proposal as an independent contractor of the
Client and shall have complete and exclusive control over its facilities,
equipment, employees and agents. The relationship between the parties shall not
constitute a partnership, joint venture or agency nor constitute either party as
the agent, employee or legal representative of the other.
19. Publicity
Neither Party will make any press release or public disclosure or use the name
of the other party or its employees in any advertising or sales promotional
material without the other Party's express prior written consent.
20. Authority
Client grants KBI BioPharma full authority to use any Client supplied materials
or substances. Each party represents and warrants to the other party that it has
the full right and authority to enter into this Agreement and to perform in
accordance with the terms and conditions set forth herein. Each Party further
represents and warrants to the other Party that it has obtained and will, at all
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times during the term of this Agreement, hold and comply with all licenses,
permits and authorizations necessary to perform this Agreement as now or
hereafter required under any applicable statutes, laws, ordinances, rules and
regulations of the United States and any applicable foreign, state and local
governments and governmental agencies.
21. Amendment and Precedence
The Proposal, the terms and conditions herein and any applicable Quality
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Agreement constitute the entire agreement between the Parties relative to the
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Proposal and may not be modified without the mutual written consent of both
Parties.
22. Choice of Law
The Agreement between the Parties governed by these standard terms and
conditions shall be construed and enforced in accordance with the laws of and in
the venue of the State of North Carolina except for its rules regarding conflict
of laws.
23. Dispute Resolution
If a dispute arises between the Parties in connection with this Agreement, the
respective presidents or senior executives of KBI BioPharma and Client shall
first meet as promptly as practicable and attempt to resolve in good faith such
dispute. If such parties cannot resolve the dispute, then the parties shall
attempt to settle the dispute through mediation in accordance with the rules of
the American Arbitration Association ("AAA"). Nothing herein shall subject the
parties to the jurisdiction of the AAA. The Parties shall participate in the
mediation in a good faith attempt to settle the dispute. The mediation shall be
held in Durham County, North Carolina. If mediation fails to resolve the
dispute, the dispute shall be resolved in the jurisdiction of the defendant by
binding arbitration, by a neutral arbitrator mutually selected by counsel from
each party, under the rules of the American Arbitration Association. Nothing
herein shall subject the parties to the jurisdiction of the AAA.
24. Assignment
The Agreement between the Parties shall not be assigned in whole or in part by
either Party without the prior written consent of the other, which consent shall
not be unreasonably withheld or delayedexcept that no such consent shall be
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required for an assignment by Client in whole or in part in connection with a
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merger or other business combination or sale of all or substantially all assets.
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25. Termination
Client may terminate this Agreement prior to completion of the Proposal by
providing sixty (60) days written notice to KBI BioPharma. Upon receipt of such
notice of termination, KBI BioPharma will promptly scale down the affected
portion of the Proposal and avoid (or minimize, where non-cancellable) any
further related expenses. In the event that Client elects to terminate for
reasons other than a material breach of this Agreement by KBI BioPharma that KBI
BioPharma fails to cure or commence such cure within thirty (30) days of written
notice of such breach, Client shall pay KBI BioPharma upon receipt of invoice
all of its costs incurred or irrevocably obligated related to the Proposal.
KBI BioPharma may terminate this Agreement prior to completion of the Proposal
by giving sixty (60) days written notice to Client in the event of a material
breach of this Agreement by Client that is not cured after a thirty (30) day
written notice of such breach. Upon such termination Client shall pay KBI
BioPharma upon receipt of invoice all of its costs incurred or irrevocably
obligated related to the Proposal.
The termination of this Agreement for any reason shall not relieve either Party
of its obligations to the other in respect of: (i) confidentiality; (ii)
consents for advertising purposes and publications; (iii) indemnification; (iv)
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intellectual property; and (v) compensation for Services performed.
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26. Survival
Sections 13, 14, 15, 18, 19, 22, 23 and this Section 26 of the terms and
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conditions hereinshall survive termination or expiration of the Agreement.
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In Witness Whereof, the Parties by their authorized representatives execute this
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Agreement as of the date first above written
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KBI BIOPHARMA, INC. CLIENT
By: By:
Name: Name: ▇▇▇▇▇▇ ▇. ▇▇▇▇▇, MD, PhD
Title: Title: Chairman and CMO
Date: Date: March 28, 2006
ATTACHMENT ONE: PROPOSAL
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ATTACHMENT TWO:QUALITY AGREEMENT
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QUALITY AGREEMENT
1. PURPOSE
This Quality Agreement defines the roles, responsibilities, deliverables and
reporting time requirements with respect to the quality activities for DNAprint
Pharmaceuticals, Inc. ("Client") Proposal for PT-401 Development and Production
performed at KBI BioPharma.
2. SCOPE
This document applies to and is incorporated into the Agreement between KBI
BioPharma and Client dated March 28, 2006 pertaining toPT-401.
3. DEFINITIONS
Any terms not defined in this Quality Agreement will be interpreted in
accordance with the definitions provided in ICH Q7A GMP Guidance for Active
Pharmaceutical Ingredients, 21 CFR, Parts 210 and 211, or other applicable
regulatory requirements.
3.1. CRITICAL CHANGE
Any change that: (a) impacts the regulatory commitments and/or reporting
requirements of the Client's API or drug product; (b) requires re-qualification
or re-validation of test methods, or reference standards; and/or (c) results in
changing or modifying the specifications or test methods.
3.2. CRITICAL DEVIATION
A deviation that has potential impact on product quality or the validation
status of a test method. These deviations require a thorough investigation to
determine the root cause and its impact on any product or test method.
3.3. FOR CAUSE VISIT
The term "For Cause Visit" is used to describe site visits where the Client may
be following up on a reported adverse event in the field or a critical deviation
impacting the quality of the Client's product. The term "For Cause Visit" does
not apply to business meetings, scope discussions, technical meetings or general
quality discussions. The visit scope and maximum number of participants will be
mutually agreed upon in advance.
