1
Exhibit 10.25
[Confidential treatment has been requested for portions of this exhibit. The
confidential portions have been redacted and are denoted by [**]. The
confidential portions have been separately filed with the commission.]
DRUG DEVELOPMENT PROJECT AGREEMENT
THIS AGREEMENT is effective as of the 1st day of April, 1993, between
CTRC RESEARCH FOUNDATION ("CTRC RESEARCH") located at 14960 Omicron, Xxx
Xxxxxxx, Xxxxx 00000 and MGI PHARMA, INC. located at Suite 300 E, Opus Center,
0000 Xxxx Xxxx Xxxx, Xxxxxxxxxxx, Xxxxxxxxx 00000-0000 ("SPONSOR"), for the
purpose of conducting a project to develop a more effectual process to
synthesize 4-hydroperoxycyclophosphamide ("4-HC") and the synthesis of 4-HC to
be used for drug development purposes (the "PROJECT"). CTRC RESEARCH and
SPONSOR agree as follows:
1. SERVICES
1.1. CTRC RESEARCH agrees to use its best efforts to conduct the
PROJECT, as an independent contractor, substantially in accordance with the
Workplan described in Exhibit 1 as attached hereto ("WORKPLAN"), sa the same
may be superseded or amended from time to time with the consent of SPONSOR and
CTRC RESEARCH, but subject to CTRC RESEARCH policy, applicable laws and
regulations. The PROJECT will be supervised by Xxxxxxxxx X. Xxxx, Ph.D.
("Project Manager") with assistance from associates and colleagues as may be
required.
1.2 SPONSOR agrees to engage the services of CTRC RESEARCH to conduct
the PROJECT on the terms hereinafter set forth. CTRC RESEARCH understands and
agrees that the PROJECT is being conducted for SPONSOR for the purpose of (i)
developing a more effectual process to synthesize 4-HC and (ii) conducting drug
development activities involving 4-HC. CTRC RESEARCH further understands and
agrees that the PROJECT shall be owned solely and exclusively by SPONSOR and
shall remain the exclusive property of SPONSOR and that CTRC RESEARCH shall
have no right, title or interest in or the PROJECT, except as provided by this
Agreement.
1.3 CTRC RESEARCH shall provide SPONSOR with progress reports on a
regular basis, including telecommunication, on-site visits to CTRC RESEARCH
facilities, sharing of technical information such as Drug Master Files and
Batch Production Records, and shall also consult with SPONSOR at such times and
provide such additional reports and other information as SPONSOR may reasonably
request.
1.4. CTRC shall, at the option of SPONSOR which option is exercisable
at the end of the initial Term and any Renewal Term of this Agreement, provide
consulting services to SPONSOR regarding the process of synthesizing 4-HC as
developed through the PROJECT. The consulting services shall include advising
MGI on the techniques used in synthesizing 4-HC.
2
2. COMPENSATION
2.1. In consideration for performance of Phase One of the PROJECT by
CTRC RESEARCH during 1993, SPONSOR shall pay to CTRC RESEARCH the aggregate
amount of $ [**] , which sum is hereby acknowledged as received by CTRC
RESEARCH.
2.2. CTRC RESEARCH's compensation for Phase Two of the PROJECT shall
be determined as follows:
For each 100 gram of 4-HC which is ordered by SPONSOR, up to a total of
300 grams, CTRC RESEARCH shall be paid the following amounts:
(i) First 100 grams - $ [**] ;
--------
(ii) Second 100 grams - $ [**] ; and
--------
(iii) Third 100 grams - $ [**] .
--------
[**] percent ([**]%) of the charges for each order shall be due and
payable upon authorization by SPONSOR as evidenced by issuance of a
purchase order, [**] percent ([**]%) when half of the material in
the order has been produced and the remaining [**] percent ([**]%)
upon delivery of the remainder of the order of 4-HC.
For any orders of 4-HC above the 300 gram level for MGI's non-commercial
drug development purposes, SPONSOR shall first negotiate with CTRC
RESEARCH in good faith for a mutually acceptable amount of reimbursement
for CTRC RESEARCH, which compensation shall not exceed [**] per
gram. If CTRC RESEARCH does not provide further services under Phase
Two of the PROJECT, this Agreement shall continue as specified in
Section 3.1 of this Agreement.
