Exhibit 10.39A
[*] indicates that a confidential portion of this Amendment has been omitted and
filed separately with the Securities and Exchange Commission.
AMENDMENT #1 TO THE
"PROCESS DEVELOPMENT AND MANUFACTURING AGREEMENT"
BETWEEN
ONYX PHARMACEUTICALS, INC., and XOMA (US) LLC
This Amendment #1 to the Process Development and Manufacturing Agreement (the
"Amendment") is made and entered into on April 15, 2002 by and between ONYX
Pharmaceuticals, Inc., a Delaware Corporation having its principal place of
business at 0000 Xxxxxxxx Xxxxx, Xxxxxxxx, Xxxxxxxxxx 00000 ("ONYX"), and XOMA
(US) LLC, a Delaware limited liability company ("XOMA") with offices at 0000
Xxxxxxx Xxxxxx, Xxxxxxxx, Xxxxxxxxxx 00000. ONYX and XOMA are sometimes referred
to herein individually as a "Party" and collectively as "Parties."
RECITALS
Whereas ONYX and XOMA entered into a Process Development and Manufacturing
Agreement, dated January 29, 2001, to engage XOMA to scale up and improve the
process for the manufacture of ONYX-015, and to manufacture and supply ONYX-015
in bulk form for clinical trials and for the commercial launch of the ONYX-015
product, such that the Development Phase was to occur at a [*] liter scale and
the commercial Manufacturing Phase was to occur at a [*] liter scale;
Whereas the Parties desire to amend the Agreement as follows:
1. Section 2.5(a) of the Agreement is deleted in its entirety, and the
following substituted in its place:
2.5 Specifications; Changes to Specifications and Work Plan.
(a) As of the Effective Date, ONYX and Pfizer have agreed upon the current
Specifications for Drug Substance, which are attached hereto as Exhibit A. ONYX
may change the Specifications from time to time, after consulting with XOMA in
advance as to such changes, and such revised Specifications shall replace the
previous Specifications and shall be deemed to be part of this Agreement as
Exhibit A. A copy of the current Specifications for Drug Substance is attached
to this Amendment as Exhibit A. In particular, after XOMA has produced [*]
releasable Batches of Drug Substance at the [*]L Development Scale, the Project
Team shall determine if any changes to the Specifications are desirable or
required. In particular, the Parties expect that ONYX will change the
Specifications as a result of process changes made during the Development Phase
under Section 4 and the data obtained from registration Batches manufactured
pursuant to Section 4.2, and that such modified Specifications will be
consistent with FDA expectations for purity, potency, and other product
characteristics. ONYX and XOMA expect that the modified Specifications will be
comparable to Specifications existing as of the Effective Date, particularly as
regards purity and potency, except as these Specifications may require revision
per the request of any Regulatory Authority (e.g., FDA, EMEA).
2. Section 4.2(a) of the Agreement is deleted in its entirety, and the
following substituted in its place:
4.2 Scale-up of Manufacture
(a) Establishment of Commercial Scale. Subject to sections 4.2(c) and 4.3,
in accordance with the Work Plan and as quickly as reasonably practicable, XOMA
will scale up the manufacturing scale for Drug Substance to Commercial Scale,
including, without limitation, performing process development work to improve
the manufacturing process for Drug Substance that is transferred to XOMA
pursuant to Section 4.1, increasing of the Drug Substance Yield, and addressing
FDA expectations for quality (i.e., purity and potency). The goal of such
efforts will be the production of the first Batch at Commercial Scale of Drug
Substance that meets Specifications and that results in an overall Drug
Substance Yield of at least [*] (which Yield level will not be deemed pursuant
to this Section 4.2(a) to be a Specification). This minimum Yield percentage of
[*] is an estimate based on production at the [*]L fermentation bioreactor
scale, and it is subject to confirmation and mutually agreed good faith
adjustment by the Parties based upon initial manufacturing runs at Development
Scale.
3. Section 4.3 of the Agreement is deleted in its entirety, and the
following substituted in its place:
4.3 Production at Development Scale. Prior to the establishment of
Commercial Scale per section 4.2(a), as quickly as reasonably practicable, but
no later than [*], XOMA will initiate [*] cGMP Batches of Drug Substance at the
[*] liter Development Scale in calendar [*], and ONYX will receive all of each
such Batch for purposes of (i) satisfying ONYX and Pfizer's projected needs for
a working stock of active ONYX-015 virus and for ONYX-015 supplies for critical
clinical trials, (ii) generating experimental data to support proposed process
changes, (iii) supporting the preparation and filing of appropriate
documentation (e.g. a Drug master file or any new or amended INDs for ONYX-015
that ONYX or an ONYX Partner may file), and/or (iv) supporting any BLA that ONYX
or Pfizer may file for ONYX-015. The Parties will consult as to ONYX's
additional needs for Development Scale Batches, based on its needs for the
purposes set forth in this Section 4.3, and XOMA will consider in good faith any
requests by ONYX for such additional production of Drug Substance at Development
Scale, with any production to be included in the Work Plan only upon the
Parties' mutual agreement. If XOMA produces any additional Development Scale
Batch pursuant to this Section 4.3, then: (i) the Parties will agree upon an
extension of the timeframes in Section 11.3(a) pursuant to which ONYX may
terminate this Agreement without penalty; and/or (ii) the Parties will agree
upon an extension of the period during which XOMA will manufacture the
guaranteed minimum number of Batches so as to permit XOMA to recapture its
economic benefits as contemplated in this Agreement.