3.4. QUALITY CONTACT
All communications concerning the scope of this Quality Agreement will be
between the Quality Contacts, named below:
For Client:
CMO (Title), Quality Assurance
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For KBI BioPharma:
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(Title), Quality Assurance
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In the event of a change, temporary or otherwise, of either Party's Quality
Contact, the Party making the change will notify the other Party in writing
prior to such a change.
3.5. TECHNOLOGY TRANSFER PACKAGE
A set of documents supporting technical transfer of analytical methods. Key
documentation included in the package includes the method development reports,
validation reports and analytical test procedures for methods to be transferred.
4. QUALITY PROGRAM
The quality program at KBI BioPharma provides:
- An organization with a focus on building quality into the product, using
balanced risk management in quality decisions and meeting of company business
objectives
- An understanding of executive management's responsibility to ensure that
the commitment for quality is understood, implemented and maintained at all
levels of operations.
- Periodic management review of the suitability and effectiveness of the
quality program.
4.1. MANAGEMENT RESPONSIBILITIES
KBI BioPharma will operate a cGMP compliant facility with regard to API testing,
drug product testing and product stability testing.
Client is responsible for ensuring that the test procedures and specifications
employed at KBI BioPharma appropriately reflect the requirements submitted to
applicable regulatory authorities. KBI BioPharma is responsible for ensuring
compliance to the test procedures and specifications for the Client product.
4.1.1. ANNUAL API REVIEW AND ANNUAL REPORT
For commercial products, KBI BioPharma will provide data to the Client for
inclusion in the Client's Annual Product Review. This data will be made
available to Client Quality Contact to fulfill any applicable annual reporting
requirements to regulatory agencies.
4.1.2. CONFLICT RESOLUTION
Any disputes or conflicts relating to this Quality Agreement will be resolved by
the Quality Contacts in a timely manner and in compliance with all applicable
quality and regulatory requirements. Such resolutions will be documented and
signed by the Quality Contacts of each company. In the event the issue cannot
be resolved at the Contact level, the senior corporate quality officials from
each Party will be responsible for resolution.
4.1.3. REGULATORY
All updates to regulatory applications related to product intermediates, API and
drug product testing are the responsibility of Client. KBI BioPharma will
provide Client all necessary information that it possesses, pertinent to
testing.
4.2. ANALYTICAL METHOD TRANSFER
Analytical test methods will be developed by KBI BioPharma or transferred from
the Client site using mutually agreed upon processes. Client will be
responsible for training KBI BioPharma personnel to use product assays or
product specific test methods that are transferred to KBI BioPharma. KBI
BioPharma will be responsible for generating protocols to confirm method
equivalency, validating or qualifying the test methods and providing a final
report for method transfer to Client. Client and KBI BioPharma will jointly
review and approve the validation or qualification protocol, final report and
test methods prior to implementation of routine testing.
KBI BioPharma will be responsible for any subsequent analytical method transfers
to or from other sites identified by Client.
4.3. ANALYTICAL TESTING
KBI BioPharma will perform release and stability testing of Client's API or drug
product per established method/procedure and review against defined
specifications as detailed in regulatory submissions.
Client will be responsible for providing product reference standards for testing
and has the responsibility for providing product reference standards to KBI
BioPharma. KBI BioPharma will be responsible for proper maintenance of the
inventory of reference standards in its possession.
KBI BioPharma and the Client will mutually approve the protocols for stability
studies to be conducted. Client will be responsible for determining, amending
and reporting expiration dates for all reference standards and product.
KBI BioPharma will provide a final test result report to the Client Quality
Contact after KBI quality review is complete. On request of the Client, copies
of KBI BioPharma raw data and laboratory investigation reports will be provided
to the Client.
Client QA will conduct a review of this documentation within ten (10) business
days after receipt. If any issues are identified during review, these will be
communicated to KBI BioPharma in writing. KBI BioPharma will reply to these
comments within ten (10) business days of receipt.
4.4. DOCUMENTATION
4.4.1. SPECIFICATIONS AND TEST METHODS
Specifications will be consistent with the requirements set forth in regulatory
filings. Where no written test method is provided by Client (such as compendial
methods), current KBI BioPharma methods or current compendial methods will be
used. Mutually approved Client specifications and methods will be provided to
KBI BioPharma thirty (30) days prior to implementation of cGMP testing.
4.4.2. DATA REPORTING REQUIREMENTS
Original (raw) product data generated in KBI BioPharma laboratories will be
stored and retained at KBI BioPharma in accordance with cGMPs and internal KBI
BioPharma guidelines. Client is to provide five (5) business days advance
notice for access to reviewed and approved data.
4.4.3. RECORD RETENTION
KBI BioPharma will retain all completed testing documentation and testing
related documentation for a minimum of one (1) year beyond the completion of the
Client Proposal. These documents will be readily accessible for review and
inspection by Client and/or regulatory authorities if requested. At the end of
the document retention period, KBI BioPharma will notify Client and either
provide these records to the Client or obtain written permission to destroy any
documents that were stored beyond the required retention period.
4.5. EXCIPIENT AND FINAL CONTAINER HANDLING
4.5.1. SOURCING AND TESTING
KBI BioPharma will source excipients and final containers used in formulation
development. The KBI BioPharma vendor quality program requirements will apply to
all excipients and final containers sourced by KBI BioPharma. The testing
procedures will be developed by KBI BioPharma or may be provided by the Client,
as appropriate. KBI BioPharma and Client will mutually agree on excipient and
final containers. Specifications will be in accordance with requirements set
forth in regulatory filings and as set forth in Client provided documents.
4.5.2. TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY (TSE) COMPLIANCE
KBI BioPharma will source excipients from either non-animal derived sources
whenever possible, or if animal derived materials are necessary, then KBI
BioPharma will comply with U.S. and European regulations regarding TSE
compliance by obtaining Country of Origin certification and verifying that the
source country is not a known TSE-contaminated country.
