Exhibit 10.49
***Text Omitted and Filed Separately
Confidential Treatment Requested
Under 17 C.F.R. §§
200.80(b)(4)
And 240.24b-2
Commercial Supply Agreement
for Exenatide
This Agreement,
effective as of December 23
, 2003, is made by and among
Amylin Pharmaceuticals, Inc. (“Amylin”) having a
principal place of business at 9360 Towne Centre
Drive, San Diego, CA 92121, and
Bachem, Inc., a California corporation (“Bachem”),
having a principal place
of business at 3132 Kashiwa Street, Torrance, CA 90505. References
to any of Amylin or
Bachem includes reference to their respective
Affiliates.
Whereas, Bachem
previously manufactured for Amylin a compound referred to as
Exenatide (as defined below).
Whereas, Amylin
wishes to engage Bachem to manufacture clinical trial,
regulatory registration and commercial
supplies of Exenatide on behalf of Amylin.
Whereas, Bachem
desires to manufacture for Amylin clinical trial, regulatory
registration and commercial supplies of Exenatide; and
Now, Therefore,
in consideration of the premises and the mutual covenants and
agreements contained herein, Bachem and Amylin agree as
follows:
1.
Definitions
As used in this
Agreement, the following words and phrases shall have the following
meanings:
1.1
“Affiliate” of a
party hereto means any entity which directly or indirectly, through
one or more intermediaries,
controls, is controlled by or is under common control with such
party where “controlling,”
“controlled” and “under common control”
means the direct or indirect beneficial ownership of at least fifty
percent (50%) of the stock, or a fifty percent (50%) or greater
interest in the income, of such
party or entity, as applicable.
1.2
“Applicable
Laws” shall mean all applicable statutes, ordinances,
regulations, rules, or orders of any kind whatsoever of
any governmental authority (including any amendments thereto),
applicable to the import, export, manufacture and distribution of
Product, including, without limitation, the applicable regulations
and guidelines of the FDA and all applicable current good
manufacturing
practices, including, without limitation, the cGMPs.
1.3
“Bachem
Technology” means all technical information, whether tangible
or intangible and whether or not patentable, including patents, and
any method, procedure, process, assay, composition of matter, trade
secret, invention, technology, information or other subject
matter, including license
application materials and all supporting documents, specifications
for materials (including purification
techniques), data, information (including information contained in
registration dossiers, drug master files and other documents filed
with Regulatory Authorities), quality control, validation and
equipment necessary or useful for the manufacture, production,
scale-up, processing or formulation of Product, which (a) Bachem
conceived, reduced to practice, developed or
obtained (or which Bachem has the ability to license or
sublicense), or (b)
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is otherwise
necessary or useful in the manufacture of the Product.
1.4
“Batch
Production Records” means the lot production records for the
Batches manufactured by Bachem pursuant to this Agreement.
1.5
“cGMPs” shall
mean then-current Good Manufacturing Practices as specified in
ICH Guideline Q7A, the
United States Code of Federal
Regulations, or equivalent laws, rules, or regulations of an
applicable Regulatory Authority at the time of
manufacture.
1.6
“Collaboration
Partner” means Eli Lilly and Company, with whom AMYLIN has
entered into a
collaboration arrangement
regarding
Product.
1.7
“Contaminant”
means any substance contained in the Product that (A) causes the
Product to fail to meet any Product
Specifications, (B) causes the Product to be adulterated within the
meaning the Act, (C) is present in the Product at a level that
exceeds the level allowed under Applicable
Laws.
1.8
“DMF” shall
mean a drug master file for Product in the United States (as such
term is defined in 21 C.F.R. Part 314. 420 ) or Europe.
1.9
“Effective Date”
means the later date of execution written on the execution page of
this Agreement
.
1.10
“Facility”
means the facility in Torrance, California where Product is
manufactured by Bachem under this
Agreement.
1.11
“FDA” means the
United States Food and Drug Administration and any successor
entity.
1.12
“Hidden
Defect” means a defect in any shipment of Product that could
not reasonably be expected to have been found
by diligent and adequate inspection by Amylin pursuant to
Section 4.1,
such as the presence of any Contaminant or failure to follow
cGMPs.
1.13
“Materials”
shall mean, collectively, all raw materials, ingredients and
packaging components required to
produce Product in accordance with the Product
Specifications.