The provisions of this Section 2.2 and of this Agreement
notwithstanding, CTRC RESEARCH agrees and understands that the 4-HC produced
under this Agreement is to be used for the purpose of preparing and submitting
an NDA to the FDA and that any and all obligations of SPONSOR to purchase 4-HC
from CTRC RESEARCH are for such purpose, and, that furthermore, nothing in this
Agreement shall be construed to require SPONSOR to purchase more grams of 4-HC
(including the 300 grams identified in this Section 2.2) from CTRC RESEARCH
under this Agreement than are reasonably required to secure such FDA approval.
2.3. The compensation enumerated in Sections 2.1 and 2.2 is for
services specified in the Work Plan. Further services of CTRC RESEARCH related
to 4-HC which are requested by SPONSOR will be provided by CTRC RESEARCH at an
amount of compensation to be mutually agreed by the parties, which agreement
shall constitute an amendment to this Agreement and shall be evidenced by a
written amendment as provided in Section 11.2.
2.4. For consulting services as specified in Section 1.4 of this
Agreement, SPONSOR shall pay to CTRC RESEARCH the sum of [**] Dollars
($ [**] ) per year which sum is due and payable at the beginning of each
Renewal Term.
3
3. TERM
3.1. This Agreement shall be for a period of three (3) years beginning
on the effective date of this Agreement, but shall sooner terminate (i) at the
option of SPONSOR, upon thirty (30) days written notice to terminate this
Agreement which is exercisable by SPONSOR after it has ordered and received
delivery of the 300 grams of 4-HC as discussed in Section 2.2 or (ii) upon the
effective date of or the date as otherwise provided in the agreement between
CTRC RESEARCH and SPONSOR as provided for in Section 4 (the "Initial Term").
This Agreement may be extended beyond the Initial Term of this Agreement for up
to five (5) successive one (1) year terms ("Renewal Terms") upon the option of
SPONSOR to obtain consultant services from CTRC RESEARCH as provided in Section
1.4. To exercise its option to obtain consultant services at the end of the
Initial Term of this Agreement or any Renewal Term, SPONSOR shall provide
written notice to CTRC RESEARCH at least ten (10) days prior to the end of the
Initial Term or the Renewal Term.
3.2. Notwithstanding the foregoing, either party may terminate this
Agreement following thirty (30) days prior written notice if the other party
shall fail to perform any material obligation imposed on it pursuant to this
Agreement provided the non-performing party has not cured such breach of this
Agreement prior to the expiration of he thirty (30) day period.
3.3. In the event of early termination of this Agreement by SPONSOR
during the Initial Term, for reasons other than a default by CTRC RESEARCH of
its obligations under this Agreement SPONSOR shall be liable for all reasonable
costs directly related to the PROJECT incurred by CTRC RESEARCH at the time of
such termination, but in no event shall SPONSOR be liable for a total amount in
excess of the total consideration payable by SPONSOR pursuant to Section 2.
SPONSOR shall pay CTRC RESEARCH for such costs within thirty (30) days of
receipt of an invoice for the same, which invoice shall include supporting
documentation sufficient to establish the costs incurred.
3.4. CTRC shall, upon the expiration or early termination of this
Agreement, or at any time upon the request of SPONSOR, immediately return and
deliver to SPONSOR any and all Confidential Information (as defined herein) and
all material developed therefrom and all information, material, data, samples,
work product, drug product and results related to the PROJECT provided CTRC
RESEARCH may retain a copy thereof for its use consistent with the terms of
this Agreement.
4. PRODUCTION AGREEMENT
4.1. At such time as SPONSOR determines that it needs quantities of 4-
HC for purposes other than drug development purposes, CTRC RESEARCH and SPONSOR
agree to negotiate in good faith toward the execution of a definitive,
commercially reasonable agreement pursuant to which CTRC RESEARCH will provide
at least [**] percent ([**]%) of SPONSOR's requirements of 4-HC beyond the
requirements contemplated by this Agreement. In conducting these negotiations,
SPONSOR shall be considered as acting in good faith even though it bargains for
reasonable time, quality and production requirements. During these
negotiations, CTRC RESEARCH must be able to demonstrate to SPONSOR its ability
to comply with reasonable
4
requirements of SPONSOR regarding quality, time and production for the
production of 4-HC. Such agreement shall also require that all of the product
provided to SPONSOR shall be synthesized at a facility of CTRC RESEARCH or its
affiliate (as defined in Section 4) meeting all applicable requirements of the
United States Food and Drug Administration for GMP manufacturing facilities.