4.6. CRITICAL CHANGE CONTROL
Critical Changes initiated by KBI BioPharma will be communicated to Client in
writing, using the KBI BioPharma Critical Change Control process. Client will
review Critical Changes prior to implementation for conformance to registration
commitments and advise KBI BioPharma on any actions to take in order to assure
compliance.
Critical Changes initiated by the Client will be communicated to KBI BioPharma
in writing using the Client's process for change control. KBI BioPharma will
review the Critical Change prior to implementation and advise Client on any
actions that must be taken to assure conformance to KBI BioPharma standards.
For Critical Changes requiring approval by KBI BioPharma and Client, both
Parties will be responsible for supplying written responses as soon as
reasonably possible but in no event more than ten (10) business days from
receipt of the request.
CHANGES REQUIRING APPROVAL BY KBI BIOPHARMA AND NOTIFICATION OF CLIENT:
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- Change in the layout or structure of the testing facility, equipment or
utilities
- Changes to compendial test methods and specifications
CHANGES REQUIRING PRE-APPROVAL OF KBI BIOPHARMA AND CLIENT:
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- Changes that require revalidation of Client's product specific release or
stability test methods.
- Changes to release or stability testing specifications for Client API or
drug product
- Change of testing site for Client's product specific release or stability
test methods
- Changes to excipients (specifications, testing, suppliers or TSE status)
4.7. DEVIATION CONTROL
KBI BioPharma will notify Client of any out of specification (OOS) results or
other Critical Deviations within three (3) working days of confirming the OOS or
observing the deviation.
OOS results will be investigated using the KBI BioPharma Laboratory
Investigation Procedure, and if any retesting is conducted, the re-test plan
must be approved by KBI BioPharma quality and the Client Quality Contact.
Critical Deviations outside of OOS investigations will be investigated for root
cause and fully documented by KBI BioPharma, targeting thirty (30) days after
the date of discovery for completion. Investigations will include appropriate
justification, scientific rationale and supporting data. The Client will
review the completed Critical Deviation report and communicate to KBI BioPharma
the result of its review, within five (5) business days.
4.8. VALIDATION, MAINTENANCE AND CALIBRATION
KBI BioPharma will be responsible for initial qualification, validation and
ongoing re-validation, as needed, of its facilities, utilities, computer
systems, stability ▇▇▇▇▇▇▇▇ and laboratory equipment.
KBI BioPharma will ensure that equipment used in the testing of the Client's API
or drug product are routinely calibrated and maintained in a good state of
repair.
4.9. AUDITS
4.9.1. CLIENT AUDITS
Client may audit KBI BioPharma premises once annually using up to four (2)
auditor days (1 auditor for 2 days or 2 auditors for 1 day) for reasons of
determining compliance with the terms of the Quality Agreement and general
compliance with the requirements of the applicable internal procedures and
regulatory requirements.
Client has the right to For Cause Visits with respect to particular functions or
areas. KBI BioPharma will schedule and host For Cause Visits within ten (10)
days of KBI BioPharma's receipt of Client's request. If a For Cause Visit is
the result of a reported adverse event, KBI BioPharma will schedule and host the
For Cause Visit within forty-eight (48) hours of KBI BioPharma's receipt of
Client's request.
4.9.2. SUPPLIER AUDITS
The auditing of excipient suppliers will be the responsibility of the Party
sourcing the item(s).
4.9.3. REGULATORY INSPECTIONS
KBI BioPharma will notify Client, within twenty-four (24) hours, of any
inspections or actions by regulatory agencies or other enforcement bodies that
could potentially impact Client product. KBI BioPharma will provide Client with
the results of all such regulatory audits, as they apply to Client product,
within ten (10) working days of the audit close out meeting. KBI BioPharma will
provide pre-approval inspection and new product approval support.
Client will fulfill all reporting requirements to the respective regulatory
agency or agencies with regard to Client registration documentation. KBI
BioPharma will fulfill all reporting requirements with regard to testing and
site registration that may be required to support Client related activities.
4.10. COMPLAINTS AND ADVERSE EVENT REPORTING
KBI BioPharma will promptly notify Client of any information coming into its
possession concerning the quality of previously released API or drug product.
Any determinations on whether a regulatory notification is necessary and the
resulting communication with the regulatory authorities will be the
responsibility of the Client Quality Contact.
QUALITY HEAD APPROVALS
CLIENT
Written Signature:
Printed Name: ▇▇▇▇▇▇ ▇. ▇▇▇▇▇
Title: CMO
---
Date: ▇▇▇▇▇ ▇▇, ▇▇▇▇
▇▇▇ BIOPHARMA, INC.
Written Signature: __________________________________________
------------------------------------------
Printed Name: __________________________________________
------------------------------------------
Title: __________________________________________
------------------------------------------
Date: __________________________________________
------------------------------------------
CONFIDENTIAL
PROPOSAL FOR PT-401 DEVELOPMENT AND PRODUCTION
Prepared for: ▇▇▇▇▇▇ ▇. ▇▇▇▇▇, M.D., Ph.D.
Chairman of the Board, Chief Medical Officer
DNA Print Pharmaceuticals
▇▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇
▇▇▇▇▇▇▇▇, ▇▇ ▇▇▇▇▇
Prepared by: KBI BioPharma, Inc.
▇.▇. ▇▇▇ ▇▇▇▇▇
▇▇▇▇ ▇▇▇▇▇▇ ▇▇▇▇
▇▇▇▇▇▇, ▇▇ ▇▇▇▇▇
Proposal Number: 06.DPT.01
Version: 01
Issue Date: March 20, 2006
This proposal is valid until April 20, 2006, after which budget estimates and
timing are subject to revision. This proposal is provided for the sole use of
DNA Print Pharmaceuticals in assessing the merits of services offered by KBI
BioPharma, Inc. The content of this document has been developed on a
project-specific basis based on information provided by DNA Print
Pharmaceuticals. Budget and timelines are presented in the proposal, however,
these are subject to terms and conditions to be agreed upon.