1.14
“NDA” means a
New Drug Application to make and/or sell commercially Product,
filed with the FDA (as more fully defined in 21 C.F.R. Part 314.5
et seq.) or with a Regulatory Authority in any
jurisdiction outside of the United States, and all amendments and
supplements thereto filed therewith.
1.15
“Product”
means the bulk drug substance, Exenatide, manufactured under this
Agreement.
1.16
“Product
Specifications” means the written specifications for Product
set forth in Exhibit 1, as amended from time to time in accordance
with the Quality Agreement.
1.17
“Purchase
Order” means Amylin firm orders for Product under this
Agreement issued on Amylin’s form of
purchase order.
1.18
“Quality
Agreement” means that certain Quality Agreement dated as of
the Effective Date between Amylin and Bachem
containing, identifying and outlining the specifications, and
certain
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of the
technical and compliance terms and conditions, for the manufacture
of Product under this Agreement. The Quality Agreement is
incorporated into and made a part of this Agreement.
1.19
“Regulatory
Approval” means (a) in the United States, approval by the FDA
of an NDA for the Product, and
satisfaction of any related applicable FDA registration and
notification requirements, if any, and
(b) in any country other than the United States, approval by
Regulatory Authorities having
jurisdiction over such country of a single application or set of
applications with respect to a Product comparable to an NDA, and
satisfaction of any related applicable regulatory and notification
requirements, if any, including pricing approvals where
applicable, together with any other
approval necessary to make, use, import, package, label, market,
and sell Product commercially in such country.
1.20
“Regulatory
Authority” means the FDA in the United States, or the
applicable regulatory agency or entity having
the responsibility, jurisdiction, and authority to approve the
manufacture, use, importation,
packaging, labeling, marketing, and sale of Product in any country
other than the United
States.
2.
Purchase and Sale of Product
2.1
Bachem agrees
to manufacture Product using the process described in the Batch
Production Records, subject to the terms and conditions of this
Agreement.
2.2
Bachem agrees
to manufacture and supply Exenatide in quantities set forth in
Purchase Orders submitted by Amylin in accordance with this
Agreement. The following table sets forth the quantities of Product
that Amylin estimates, as of the Effective Date, that it will
purchase during the period
commencing [ *** ] and ending [ *** ].
[***]
[***]
Commencing on
the Effective Date Amylin will supply to Bachem rolling [
*** ] forecasts containing its estimated
requirements of Product, [ ***
]. This may be
a fixed amount or a range of quantities.
Amylin shall update such forecasts every [ ***
]. Amylin
shall submit Purchase Orders
specifying the quantity of Product ordered, the required delivery
date, and any special
instructions. Purchase Orders for delivery of Product in [
*** ], will be issued (A) no later than [ *** ], and
(B) at least [ *** ] in advance of the requested delivery
date, provided that such [ ***
] lead time may
be reduced by [ ***
], if Amylin
pre-purchases Materials. The Purchase Orders issued in accordance
with this Section 2.2 will be binding on both Seller and
Buyer.
2.3
The price for the Product shall be based on [ *** ] as set
forth below and includes the costs of Materials and
analytical release testing. If Materials’
costs or
waste disposal costs change by more than [
*** ], the price for the Product may be adjusted, subject
to the
parties’ mutual written agreement, to reflect the change in
such costs.
Prices will
be the following: [ *** ]
* Based on
current specifications. The parties agree that changes to the
Product Specifications that are
set forth in Exhibit 1 as of the Effective Date to reflect
requirements for commercial supply will not result in any change to
the prices set forth
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above;
provided, however that, if such changes to the Product
Specifications reflect process capabilities that are outside the
process capabilities demonstrated by Bachem in manufacturing validation
batches, then the parties will discuss whether such prices would
require adjustment as a consequence.
If certain
process improvements can be identified post approval, Bachem and
Amylin will jointly decide on a course of
action, provided that no change to the manufacturing process for
Products may be implemented without Amylin’s prior written
approval. Bachem will quote for the work this implementation of
changes involves. Amylin can then elect to pursue this option. Any
cost savings that ensue from
the implementation of these changes would be [ *** ] between
the parties.
2.4
Any federal, state, county of municipal sales or use tax, excise or
similar charge, or other tax assessment (other than
that assessed against income), license fee or other charge lawfully
assessed or charged on the manufacture, sale or transportation of
Product sold pursuant to this Agreement shall be paid
by Amylin, provided evidence of such charge is provided to Amylin
in writing .