4.2. Should CTRC RESEARCH and SPONSOR be unable to reach a definitive
agreement after the completion of good faith negotiations, SPONSOR may seek to
obtain a good faith, bona fide preliminary offer, proposal or bid (the "Bid")
from a third party to synthesize 4-HC for SPONSOR which Bid contains at least
the essential elements for an agreement to synthesize 4-HC. CTRC RESEARCH
shall have the option to match the Bid upon the same terms and conditions as
proposed by the third party as they relate to the provision of at least [**]
percent ([**]%) of SPONSOR's requirements of 4-HC for non-research purposes.
SPONSOR shall provide CTRC RESEARCH written notice of the terms of and
conditions of he Bid and CTRC RESEARCH shall have thirty (30) days to exercise
its option to match the Bid to synthesize the 4-HC by providing written notice
to SPONSOR. Nothing in this Section 4, however, shall prevent SPONSOR from
entering into an agreement with a third party for the remaining [**] percent
([**]%) of SPONSOR's 4-HC requirements.
4.3. CTRC RESEARCH shall have the right to assign the rights in this
Section 4 to an affiliate of CTRC RESEARCH, Lipitek, Inc. (provided it is owned
in whole or in part by Xxxxxxxxx X. Xxxx, Ph.D.) or a third party which is
approved by SPONSOR. An affiliate of CTRC RESEARCH shall be any entity that
directly or indirectly, through one or more intermediaries, in whole or in
part, is owned/controlled by, or is under common ownership/control with CTRC
RESEARCH. For the affiliate to be considered to be "owned/controlled" or
"under common ownership/control", the amount of ownership or control of the
affiliate must be at least [**] percent ([**]%) and the affiliate
must have Xxxxxxx X. Love or a SPONSOR approved substitute, as a part of its
management team.
4.4. This Section shall survive the termination of this Agreement for
a period of three (3) days.
5. INDEMNIFICATION
5.1. CTRC RESEARCH shall, to the extent permitted under the laws of
the State of Texas, indemnify and hold harmless SPONSOR, its directors,
officers, agents, and employees from any liability, expense, cost, damage and
loss resulting from any willful misconduct or negligent acts or omissions of
CTRC RESEARCH, its officers, agents or employees, relating to the activities to
be carried out pursuant to this Agreement.
5.2 SPONSOR shall indemnify and hold harmless CTRC RESEARCH, its
directors, officers, agents, and employees from any liability, expense, cost,
damage and loss arising from the use, testing, research or marketing of 4-HC
(clinical or otherwise), except for any liability, expense, cost, damage and
loss which results from the willful misconduct or negligent acts or omissions
of CTRC RESEARCH. for any 4-HC delivered by CTRC RESEARCH pursuant to this
Agreement, the actions of CTRC RESEARCH in synthesizing the 4-HC in accordance
with
5
the specifications of this Agreement shall not constitute willful misconduct or
negligent acts or omissions for purposes of this Agreement.
5.3. SPONSOR shall, at SPONSOR's expense, defend and hold harmless
CTRC RESEARCH against any and all claims that 4-HC infringes upon or
appropriates any patent or other proprietary right. SPONSOR shall pay all
costs, damages and reasonable attorney's fees that the court finally awards as
a result of such a claim.