BACKGROUND & SUMMARY
In its Request for Proposal, DNA Print Pharmaceuticals (DNA PRINT) has requested
KBI BioPharma, Inc. (KBI) provide a proposal related to PT-401 development and
production. In response, KBI is pleased to submit this proposal.
VERSION HISTORY
REVISION NUMBER DESCRIPTION OF CHANGES
----------------------
00 New Document
-- -------------
01 Revised to add in vivo potency assay, BIACORE assay and Payment schedule
-- -------------------------------------------------------------------------
1.0 SCOPE RESPONSIBILITIES
This section outlines responsibilities for KBI and DNA PRINT as they apply to
the work scope.
1.1 SAFETY
1.1.1 DNA PRINT will provide an MSDS and all sample/material handling data
for the materials associated with this project (if available). If materials
have any special handling considerations, DNA PRINT will notify KBI prior to the
initiation of the project.
1.1.2 KBI will assess the MSDS and all safety handling data for the
materials associated with this project. Should the materials have any special
handling considerations KBI may apply a reasonable additional fee to cover
actual costs of handling.
1.2 METHODS/DOCUMENTATION
1.2.1 DNA PRINT will provide all relevant project-related documentation to
be used for this project.
1.2.2 KBI will review all relevant project-related documentation and methods
received from DNA PRINT.
1.2.3 All documentation for developed or revised methods will be provided by
KBI for review and approval by DNA PRINT prior to implementation.
1.3 SAMPLE/MATERIALS
1.3.1 DNA PRINT will provide all non-standard samples/materials necessary to
perform this project. Such materials will include all necessary reference
standards and any product-specific or assay-specific reagents. The
samples/materials should arrive at KBI with all proper documentation.
1.3.2 KBI will, on behalf of DNA PRINT, procure all necessary standard raw
materials, reagents and disposables necessary to perform the project. KBI will,
as necessary, log in all samples/materials according to current Standard
Operating Procedures. The sample/material lot numbers will be recorded in the
laboratory notebooks or standardized data sheets at the time of use.
1.3.3 KBI will provide any samples of formulated material for testing by DNA
PRINT as deemed necessary by both KBI and DNA PRINT.
2.0 SCOPE
2.1 PROJECT SCOPE AND EXECUTIVE SUMMARY
2.1.1 Objective
DNA PRINT has developed a CHO cell line which expresses PT-401, an
erythropoietin (EPO) fusion protein consisting of two EPO domains in tandem
joined by a flexible peptide linker. A clone expressing this fusion protein has
been isolated.
2.1.2 KBI will develop a scaleable cell culture and purification process,
develop and qualify assays for product release, develop a suitable formulation,
execute cGMP runs to produce sufficient product for Phase 1 clinical trials, and
perform QA/QC release of the bulk drug substance and drug product.
2.2 PROJECT ASSUMPTIONS
- Sponsor has developed a CHO-S cell line secreting PT-401, an EPO fusion
protein. This fusion protein will be referred to as Product.
- Sponsor has isolated a clone which secretes 15-20 mg/L Product.
- Sponsor has adapted the clone for growth in suspension and in protein free
medium.
- The selected clone is expected to produce 50 mg/L Product in a fed-batch
cell culture process.
- The recovery and purification process is expected to have a 50% Product
recovery.
- The Sponsor estimates that ~1 gram Product will be sufficient to meet his
Phase 1 clinical trial requirements.
- The above three assumptions imply that TWO cGMP production runs (consisting
of 2 x10-L culture harvest, pooled and purified) will suffice to meet these
requirements.
- The sample requirements for QC will not significantly impact the amount of
Bulk Drug Substance obtained per production run.
- Approximately 40 samples for in-vivo potency will be analyzed in support of
manufacturing, drug substance/drug product release, and stability. This
analysis will be outsourced.
2.3 RECEIPT OF CELL LINE FROM DNA PRINT
2.3.1 Objective
To transfer a tested cell line from DNA PRINT to KBI. The transferred cell line
must be tested for microbial, mycoplasma and MVM contamination. This testing
ensures that our facilities as well as other clients' cell lines are not
inadvertently contaminated and project progress jeopardized.
2.3.2 Activities
- DNA PRINT will arrange to have their cell line tested by an outside vendor.
The minimum tests required are non-host, mycoplasma and MVM contamination.
- Once the cell line is tested, DNA PRINT will send KBI the results.
- KBI will review the results and, if acceptable, KBI will authorize DNA
PRINT to ship the cell line. Cell lines shipped, without KBI authorization,
will not be accepted at our loading dock and will be returned to DNA PRINT.
2.3.3 Deliverables
- From DNA PRINT, cell line testing report.
- From KBI, authorization to ship cell line to KBI.
2.4 INITIAL CELL LINE CHARACTERIZATION
2.4.1 Objective
The DNA PRINT cell line will be characterized for culture parameters such as
growth rate, maximum cell density, viability, product formation, nutrient
utilization and by-product formation to gauge its readiness for introduction to
a bioreactor for cell culture process development.
2.4.2 Activities
- DNA PRINT provided data will be reviewed and evaluated before the cell vial
is thawed and evaluation begun in T-flasks or spinners.
- These cell culture studies will investigate the following:
- Cell growth rate (doubling time) and its comparison to other similar cell
lines
- Maximum cell density achievable in a batch culture and the maintenance of
cell viability
- Nutrient consumption (glucose, glutamine, amino acids, etc) and byproduct
formation (lactate, ammonia, etc) profile
- Product expression rate (product titer in medium as well as specific
productivity per cell) in batch culture and comparison to DNA PRINT
reported values
- Improvement in maximum cell density, cell viability and product expression
by the addition of simple nutrients (glucose and glutamine)
- Evaluation of DNA PRINT specified cell culture medium and its adequacy for
the development of a bioreactor process. Evaluate other media if necessary
to improve the culture performance
- The above experiments will allow KBI to design a preliminary bioreactor
process. The improved control of pH and dissolved oxygen in a bioreactor
versus a spinner or T-flask will generally result in higher cell densities
and product titers.