In addition, as soon as practical but not later than [*], XOMA shall produce [*]
cell suspension-adapted HEK 293 cell banks (to include [*]) in full compliance
with cGMP and produced in Xoma's cGMP cell banking facility. Each bank must
contain at least [*] vials (net of vials removed for QC testing and retains),
and must meet Onyx specifications for suspension-adapted HEK 293 master or
working cell banks ("Cell Bank Specifications"), as appropriate. Additionally,
Xoma shall use reasonable efforts to produce [*] additional cell
suspension-adapted HEK 293 cell banks, also to include [*], in full compliance
with cGMP and produced in Xoma's cGMP cell banking facility. Each bank must also
contain at least [*] vials (net of vials removed for QC testing and retains),
and must meet
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Onyx specifications, as appropriate. Copies of the current cell bank
specifications are attached to this Amendment as Exhibits B and C.
4. Section 5.4 of the Agreement is deleted in its entirety, and the
following substituted in its place:
5.4 Commercial Supply Forecast. On or before [*], Onyx will provide XOMA
with a non-binding written [*] year forecast by calendar quarter of Onyx's or
any Onyx Partner's anticipated orders for Drug Substance, based upon demand for
clinical trials and commercial sales and upon reasonably anticipated dates for
issuance of Regulatory Approvals for the ONYX-015 product and launch dates
therefor. This forecast shall be for facility planning purposes only and shall
not constitute an order. Onyx will update this forecast on a calendar quarterly
basis.
5. Section 6.2 of the Agreement is deleted in its entirety, and the
following substituted in its place:
6.2 Space Fee. Beginning with the calendar quarter commencing [*], and
until production of the first registration Batch at Commercial Scale pursuant to
Section 4.2(a), ONYX shall pay XOMA a dedicated space fee for the Suite of [*]
per calendar quarter, payable on a calendar quarterly basis in advance by wire
transfer of immediately available funds to an account designated by XOMA. After
the calendar quarter in which such first registration Batch is supplied to ONYX,
no further dedicated space fee shall be payable. Adjustment for the first two
quarters of 2002 will be wired to XOMA promptly after signing this Amendment.
6. Section 6.5 of the Agreement is deleted in its entirety, and the
following substituted in its place:
6.5 Milestone Payments. Within thirty (30) days of the achievement of each
milestone set forth in this Section 6.5, ONYX will pay to XOMA the applicable
milestone payment by wire transfer of immediately available funds to an account
designated by XOMA.
(a) Commercial Scale
Other than milestones for additional Yield improvements pursuant to Section
6.5(a)(ii), no Commercial Scale milestone payment will be payable more than
once.
(i) Initial Commercial Scale Batch Meeting Specifications and with
Adequate Yield. Upon production of the initial Batch at the [*]L Commercial
Scale in compliance with Specifications and cGMP with the required minimum
Yield pursuant to Section 4.2(a), as adjusted, ONYX will pay to XOMA a
milestone payment of [*].
(ii) Yield Improvements. For each increase of [*] percentage points in
manufacturing Yield in excess of [*] Yield (as such Yield level may be
adjusted pursuant to Section 4.2(a)), as calculated at the completion of
the first [*] Batches of Drug Substance at [*]L Commercial Scale that
comply with the warranties in Section 8.1(a) pursuant to Sections 4.2(a)
and (b), ONYX will pay to XOMA a milestone payment of [*]. Increases in
Yield must be evidenced by the average Yield of the [*] Batches of Drug
Substance (or, if the Yield for one Batch differs by at least [*]
percentage points from the average Yield of the other [*] Batches, the
average Yield of
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such [*] Batches and the next Batch at Commercial Scale that complies with
the warranties in Section 8.1(a)) at or in excess of [*] Yield (as so
adjusted).
For purposes of example:
If [*] consecutive Batches result in Yields of [*], respectively, XOMA will have
earned an aggregate milestone payment of [*], as there has been a demonstrated
Yield improvement of [*] percentage points, which is equal to [*] increments of
[*] percentage points so that XOMA would receive [*] milestone payments of [*].
If [*] consecutive Batches result in Yields of [*], respectively, and a [*]
Batch results in a Yield of [*], the [*] Batch would be disregarded, and XOMA
will have earned an aggregate milestone payment of [*] based upon the other [*]
Batches, as there has been a demonstrated Yield improvement of [*] percentage
points, which is equal to [*] increments of [*] percentage points so that XOMA
would receive [*] milestone payments of [*].
Milestone payments for Yield improvements under this Section 6.5(b) shall be
payable only once for each [*] percentage points of Yield improvement.