6. CONFIDENTIALITY
6.1. During the term of this Agreement and for a period of five (5)
years after termination of this Agreement, CTRC RESEARCH shall, except as may
be authorized by this Agreement, maintain the confidentiality of any
confidential or secret knowledge, information or material, whether developed by
CTRC RESEARCH, SPONSOR, or by others, which CTRC RESEARCH has acquired or
become acquainted with as a direct result of this Agreement and the PROJECT,
including any trade secrets, confidential or secret designs, processes,
formulae, plans, devices or material (whether or not patented or patentable),
any customer or supplier lists, any confidential or secret development or
research work, or any other confidential or secret aspects of the business of
SPONSOR (collectively, "Confidential Information"). CTRC RESEARCH hereby
acknowledges that the Confidential Information constitutes a unique and
valuable asset of SPONSOR and represent a substantial investment of time and
expense, and such Confidential Information shall not be disclosed or used other
than as contemplated by this Agreement. The foregoing obligations of
confidentiality shall not apply to any knowledge or information that (a) was
known to CTRC RESEARCH prior to SPONSOR's disclosing it; (b) was generally
known to the public prior to SPONSOR's disclosing it; (c) becomes generally
known to the public through no fault of CTRC RESEARCH, (d) is acquired from a
third party, without violation of this Section 6; (e) is required to be
disclosed to a governmental authority to obtain or maintain regulatory
approval; or (f) was independently developed by CTRC RESEARCH without the use
of or reliance on any Confidential Information, as shown by written records
prepared contemporaneously with such independent development. CTRC RESEARCH
recognizes that a violation of this Section 6.1 will result in injury to
SPONSOR, the extent to which is impossible to ascertain and as such, SPONSOR
will be entitled to an injunction restraining and enjoining CTRC RESEARCH from
violating or continuing to violate this Section 6.1.
6.2. The parties have signed a Mutual Secrecy Agreement in the form
attached hereto as Exhibit II. This Agreement shall supersede and shall
operate in lieu of the terms and conditions of said Mutual Secrecy Agreement.
7. INVENTIONS AND PATENTS
7.1. CTRC RESEARCH will promptly disclose in writing to SPONSOR
complete information concerning each and every invention, discovery,
improvement, device, design, apparatus, practice, process, method or product,
whether patentable or not, made, developed, perfected, devised, conceived or
first reduced to practice by CTRC RESEARCH, either solely or in collaboration
with others, during the terms of this Agreement whether or not during regular
6
working hours, relating directly to the PROJECT (hereinafter referred to as
"Developments"). CTRC RESEARCH to the extent that CTRC RESEARCH has the legal
right to do so, hereby acknowledges that any and all of such Developments are
the property of SPONSOR, and CTRC RESEARCH hereby assigns and agrees to assign
to SPONSOR any and all of CTRC RESEARCH's right, title and interest in and to
any and all of such Developments, except that CTRC Research hereby retains the
following licenses:
(i) an assignable, non-exclusive, royalty-free license to use and
practice such Developments for research and non-research
purposes, provided such Developments are not used to produce 4-HC
for commercial purposes; and
(ii) an assignable, non-exclusive, royalty-free license, which shall
be effective upon termination of this Agreement, to utilize and
practice such Developments for non-research purposes, including
the right to produce 4-HC.
7.2. As to any future Developments made by CTRC RESEARCH which relate
directly to the PROJECT and which are first conceived or reduced to practice
during the term of this Agreement, but which are claimed for any reason to
belong to an entity or person other than SPONSOR, CTRC RESEARCH will promptly
disclose the same in writing to SPONSOR. If SPONSOR makes claim of ownership
to such Development, the rights (if any) of CTRC RESEARCH will be settled by
arbitration in accordance with Section 11.5 hereof.
7.3. The provisions of Sections 7.1 and 7.2 shall not apply to any
Development meeting the following conditions: (a) such Development was made
without the use of any equipment, supplies, or trade secret information of
SPONSOR; and (b) such Development does not result from any work performed by
CTRC RESEARCH for SPONSOR under this Agreement.
7.4 Upon request and without further compensation therefor, but at no
expense to CTRC RESEARCH, and whether during the term of this Agreement, or
thereafter, CTRC RESEARCH will do all lawful acts, including, but not limited
to, the execution of papers and lawful oaths and the giving of testimony, that
in the opinion of SPONSOR, its successors and assigns, may be reasonably
necessary or desirable in obtaining, sustaining, reissuing, extending and
enforcing United States and foreign Letters Patent, including, but not limited
to, design patents, on any and all of such Developments, and for perfecting,
affirming and recording SPONSOR's complete ownership and title thereto, and to
cooperate otherwise in all proceedings and matters relating thereto.
7.5. CTRC RESEARCH will keep complete, accurate and authentic
accounts, notes and records of all Developments in the manner and form
reasonably requested by SPONSOR. Such accounts, notes, data and records shall
be the property of SPONSOR, and, upon its request, CTRC RESEARCH will promptly
surrender the original of the same to it or, if not previously surrendered upon
its request or otherwise, CTRC RESEARCH will surrender the original of the same
to SPONSOR upon the termination of this Agreement. CTRC RESEARCH shall have
the right to retain a copy of all accounts, notes and records of all
Developments which are created pursuant to this Agreement.