- The next step is the development of a fed-batch process in a 15-L
bioreactor (8-10 L working volume).
2.4.3 Deliverables
- Report summarizing the Cell Line Characterization results of the above
experiments.
2.5 PRELIMINARY METHOD DEVELOPMENT AND ANALYTICAL SUPPORT FOR CELL LINE
CHARACTERIZATION
2.5.1 Objective
Develop analytical assays to allow evaluation of performance of the cell line
during cell characterization.
2.5.2 Activities
- Transfer/develop a SDS-PAGE method to estimate product purity in the cell
culture samples.
- Transfer/develop a Western blot method to verify product identity in the
cell culture samples.
- Transfer/develop an ELISA assay to estimate product titers in the cell
culture samples.
- Analyze cell culture samples using above methods to support cell
characterization.
2.5.3 Deliverables
- Method development reports.
2.6 DEVELOPMENT AND SCALE UP OF THE CELL CULTURE PROCESS
2.6.1 Objective
Develop a reproducible and scaleable fed-batch cell culture process for
production of Product. Considering the low product quantity (~1 gram) needed
for the Phase 1 clinical trials, it is expected that this Product will be
produced using multiple 10-Liter runs.
2.6.2 Activities
- The results of the cell line characterization work will define a basic
batch process for the production of Product in a bioreactor.
- Various bioreactor parameters will be investigated to develop a
reproducible and scaleable cell culture process. Examples of these
parameters are:
- Culture pH to optimize growth versus culture viability and longevity as
well as product stability
- Aeration of culture with air, O2 and CO2 to maintain pH and dissolved
oxygen in the most favorable range.
- Maintenance of nutrient levels (glucose, glutamine, AA feeds, etc) to
prolong culture life, thus improving product titers in harvest.
- Minimization of harmful byproducts (lactate and ammonia) which effect
culture viability and thus effect culture life.
- Feed profile of nutrients to maximize culture life and hence product
titers.
- Harvest time to minimize product degradation.
- Addition of other nutrients (insulin, cholesterol, lipids, etc) to improve
culture performance.
- Multiple bioreactor runs will be performed to design the cell culture
process.
- The cell culture harvest from favorable runs will be used by Purification
to design the Product recovery and purification train.
2.6.3 Deliverables
- A reproducible and scaleable cell culture process suitable for use in cGMP
manufacturing.
2.7 DEVELOPMENT AND SCALE UP OF THE PURIFICATION PROCESS
2.7.1 Objective
To develop a Product recovery and purification process, starting with the cell
culture harvest and ending with bulk Product meeting agreed specifications.
2.7.2 Activities
- The cell culture harvest will be transferred to 1-L centrifuge bottles and
centrifuged in a refrigerated centrifuge containing a 6x1-L bottles rotor.
The transfer of the cell culture harvest to bottles and the pooling of the
clear supernatant will be accomplished aseptically in a Class-100 biosafety
hood. (As the process is scaled up beyond 10-L, we expect this step to
replaced by dead-end filtration or a continuous centrifuge.)
- The purification process is expected to have 3-4 column steps: Product
capture, purification 1, purification 2 and polishing.
- The product capture step will concentrate the product in the eluate as well
as remove most cell culture medium derived small molecule and protein
components.
- The purification steps will use an orthogonal purification techniques to
improve product quality as well remove any endotoxin and residual DNA.
These steps may also act as a concentration and solvent removal step.
- The polishing step (gel filtration) will be used to remove any product
aggregates.
- All steps will use commercially available cGMP-produced resins and buffers
and use scaleable process conditions.
2.7.3 Deliverables
- A scaleable purification process producing Bulk Product meeting agreed
specifications, suitable for use in cGMP manufacturing.
2.8 PREPARATION OF A MASTER CELL BANK AND WORKING CELL BANK
2.8.1 Objective
To ensure that the cell line meets the regulatory requirements for use in the
manufacture of product for Phase 1 clinical trials. A Master Cell Bank (MCB)
and a Working Cell Bank (WCB) wil be produced and tested.
2.8.2 Activities
- The MCB and WCB production and cell line testing will be done by an outside
vendor.
- KBI will coordinate these activities with the outside vendor. KBI will
review the vendor report, prior to using the WCB for cGMP production.
2.8.3 Deliverables
- From KBI, coordination with vendor and review of final report.
2.9 ANALYTICAL METHOD DEVELOPMENT
2.9.1 Objective
To develop/optimize methods to characterize the Product. These methods will be
used in preformulation development and stability, and may be used for
characterization and release of drug substance and drug product.
2.9.2 Activities
- Select methods to be developed in consultation with DNA PRINT.
- The following methods will be developed or optimized. Methods will be used
to characterize the purified bulk and final product and will be used in
preformulation development.
- Peptide Map - Identity and degradation (deamidation, oxidation)
- SEC-HPLC - Soluble aggregates and breakdown products, purity
- UV - Concentration and insoluble aggregates
- IEF - Charge variants and pI
- Oligosaccharide compositional analysis via Ion Chromatography, or CHO
profiling via CE or HPLC
- Sialic Acid Determination
- Host cell protein ELISA
- Residual DNA
- Biacore or ELISA method to assess immunogenicity based on relative titer
2.9.3 Deliverables
- Analytical method development reports.
2.10 PREFORMULATION DEVELOPMENT
2.10.1 Objective
To evaluate basic formulation conditions that will confer optimal
conformational, physical and chemical stability to the protein in solution.
2.10.2 Activities
- Evaluate effects of pH, buffer type, and excipients on conformational
stability, using biophysical characterization techniques such as DSC, CD,
FTIR, and/or Fluorescence.