3.
Manufacture of Product
3.1 Changes
in the manufacturing site or the materials, equipment, process, or
procedures used to manufacture the Products
shall be handled by the parties as stated in the Quality Agreement.
Bachem shall obtain Amylin’s prior written approval before it
implements any such change. Amylin shall have the right to raise
with Bachem any perceived deficiencies regarding any
aspect of
Bachem’s manufacture of Product. In the event that Amylin
raises with Bachem any such deficiency both
parties will engage in negotiations regarding remedial action. Upon
mutual agreement, (A) Bachem
shall, at its sole cost, promptly submit to Amylin a written plan
to correct any such
deficiency and promptly correct any such deficiency to
Amylin’s satisfaction, (B)
Amylin shall reimburse Bachem for any reasonable incremental
one-time costs associated with such changes while any ongoing costs
associated with such changes shall be reviewed by
the parties and allocated
between Amylin and Bachem as mutually agreed upon by the parties at
such time. If such corrections are required to bring the Facility
into compliance with Applicable Laws, then Bachem shall bear all
associated costs.
3.2
Product
Specifications may be modified from time to time by written
agreement of the parties without the necessity of amending this
Agreement. However, no changes in the Product Specifications will
be made unless made in accordance with the terms and conditions of
the Quality Agreement. If
Amylin requests a change in the Product Specifications that would
result in a material increase in Bachem’s cost of
manufacture, the parties shall discuss what impact, if
any, such change
should have on the price of Product. If either Bachem agrees to
implement such change without
additional charge, or Amylin agrees in writing to a proposed price
increase to implement such change,
the price change shall become effective only with respect to
those orders of Product that are
manufactured in accordance with the modified Product
Specifications. If a Regulatory Authority
requires a change in
the Product Specifications that
would result in a material increase in Bachem’s cost of
manufacture, the parties shall discuss what impact, if any,
such change should have on the
price of Product and Amylin shall bear the increased
cost.
3.3
Bachem and
Amylin shall comply with the terms and conditions of the Quality
Agreement. Bachem shall manufacture,
package, label, and supply Product in
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accordance
with the Product Specifications, cGMPs, the
NDA, DMF or other applicable Regulatory Approvals, and all
applicable
rules and regulations of Regulatory Authorities with jurisdiction
over the manufacture , packaging, labeling, use
or sale of Product, as they may be amended from time to time.
Bachem’s responsibilities and obligations with respect to the
manufacture of Products as set forth in this Section 3.3 are
hereinafter referred to as the “Manufacturing
Requirements.” Bachem shall perform such quality
control testing prior to shipment of Product to Amylin as is
required to ensure that the Products delivered to Amylin under this
Agreement comply with the Manufacturing Requirements and warranties
described in Section 8, which testing shall include, without
limitation, the performance of all required release testing and
stability testing using the Amylin Test Methods and other tests
designated by Amylin as found in Appendix A of this
Agreement.
Bachem shall perform such tests itself or, with Amylin’s
prior written consent, cause to be tested by a
third party, each lot of Product before delivery, and shall provide
to Amylin (A) a certificate of
analysis containing the quality control test results for each such
lot, and
confirming that each such lot of Product conforms to the Product
Specifications (the “Certificate of Analysis”), (B) a
Certificate of Conformance confirming that such lot of Product was
made in accordance with cGMPs and the process defined in the
approved master batch record for such Product, and (C) copies of
documents detailing any deviations from any manufacturing processes
then in effect (the documents and information described in (A), (B)
and (C),
the “Bachem Release Documents”). Upon completion of the
manufacture and testing of each lot of Product
ordered by Amylin under this Agreement, Bachem shall send all the
Bachem Release Documents to Amylin. Amylin is entitled to rely on
the Bachem Release Documents for all purposes of this
Agreement.
3.4 Bachem shall be responsible for obtaining any
Materials required for the manufacture of Product, in reasonable
quantities consistent with Amylin’s orders for Product and in
accordance with the requirements of Section 8.1(H). Bachem shall
use and rotate all stock of Materials on a first-in, first-out basis as required by
cGMPs. Amylin shall assign lot numbers and retest dates to
each lot of Product, and Bachem
shall imprint such lot numbers and retest dates on each unit
of Product shipped as
required by cGMPs.