7
7.6. Except as contained in this Agreement, no license under any
SPONSOR patent is granted to CTRC RESEARCH hereby.
8. INDEPENDENT CONTRACTOR
Subject to Section 1 hereof, SPONSOR will not have the right to direct
or control the activities of CTRC RESEARCH performing the services provided
herein, and CTRC RESEARCH shall perform services hereunder only as an
independent contractor, and nothing herein shall be construed to be
inconsistent with the relationship or status. Under no circumstances shall
CTRC RESEARCH be considered to be an employee or agent of SPONSOR. This
Agreement shall not constitute, create or in any way be interpreted as a joint
venture, partnership or formal business organization of any kind.
9. NON-COMPETITION COVENANT
CTRC RESEARCH covenants and agrees that, except as provided for in any
agreement which may be negotiated between the parties as specified in Section
4, during the term of this Agreement, CTRC RESEARCH shall not directly or
indirectly engage in competition with SPONSOR in any manner or capacity (e.g.,
as a supplier, advisor, consultant, manufacturer, principal, agent, partner,
stockholder, independent contractor, member of any association or otherwise) by
engaging in the synthesis of 4-HC for any purpose except research being
conducted by CTRC RESEARCH. The geographic scope of this covenant shall be the
entire world. CTRC RESEARCH further agrees that during the term of this
Agreement and thereafter, it will not, directly or indirectly, assist any other
person or entity in carrying out, directly or indirectly, any activity that
would be prohibited by this Section 9 if such activity were carried out by CTRC
RESEARCH.
10. NOTICES
All notices of every kind and description whatsoever required or
permitted under this Agreement shall be in writing and shall be deemed to have
been received when personally delivered or when mailed through the U.S. Postal
Service, postage prepaid, as evidenced by a postmark certificate of mailing, or
by similar means for delivery, such as a signed receipt acknowledging personal
delivery, to the party to whom delivery shall be made at the respective
addresses set out below:
If to CTRC RESEARCH: Xxxxx X. Xxxxxxxx
Institute for Drug Development
14960 Omicron
Xxx Xxxxxxx, Xxxxx 00000
If to SPONSOR: Attention: Xxxxxxx X. Xxxxxxxxx, Ph.D.
Executive Vice President, New Business
MGI PHARMA, INC.
Xxxxx 000 X., Xxxx Xxxxxx
0000 Xxxx Xxxx Xxxx
Xxxxxxxxxxx, Xxxxxxxxx 00000-0000
8
11. MISCELLANEOUS
11.1. In the event of acts of God, action of the elements, war,
invasion, civil commotion, insurrection, labor disturbance, fire, floor,
earthquake, or government restriction, or intervention which is beyond the
control of CTRC RESEARCH which renders performance under this Agreement
impossible or economically impractical, failure on that account during each
period shall be excused during such period or periods of inability to perform.
11.2. This Agreement, together with the attached exhibits and
schedules, constitutes the entire understanding between the parties as of the
date of the execution of this Agreement with respect to the subject matter
hereof and shall supersede any prior agreements or understandings (whether oral
or written) between the parties hereto relating to the subject matter hereof
and may be modified only by a written instrument duly executed by each party's
authorized representative. If either party shall on any occasion fail to
perform any provision of this Agreement and the other party shall not enforce
that provision, the failure to enforce on that occasion shall not prevent
enforcement on any other occasion.
11.3. If any provision of this Agreement is held invalid by any law,
rule, order or regulation of any government or by the final determination of
any state or federal court, such invalidity shall not affect the enforceability
of any other provision not held to be invalid, and such invalidity shall not
affect the enforceability of such provision in any jurisdiction where such
provision has not been held to be invalid. In furtherance of and not in
limitation of the foregoing, it is expressly agreed that should the duration of
or geographical scope of, or activities covered by, the non-competition
covenant of Section 9 to be determined to be in excess of that which is valid
or enforceable under applicable law, then such Section 9 shall be construed to
cover that duration or scope or those activities which may be validly or
enforceably be covered.