- Evaluate the effect of pH, buffers, excipients and ionic strength on
physical and chemical stability. Evaluation will include a 2 week
accelerated stability study.
- Utilize a statistical design approach to identify the optimal conditions
for structural, physical and chemical stability.
- Utilize the information gained during preformulation development to inform
the purification process development.
2.10.3 Deliverables
- Development report recommending formulation buffer, pH and excipient
conditions.
2.11 FORCED DEGRADATION STUDIES
Forced degradation studies will be performed to ensure that the developed
methods to be used in formulation development are stability indicating and can
resolve potential degradation products. The molecule will be subjected to heat,
light, physical and chemical degradation stresses. Forced degradation will be
performed at a single product concentration based on the preformulation studies.
2.11.1 Objective
To elucidate degradation pathways and ensure that the developed analytical
methods are suitable for detection of physical and chemical degradation.
2.11.2 Activities
- Evaluate forced oxidation, deamidation, aggregation (via agitation),
and/or acid/base hydrolysis.
- Evaluate heat stress, photo stress, and freeze thaw.
- Evaluate detection of the various degradation products using the developed
assays.
2.11.3 Deliverables
- Forced degradation report.
2.12 FORMULATION DEVELOPMENT
Based on the preformulation study, optimal pH, buffer, ionic strength, excipient
and protein concentration conditions will be evaluated for the final liquid
formulation.
2.12.1 Objective
To develop a final liquid formulation for use as an intramuscular injection in
pre-filled syringes.
2.12.2 Activities
- Evaluate the viscosity and ease of injection through specified syringes of
various formulation conditions.
- Evaluate the effect of excipients on improving viscosity if needed.
- Evaluate the compatibility of the specified syringes with the Product.
This evaluation will include a 2 week accelerated stability study.
2.12.3 Deliverables
- Liquid Formulation Development report.
2.13 ANALYTICAL METHOD QUALIFICATION
2.13.1 Objective
To qualify the methods, following the appropriate regulatory requirements and
guidance, to ensure that the methods are suitable for release and stability
testing of clinical supplies.
2.13.2 Activities
- Discuss with DNA PRINT the required method qualification.
- DNA PRINT will approve the qualification protocols.
- Qualification of the methods will be performed utilizing a single analyst
to ensure that methods are suitable for use in an early phase clinical
study. Parameters to be evaluated will include linearity, limits of
detection (LOD), limits of quantitation (LOQ), accuracy and precision.
- Qualification criteria will be agreed upon by both KBI and DNA PRINT.
- Methods that may be qualified include:
- Peptide Map - Identity and degradation (deamidation, oxidation)
- SDS-PAGE (reduced and non-reduced) - Covalent and non-covalent
aggregation, degradation
- Western blot - Identity
- SEC-HPLC - Soluble aggregates and breakdown products, purity
- ELISA - product concentration/potency
- UV - Concentration and insoluble aggregates
- IEF
- Host cell protein ELISA
- Bioburden
- Endotoxin
- In-vivo potency assay (KBI will coordinate the qualification of this assay
with outside vendor.)
- Qualification for Bioburden will consist of bacteriostasis/fungistasis
evaluation. Qualification for endotoxin will consist of
inhibition/enhancement evaluation.
- The final determination for which methods require qualification will be
made in consultation with DNA PRINT after the completion of method
development.
2.13.3 Deliverables
- Method qualification reports.
2.14 PRODUCT CHARACTERIZATION
2.14.1 Objective
To characterize the Product and related impurities.
2.14.2 Activities
- Develop and perform the following characterization analyses for the
Product:
o Amino Acid Analysis (including determination of extinction coefficient)
o Molecular mass determination via LC-MS
o Carboxyl terminal analysis
o N-terminal sequencing via MS/MS
o Biophysical Characterization (DSC, CD, FTIR, Fluorescence)
o Carbohydrate profile and composition
o Light scattering (MALS)
2.14.3 Deliverables
- Product characterization report
2.15 DEVELOPMENT OF BULK DRUG SUBSTANCE AND DRUG PRODUCT SPECIFICATIONS
2.15.1 Objective
To develop Bulk Drug Substance and Drug Product specifications for use in the
release of Product.
2.15.2 Activities
- DNA PRINT and KBI will work jointly to develop the specifications, based
on the analytical methods, characterization package, critical process
parameters, and established EPO requirements.
2.15.3 Deliverables
- Bulk Drug Substance and Drug Product specifications.
2.16 PREPARATION OF DOCUMENTATION FOR CGMP PRODUCTION
2.16.1 Objective
To prepare the necessary documentation for the commencement of cGMP production
of Product.
2.16.2 Activities
- Prepare raw material specifications.
- Prepare intermediate product specifications.
- Prepare batch records for use in cGMP manufacturing.
- Prepare any custom procedures for non-standard operation required by the
manufacturing process.
- Prepare and finalize test methods.
2.16.3 Deliverables
- Documents listed above.
2.17 TOXICOLOGY LOT PRODUCTION
2.17.1 Objective
Upon completion of the process development activities, a demo run will be
conducted to finalize documents as well as produce tox material for use in
animal studies.
2.17.2 Activities
- Draft specifications and batch records will be used in this demonstration
run.
- It is expected that two 15-L bioreactors (8-10 L working volume each)
running in parallel will constitute one production run. The supernatant
from both bioreactors will be pooled and processed further through the
recovery and purification trains.
- The purified non-cGMP Bulk Product will be available for use in animal
trials.
- This purified non-cGMP Bulk Product is NOT suitable for human use.
- The results of this demo run will be used to refine the process, if
necessary. These results will also be used to finalize the specifications
and batch records.
2.17.3 Deliverables
- Non-cGMP Bulk Product for use in toxicology studies.
2.18 CGMP PRODUCTION CAMPAIGN
2.18.1 Objective
To produce and release Bulk Product for use in Phase 1 clinical trials
2.18.2 Activities
- A cGMP production run is defined as 2x15-L bioreactors run in parallel,
pooled after harvest and processed to Bulk Product.