(b) [*] Liter Development Scale
(i) Number of Batches and Production of Drug Substance
ONYX shall pay XOMA a milestone payment of [*] upon initiation of the [*]
run at [*] liter Development Scale provided all [*] runs are initiated during
the calendar year [*], and further provided that at least [*] liter runs yield
releasable Batches of Drug Substance. In addition, during the calendar year [*],
ONYX shall pay XOMA [*] for each releasable Batch of Drug Substance produced
after the first [*] releasable Batches have been produced.
(ii) Yield Improvements
ONYX shall pay XOMA a milestone payment of [*] for every incremental [*]
point improvement in Drug Substance Yield evidenced by the average Yield of [*]
consecutive releasable Batches of Drug Substance, starting from the current
baseline Yield of [*]. A given batch may be used only once for the purpose of
determining an incremental Yield improvement under this Amendment. The average
Yield used to demonstrate attainment of each Yield improvement milestone will be
used as the new baseline Yield for determining the next incremental Yield
improvement milestone.
For purposes of example:
With regard to the initial milestone payment, if [*] consecutive releasable
Batches result in Yields of [*], respectively, XOMA will have earned an
aggregate milestone payment of [*], as there has been an average demonstrated
Yield improvement over the [*] Batches of [*] percentage points, which is equal
to [*] increments of [*] percentage points above the initial baseline Yield of
[*], so that XOMA would receive [*] milestone payments of [*].
In the above example, the average Yield for the [*] Batches of [*] would become
the new baseline Yield for the next incremental Yield improvement milestone
payment. If the following [*] consecutive releasable Batches result in Yields of
[*], respectively, XOMA will have earned an additional milestone payment of [*],
as there has been a demonstrated Yield improvement over the [*] Batches of [*]
percentage points, which is equal to [*] increments of [*] percentage points
above the new baseline Yield of [*].
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(c) Regulatory Approval for Facility. Upon licensure by the FDA of ONYX-015
for manufacture of Drug Substance by XOMA at the Facility, ONYX will pay to XOMA
a milestone payment of [*].
7. Section 11.3(a) of the Agreement is deleted in its entirety, and the
following substituted in its place:
(a) Delay in Performance by XOMA. If ONYX has not materially breached its
obligations to assist XOMA or enable XOMA's performance under this Agreement,
then ONYX may terminate this Agreement without penalty or further obligation to
XOMA (except as otherwise stated in this Section 11.3) upon at least ninety (90)
days prior written notice if:
(i) XOMA has not initiated manufacture of Drug Substance (defined as
thawing a vial of cells in preparation for manufacturing a Batch of Drug
Substance) in the Suite by [*];
(ii) XOMA has not manufactured and supplied to ONYX or its designee a
Batch of Drug Substance meeting the then current Specifications at the [*]L
Development Scale by [*], provided that ONYX has not significantly delayed
the timelines for the Project due to ONYX's decisions based on changed
needs for ONYX-015 for clinical trials or on implementation of process
changes;
(iii) XOMA has not manufactured and supplied to ONYX or its designee a
Batch of Drug Substance at [*]L Commercial Scale meeting the then-current
Specifications by [*], provided that ONYX has not significantly delayed the
timelines for the Project due to ONYX's decisions based on changed needs
for ONYX-015 for clinical trials on implementation of process changes; or
(iv) After the Attainment of Commercial Scale, XOMA fails to
successfully manufacture the number of Batches of Drug Substance ordered by
ONYX in compliance with its guaranteed minimum annual number of Batches in
any applicable twelve (12) month period under Section 5.2.
If ONYX's actions, inactions (e.g. ONYX's failure to provide raw materials,
etc., pursuant to Section 2.1(b)) or decisions cause a delay in achievement of
the target dates in this Section 11.3(a), ONYX and XOMA will in good faith agree
upon an extension of the target dates. If ONYX terminates this Agreement
pursuant to this Section 11.3(a), ONYX will reimburse XOMA for all appropriate
costs under this Agreement incurred by XOMA to the date of notice of termination
by ONYX for services performed, for commitments that cannot be canceled, and for
resources that cannot be reallocated, and for all other costs that XOMA incurs
in transferring the technology to ONYX or a Third Party at ONYX's request
pursuant to Section 7.1(b). XOMA will use diligent, commercially reasonable
efforts to minimize any costs or obligations that cannot be canceled and to
reallocate any resources that were dedicated to the Project.
8. Counterparts. This Amendment may be executed in counterparts with the
same force and effect as if each of the signatories had executed the same
instrument.
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IN WITNESS WHEREOF, the parties hereto have caused this Amendment to be executed
by their duly authorized officers as of the date first set forth above.
XOMA (US) LLC ONYX PHARMACEUTICALS, INC.
By: /s/ Xxxxxxxx X. Xxxxxx By: /s/ Hollings C. Renton
--------------------------------------- ----------------------
Name: Xxxxxxxx X. Xxxxxx Name: Hollings C. Renton
Title: Senior Vice President, Operations Title: Chief Executive Officer
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EXHIBIT A
[*]
A-1
EXHIBIT B
[*]
B-1
EXHIBIT C
[*]
C-1