11.4. Neither party, except as otherwise provided in this Agreement,
shall assign this Agreement or its rights and obligations hereunder without the
prior written consent of the other party, provided, however, that this
Agreement may be assigned by CTRC RESEARCH to a successor or assignee of its
services upon prior written notice to SPONSOR, and SPONSOR may assign this
Agreement to any entity or person that directly or indirectly, through one or
more intermediaries, controls, or is controlled by, or is under common control
with SPONSOR, or to any successor in interest of SPONSOR resulting from the
merger, consolidation or sale of all or substantially all of the assets of
SPONSOR, without the prior consent of CTRC RESEARCH.
11.5. This Agreement shall be governed by the laws of the State of
Texas. All disputes arising under this Agreement which cannot be settled by
mutual consent of the parties shall be submitted to arbitration in accordance
with the rules of the American Arbitration Association, the costs and expenses
of which arbitration shall be borne by the party against which a decision is
rendered.
9
11.6. Notwithstanding the termination of this Agreement, Sections 4.1-
4.4, 5.1-5.3, 6.1, 7.1-7.5 and 8 shall survive the termination of this
Agreement and shall be binding and enforceable as may be provided in said
sections.
11.7. CTRC RESEARCH is on notice that SPONSOR may utilize the goods to
be purchased hereunder in the manufacture of products destined for sale to the
U.S. Government or a U.S. Government financed project. Unless exempt
therefrom, CTRC RESEARCH agrees to comply with the Executive Order 11246, the
Rehabilitation Act of 1973, including amendments thereto, and all rules and
regulations issued thereunder. Unless exempt, this contract is subject to the
Equal Opportunity Clause set forth in 41 C.F.R. Section 60-1.4 and the
Affirmative Action Clauses set forth in 41 C.F.R. Section Section 60-250.4,
741.4. Those clauses are hereby incorporated by reference.
11.8. Paragraph readings and captions used herein are for convenience
of reference only and shall not be used in the construction or interpretation
of this Agreement. This Agreement has been jointly prepared on the basis of
the mutual understanding of the parties and shall not be construed against
either party by reason of such party's being the drafter hereof.
11.9. No right, express or implied, is granted by this Agreement to
either party to use in any manner the trademarks or the name of the other or
any other trade name, service xxxx, or trademark owned by or licensed to the
other in connection with the performance of this Agreement.
IN WITNESS WHEREOF, the parties hereto have executed this Agreement to
be effective as of the date written above.
CTRC RESEARCH FOUNDATION
By: /s/ Xxxxxxx X. Love
----------------------------------
Xxxxxxx X. Love
Chief Operating Officer
By: /s/ Xxxxxxxxx X. Xxxx
---------------------------------
Xxxxxxxxx X. Xxxx, Ph.D.
Project Manager
Date: December 2, 1993
-------------------------------
10
MGI PHARMA, INC.
By:
---------------------------------
Its Executive Vice President
--------------------------
Date: December 28, 1993
-------------------------------
11
EXHIBIT I
WORKPLAN
SYNTHESIS OF 4-HYDROPEROXYCYCLOPHOSPHAMIDE
PHASE ONE
CTRC's Institute for Drug Development ("IDD"), under the leadership of
Xx. Xxxx Xxxx, will undertake to develop a scalable process to make and purify
4-hydroperoxycyclophosphamide (4-HC). The specific objectives will be:
1. In calendar year 1993 develop a process which will reproducibly yield 20
to 30 grams of 4-HC to a purity of at least 98.5% and which can be
scaled for eventual production of 5 to 10 kg per year.
2. Provide MGI Pharma with 20 grams of 4-HC, produced in IDD's labs under
Good Manufacturing Practices (GMP), by November 1, 1993.
3. In collaboration with MGI Pharma, prepare a DMF which shall be available
to MGI Pharma upon request.