- Based on information provided by DNA PRINT, it is expected that two cGMP
production runs will suffice to meet the clients Phase 1 clinical trial
requirements. If cell line performance does not meet DNA PRINT provided
product titers (~50 mg/L product), then additional runs AT ADDITIONAL COST
may be required.
- Two cGMP productions runs will be conducted to produce and release Bulk
Product.
- QC support consisting of environmental and in-process control (IPC) testing
as appropriate based on critical process parameters and the batch record
requirements.
- QA support consisting of guidance for cGMP compliance, deviation review and
assistance, etc.
2.18.3 Deliverables
- Bulk drug substance for release
2.19 BULK DRUG SUBSTANCE RELEASE
2.19.1 Objective
To perform testing and provide documentation required to support the release of
bulk drug substance for further downstream processing (i.e., fill/finish).
2.19.2 Activities
- Perform release testing as per batch record and bulk drug substance
specification, using qualified methods.
- The methods to be employed in the study will be agreed upon by KBI and DNA
PRINT. A subset of the following methods will be employed:
o Appearance
o pH
o Peptide Mapping
o SDS-PAGE
o Western blot
o SEC-HPLC
o IEF
o Endotoxin
o Bioburden
o In-vivo potency assay
- Investigate any out of specification results according to KBI established
procedures.
- Review and approve executed batch records, release testing data, and any
associated deviations, OOS reports, out-of-calibration reports, environmental
excursions, and any other documents pertaining to Product quality.
- Generate COA for each lot of bulk drug substance.
- Ship bulk drug substance to DNA PRINT selected fill/finish contractor
under cGMP conditions.
2.19.3 Deliverables
- COA for each lot of bulk drug substance.
- Reviewed batch records and other associated production documents.
- Shipment of bulk drug substance to fill/finish contractor.
2.20 DRUG PRODUCT RELEASE TESTING
2.20.1 Objective
To perform release testing on the final drug product manufactured at DNA PRINT's
fill/finish contractor.
2.20.2 Activities
- Perform release testing as per batch record and drug product
specification, using qualified methods.
- The methods to be employed in the study will be agreed upon by KBI and DNA
PRINT. A subset of the following methods will be employed at KBI:
o Appearance
o pH
o Peptide Mapping
o SDS-PAGE
o Western blot
o SEC-HPLC
o IEF
o In-vivo potency assay
o Endotoxin
o Particulate Matter
o Sterility (performed by fill/finish contractor or contracted out)
- Investigate any out of specification results according to KBI established
procedures.
- Review and approve release testing data, and any associated deviations,
OOS reports, out-of-calibration reports, and any other documents pertaining to
Product quality.
- Generate COA for each lot of drug product.
2.20.3 Deliverables
- COA for each lot of drug product.
2.21 STABILITY STUDIES
2.21.1 Objective
Perform real time and accelerated stability studies on bulk drug substance and
drug product to support clinical studies.
2.21.2 Activities
- Develop protocols in consultation with DNA PRINT.
- DNA PRINT will approve the stability protocols.
- For planning purposes, it is assumed that two lots of bulk drug substance
and one lot of drug product will be placed on stability.
- Store samples at KBI under conditions appropriate for the study design.
- Store reserve samples at each temperature for use in the event that
additional testing is required.
- The analytical methods to be employed in the study will be agreed upon by
KBI and DNA PRINT. A subset of the following methods will be employed at KBI:
o Appearance
o pH
o Peptide Mapping
o SDS-PAGE
o Western blot
o SEC-HPLC
o IEF
o Particulate matter
o In-vivo potency assay
- Investigate any out of specification results according to KBI established
procedures.
- Issue Certificate of Analysis for each stability time point.
- For any out of specification results, testing will be performed at the
subsequent time point to verify degradation. If degradation is verified
subsequent time points may be cancelled.
- Pull times and schedules as well as windows for pulls and initiation of
analysis will be detailed in the stability protocol to be approved by DNA PRINT
prior to the initiation of the stability program.
2.21.3 Deliverables
- Stability report will be provided at each time point in the form of a
certificate of analysis.
3.0 PROGRAM MANAGEMENT
3.1 OBJECTIVE
Provide overall management of the project according to scope and contractual
terms. Develop & maintain excellent communications and collaborative
relationship with DNA PRINT.
3.2 ACTIVITIES
KBI values collaborative and open relationships with its customers. KBI will
appoint a Study Director from within the project team who will be responsible
for project performance, deliverables, invoicing and regular customer
communications. The Study Director will be DNA PRINT's primary technical
point-of-contact within KBI. KBI will, however, further appoint a "project
sponsor" from within its management group who will be available to DNA PRINT in
the event of non-technical issues arising. Teleconferences will be scheduled
once per week and meetings will be held at KBI as appropriate.
4.0 ESTIMATED TIMELINES
KBI estimates the duration of each individual defined project activity as
detailed in table 1 below. Duration includes QA review and report writing.