3.5
Bachem shall
keep complete, accurate, and authentic accounts, notes, data, and
records pertaining to its
manufacture, processing, testing, packaging, storage and
distribution of Product, including, without limitation, master
production and control records and Product complaint files,
in accordance
with Applicable Laws. In addition, Bachem shall retain samples of
Products and isolated intermediates of each lot manufactured
pursuant to this Agreement for a period of five (5) years after
Amylin’s acceptance of such lot. The sample size shall be
twice the size necessary to conduct
quality control testing. Bachem shall retain such records and
samples for a period of five (5) years
following the date of manufacture, or longer if required by
Applicable Laws , and, upon request, shall make available
to Amylin and its Collaboration Partner copies of
such records and portions of the
samples. After such time period, Bachem shall notify Amylin
prior to destroying such records
and samples and, at Amylin’s request and expense, shall
provide such records and samples to Amylin. Bachem shall permit
Amylin and its Collaboration Partner and their respective representatives with
access during reasonable business hours and after reasonable notice
to those areas of Bachem’s manufacturing facilities where
Product is manufactured, stored and handled and to manufacturing
records, and testing and control records (including without limitation release and
stability records), of Product manufactured by Bachem,
so that Amylin
and
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its
Collaboration Partner and their respective representatives may
perform a quality assurance audit of such facilities and
activities. Use of all information gained in the course of audits
is restricted to the purpose of Quality Assurance. Likewise, Bachem
shall grant similar access to
governmental regulatory agencies upon reasonable notice so that
such agencies can perform inspections of its facilities.
3.6
Bachem shall promptly advise Amylin
of any notice or request it receives from a Regulatory Authority or other governmental agency
regarding inspection of its facilities relating to its manufacture
of Product, and shall permit Amylin and its Collaboration
Partner and their
respective representatives to attend such inspection. Bachem shall
provide to Amylin and its Collaboration Partner all
correspondence and reports that it receives from a Regulatory
Authority or other governmental
agency in connection with the manufacture of Product or with
respect to the facility(ies) at which Bachem manufactures Product.
Bachem shall retain the right to delete information from
these reports that would breach a confidentiality provision with
any third party.
3.7
Bachem shall,
at its own expense, obtain
and maintain the necessary
permits required for its manufacture and supply of the Products in
accordance with this Agreement, including all required facility licenses.
3.8 Bachem further agrees to use its commercially
reasonable efforts to assist Amylin and its Collaboration Partner
in obtaining FDA approval of its NDA with respect to Product, as
well as approvals from any other government or agency which may be
required for the marketing of Product in any country. Bachem specifically agrees
to cooperate with any inspection by the FDA or other Regulatory Authority, including
but not limited to any inspection prior to approval
of Amylin’s or its
Collaboration Partner’s NDA. Bachem shall, on a timely basis,
provide Amylin and its
Collaboration Partner with information in Bachem’s possession
relevant to its role as the manufacturer of Products that is
reasonably necessary for and relevant to Amylin’s and its
Collaboration Partner’s efforts to obtain and maintain
Regulatory Approvals for Product. Without limiting the generality
of the foregoing, Bachem agrees to establish and maintain a DMF for
the Product in accordance with the requirements of the FDA and any
other applicable Regulatory Authorities, and to provide Amylin and
its Collaboration Partner with letters of access to, and rights to
reference, the DMF and any other comparable files. Bachem shall
file and establish the DMF in a timely manner to support
Amylin’s or its Collaboration Partner’s
NDA filing, and shall provide to
Amylin and its Collaboration Partner such documentation, data and
other information relating to Products as Amylin or its
Collaboration Partner may require for submission to Regulatory Authorities. Bachem
shall also provide, upon request by Amylin, information concerning
its production processes and quality control procedures with
respect to Products.
3.9
Each party shall promptly advise the others
of any safety or toxicity problem of which such party becomes aware
regarding the Product.
3.10
Bachem shall promptly notify Amylin of any
problems, supply, or other situations that are likely to adversely affect the production of
any Product, or its timely delivery to Amylin in accordance with
the Purchase Order therefor. Amylin may participate in the
resolution of any such
problem or production situation unless Amylin agrees with Bachem
that such participation is unnecessary.
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3.11
The conditions
under which Product is manufactured shall be provided to Amylin and
its Collaboration Partner for
inclusion in Amylin’s or its Collaboration Partner’s
regulatory filings. Bachem further agrees to
provide