4. In connection with the intent to prepare for on-going GMP synthesis at
IDD, the following specific tasks will be performed:
o IDD will allow MGI to inspect IDD's facilities and procedures.
o IDD will establish and maintain a Type I DMF for the manufacture
of 4-HC and will ensure that the DMF coverage extends to other
subcontracted facilities (e.g. Lipitek, Inc.), utilized by IDD.
o IDD will provide letter of access to IDD's DMF at MGI's request.
o IDD is to manufacture drug substance utilizing raw materials that
have been released per MGI supplied raw material specifications,
and pursuant to MGI supplied Master Formula/Batch Record(s).
o IDD is to be responsible for the procurement, testing and
maintaining inventory of raw materials, for the manufacture of
the drug substance and for providing required documentation
related to same. IDD will maintain original documentation of raw
material receipt, testing and drug substance synthesis. IDD will
provide reserve samples of each batch of drug substance to MGI
and may maintain reserve samples for IDD use.
o IDD to specify the significant steps in the manufacturing process
and will identify tests and control parameters for the precursor
and the ozonolysis product.
12
o IDD to outline a validation of the precursor and of the
ozonolysis to be provided to MGI. MGI will then generate the
protocol and document the execution of the protocol by IDD.
o IDD is to complete the characterization of the drug substance to
include the following tests on a lot identified by MGI, NMR, and
TLC.
o IDD is to develop solubility profiles in at least 3 solvents.
o IDD is to provide detail of purification and characterization of
ozonolysis performed at 0 deg. C and -40 deg. C (test for robust
synthesis).
o IDD to provide a detailed flow chart to include process steps,
equipment, and scale of the synthesis process.
o IDD is to describe any modifications and changes made to the
synthesis and characterizations of resultant products.
o IDD to recommend the characterization of the Reference Standard,
provide the complete documentation of the manufacture of the
standard per an approved batch record, and assist MGI in
characterization of standard.
o IDD to provide rationale and explanation of controls of the
Pivotal Step identified as Ozonolysis and the Key Intermediate
identified as the Precursor, Tri-substituted Phosphate according
to the format provided by MGI.
o IDD and MGI will collaborate to write a scientific discussion
that will describe the applicable stages in drug substance
manufacture where the following apply:
where the BPC can be identified and quantified, and where
yields can be calculated
where a contaminant, impurity, or other substance likely
to adversely affect the BPC molecule is first identified
and subsequent attempts are made to remove it
where an attempt is made to separate a mixture of
different forms of the same molecule and isolate a desired
form
o IDD agrees that lots will not be commingled at IDD without MGI's
express permission.
o IDD to commit to provide batch records and associated
documentation for all attempts and drug substance synthesis
failures.
13
o IDD to propose optimization and scale-up evaluations within 6
months of manufacture of the first 20 gram batch. MGI will
recommend the lot sizes desired.
o IDD to store under refrigerated conditions 40 mgs per assay for 3
HPLC assays for each drug substance synthesis attempt as reserve
samples and for impurity profile information.
o IDD to recommend which solvents, intermediates, etc. are
appropriate for the reserve sample program, (dependent on
stability and significance).
o MGI will accept delivery of drug substance only after the lot has
met all drug substance specification requirements, and MGI has
received an executed batch record approved by IDD's Quality
Assurance representative and MGI Quality Assurance. Any
investigations initiated as a result of the drug substance
manufacturing process must receive review and approval by IDD and
MGI prior to release and acceptance by MGI.
o MGI will be responsible for the release testing of the drug
substance, and providing release documentation to IDD.
o MGI to prepare a BOM for the materials utilized in the
manufacture of the drug substance, and IDD to identify grade and
method of raw material testing, as well as reserve sample
requirements of the above.
o MGI will provide the raw material specifications, test methods
and perform the testing and release.
o MGI will specify samples for testing and will provide lot number
and expiration dating period for each lot.
o MGI will be responsible for the release of the drug substance
product.
o MGI will provide shipping destination information for drug
substance.
o MGI is to retain sole ownership of all drug substance product,
including but not limited to manufactured lots, experimental
lots, reserve samples and other samples maintained by IDD.
PHASE TWO
o IDD will produce up to 300 grams of 4-HC for MGI Pharma under
Good Manufacturing Practices, which will be synthesized by IDD
upon receipt of a purchase order from MGI Pharma which shall be
in a minimum lot size of 100 grams.
14
o Provided that IDD is requested to produce 4-HC on an on-going
basis, IDD will evaluate and recommend reprocessing steps that
may be undertaken which will meet the drug substance
specifications, and provide the manufacturing process for same.
IDD estimates that this task will be addressed in 1994.
o IDD to attempt to manufacture via the drug substance synthesis,
the related compounds and provide the resultant material to MGI
for analysis.