TABLE 1: DURATION OF ACTIVITIES
ACTIVITY DURATION OF ACTIVITY
-------- --------------------
Initial Cell Line Characterization 2 months
---------------------------------- --------
Preliminary Method Development 2 months
------------------------------ --------
Development and Scale Up of Cell Culture Process 2 months
------------------------------------------------ --------
Development and Scale Up of Purification Process 4 months
------------------------------------------------ --------
Cell line Testing and Preparation of MCB and WCB 4 months
------------------------------------------------ --------
Analytical Method Development 6-8 months
------------------------------- -----------
Preformulation Development
---------------------------
Forced Degradation Studies
----------------------------
Formulation Development
------------------------
Analytical Method Qualification
---------------------------------
Product Characterization
-------------------------
Toxicology Lot Production 2 months
------------------------- --------
Specification Development 8 months
-------------------------- ---------
Preparation of Documentation for cGMP Production
-----------------------------------------------------
cGMP Production Campaign
--------------------------
Bulk Drug Substance Release
------------------------------
Drug Product Release Testing
-------------------------------
Stability Studies 24 months
----------------- ---------
TOTAL ELAPSED TIME FOR PROJECT (excl. of Stability) 16 MONTHS
--------------------------------------------------- ---------
TABLE 2: BULK DRUG SUBSTANCE STABILITY PROGRAM DESIGN
STORAGE
CONDITIONS 1M 3M 6M 9M 12M 18M 24M
---------- -- -- -- -- --- --- ---
-80 C X X X X X X X
----- - - - - - - -
2-8oC X X X X X X X
----- - - - - - - -
30oC/ 60RH X X X
---------- - - -
X = Analyses as described in section 2.21.2
TABLE 3: DRUG PRODUCT STABILITY PROGRAM DESIGN
STORAGE
CONDITIONS 1M 3M 6M 9M 12M 18M 24M
---------- -- -- -- -- --- --- ---
2-8oC X X X X X X X
----- - - - - - - -
30oC/ 60RH X X X X X X X
---------- - - - - - - -
40oC/ 75RH X X X
---------- - - -
X = Analyses as described in section 2.21.2
5.0
PRICE AND BUDGET ESTIMATES
TABLE 4: PRICE FOR PT-401 DEVELOPMENT AND PRODUCTION
REGULATORY STATUS ACTIVITY ESTIMATED PRICE ($)
----------------- -------- -------------------
1 Non cGMP Initial Cell Line testing (outside vendor estimate) 5,000
- -------- --------------------------------------------------- -------
2 Non cGMP Initial Cell Line Characterization 160,000
- -------- ---------------------------------- -------
3 Non cGMP Preliminary Method Development 60,000
- -------- ------------------------------ -------
4 Non cGMP Development and Scale Up of Cell Culture Process 185,000
- -------- ------------------------------------------------ -------
5 Non cGMP Development and Scale Up of Purification Process 340,000
- -------- ------------------------------------------------ -------
6 Non cGMP Analytical Method Development 510,000
- -------- ----------------------------- -------
Non cGMP Preformulation Development
--------- ---------------------------
Non cGMP Forced Degradation Studies
--------- ----------------------------
Non cGMP Formulation Development
--------- ------------------------
Non cGMP Product Characterization
--------- -------------------------
cGMP Analytical Method Qualification
---- ---------------------------------
7 cGMP Cell line testing and Preparation of MCB and WCB
(estimated cost for outside vendor) 100,000
- ---- ------------------------------------------------- -------
8 Non cGMP Toxicology Lot Production 340,000
- -------- ------------------------- -------
9 cGMP Specification Development 870,000
- ---- ------------------------- -------
cGMP Preparation of Documentation for cGMP Production
---- -----------------------------------------------------
cGMP cGMP Production Campaign
---- --------------------------
cGMP Bulk Drug Substance Release
---- ------------------------------
cGMP Drug Product Release Testing
---- -------------------------------
10 cGMP Drug Substance/Product Stability Program 270,000
-- ---- ---------------------------------------- -------
TOTAL PRICE 2,840,000
----------- ---------
6.0 ADDITIONAL FEES AND PRICING
6.1 ADDITIONAL FEES
If copies of raw data are requested in the course of an active project, DNA
PRINT will be invoiced at $175/hour for the hours required to generate and
compile the data requested. If copies of raw data are requested after a final
report has been issued, the DNA PRINT will be invoiced at the current laboratory
rate for the hours required to generate and compile the data requested.
Expenses incurred by KBI to procure materials and laboratory supplies for the
execution of the project (direct and indirect) will be invoiced to DNA PRINT.
6.2 REVISIONS TO PRICING
KBI reserves the right to revise quoted costs for any project as a result of
changes in initial scope, revisions in protocols, modifications of test methods,
final review of test methods, undocumented requirements, or any unforeseen
difficulty in executing the project. The additional work will be performed
based on written agreement from DNA PRINT and will be documented on a KBI Change
Order.
All required investigational work (such as OOS investigations, trouble shooting
chromatographic methods, etc.) may be conducted without prior approval from DNA
PRINT, for up to 24 scientist hours per occurrence. If the additional work
requires more than 24 hours, DNA PRINT will be contacted prior to continuation.
All investigational testing performed that is not directly due to a KBI error
will be invoiced to DNA PRINT at current lab rates and will be documented on a
Change Order.
7.0 INVOICING AND PAYMENT TERMS
7.1 PAYMENT SCHEDULE
TABLE 5 PAYMENT SCHEDULE (PLEASE REFER TO TABLE 4 FOR ACTIVITY NUMBERS)
Phase Activities Total Price Initial Payment
(Remainder billed semi-monthly) Initial payment due on
Development 1 - 5
and
50% of 6 $1,005,000 $335,000 1-Apr-06
Scale up and
Tox run and
cGMP prep 50% of 6,
7 - 8
and 25% of 9 $ 912,500 $304,167 1-Jul-06
cGMP runs and
Stability 75% of 9
and 10 $ 922,500 $307,500 1-Jan-07
Total $2,840,000
7.2 INVOICING
KBI will issue semi-monthly invoices for work in process based upon the agreed
scope of work and terms and conditions. One third of the project cost will be
billed upon initiation of the project.
7.3 PAYMENT TERMS
Payments toward all invoices are due within thirty (30) days of receipt of
invoice and are non-refundable. Any applicable wire transfer fee must be
included in the payment issued to KBI.
8.0
PROJECT APPROVAL AND AUTHORIZATION
By signing below, DNA PRINT agrees to the project details as set forth in this
proposal and to negotiate in good faith a definitive Services Agreement that
will include a mutually designed detailed scope-of-work and customary terms and
conditions.
DNA PRINT PHARMACEUTICALS KBI BIOPHARMA, INC.
Signature Signature
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Printed Name Printed Name
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Title Title
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Date Date
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PO Number
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