EXHIBIT 10.1
* CERTAIN CONFIDENTIAL INFORMATION CONTAINED
IN THIS DOCUMENT, MARKED BY BRACKETS, HAS
BEEN OMITTED AND FILED WITH THE SECURITIES
AND EXCHANGE COMMISSION PURSUANT TO RULE
24b-2 OF THE SECURITIES EXCHANGE ACT OF
1934, AS AMENDED.
July 20, 2004
SmithKline Xxxxxxx plc
Xxx Xxxxxxxx Xxxxx
XX0 0XX
Xxxxxx Xxxxxxx
Attn : Jean Stephenne
RE: LETTER AMENDMENT TO MPL AGREEMENTS
Dear Xxxx:
This letter amendment (this "Amendment") memorializes our understanding
and agreement to amend the MPL Agreements regarding the scale-up of the
production of 3-O-deacylated monophosphoryl lipid A from Salmonella minnesota
R595 ("MPL") and the manufacture and supply of MPL by Corixa Corporation
("Corixa") to SmithKline Xxxxxxx plc ("GSK").
1. INTRODUCTION
By merger with Ribi ImmunoChem, Inc. ("Ribi"), Corixa is party to the
following agreements with GSK or one of its affiliates:
(a) License and Supply Agreement, dated May 3, 1991, between Ribi and
SmithKline Xxxxxxx Biologicals, S.A. ("SBBio") (the "1991
Agreement");
(b) License/Supply Agreement, entered into December 10, 1992, between
Ribi and GSK (the "1992 Agreement");
(c) License/Supply Agreement, dated December 1, 1995, between Ribi and
SBBio (the "1995 Agreement");
(d) License and Supply Agreement, dated December 31, 1996, between Ribi
and SmithKline Xxxxxxx Biologicals Manufacturing s.a., as amended by
Letter Agreement dated December 12, 2001 (the "1996 Agreement"); and
(e) License/Supply Agreement, entered into October 5, 1999, between Ribi
and GSK (the "1999 Agreement").
The foregoing five (5) agreements are referred to herein collectively as
the "MPL License and Supply Agreements".
In addition, Corixa is party to the following agreements with affiliates
of GSK:
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(f) Letter Agreement, dated December 5, 2000, between Corixa and SBBio
(the "2000 Agreement"); and
(g) MPL Fermentation/Purification Collaboration Agreement, dated
December 2, 2002, between Corixa and GlaxoSmithKline Biologicals,
S.A. (the "2002 Agreement").
The foregoing two (2) agreements together with the MPL License and Supply
Agreements are referred to herein collectively as the "MPL Agreements".
2. DEFINITIONS
(a) "1991 Agreement", "1992 Agreement", "1995 Agreement", "1996
Agreement", "1999 Agreement", "2000 Agreement" and "2002 Agreement"
shall have the respective meanings ascribed to them in Section 1 of
this Amendment.
(b) "CSC" shall have the meaning ascribed to it in Section 3 (b) (i) of
this Amendment.
(c) "Evaluation" shall have the meaning ascribed to it in Section 3 (a)
(i) of this Amendment.
(d) "Exercise Fee" shall have the meaning ascribed to it in Section 3
(d) (ii) of this Amendment.
(e) "Facility Modifications" shall have the meaning ascribed to it in
Section 3 (a) (iii) of this Amendment.
(f) "FDA" shall have the meaning ascribed to it in Section 3 (a) (i) of
this Amendment.
(g) "Force Majeure" shall have the meaning ascribed to it in the 1996
Agreement.
(h) "Xxxxxxxx Facility" shall have the meaning ascribed to it in Section
3 (a) of this Amendment.
(i) "Know-How" shall have the meaning ascribed to it in the MPL License
and Supply Agreements.
(j) "Manufacturing Know-How" shall mean all present and future technical
information and know-how owned and/or controlled by Corixa with the
right to grant licenses during the term of this Amendment or the
co-exclusive license referred to in Section 3 (d) below, which is
useful or necessary to produce (a) MPL, (b) intermediates used in a
process required or useful for manufacturing MPL, (c) improvements
of MPL or (d) intermediates used in a process required or useful for
manufacturing improvements of MPL, and which technical information
and know-how shall include, without limitation, any and all process,
manufacturing, control, assay, QC, and any other information
relating to MPL and/or manufacture of MPL and all documentation and
technical assistance needed or useful for the production of Product.
(k) "Manufacturing Patents" shall mean all patents and patent
applications owned
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and/or controlled by Corixa with the right to grant licenses during
the term of this Amendment or the co-exclusive license referred to
in Section 3 (d) below, which patents and patent applications claim
a process required or useful for manufacturing (a) MPL, (b)
intermediates used in a process required or useful for manufacturing
MPL, (c) improvements of MPL or (d) intermediates used in a process
required or useful for manufacturing improvements of MPL. Included
within the definition of Manufacturing Patents are any
continuations, continuations-in-part, divisions, patents of
addition, reissues, renewals or extensions of the patents and patent
applications described in the foregoing sentence. The current list
of Manufacturing Patents is set forth in Exhibit I attached hereto.
(l) "MPL" shall have the meaning ascribed to it in the first paragraph
of this Amendment.
(m) "MPL Agreements" shall have the meaning ascribed to it in Section 1
of this Amendment.
(n) "MPL License and Supply Agreements" shall have the meaning ascribed
to it in Section 1 of this Amendment.
(o) "Net Sales" shall have the meaning ascribed to Net Invoice Price or
Net Sales in the MPL License and Supply Agreement applicable to the
sold Product.
(p) "Option" shall have the meaning ascribed to it in Section 3 (d) (i)
of this Amendment.
(q) "Option Period" shall have the meaning ascribed to it in Section 3
(d) (ii) of this Amendment.
(r) "Patents" shall have the meaning given thereto in the MPL License
and Supply Agreements. The current list of Patents is attached
hereto as Exhibit II.
(s) "Product" shall have the meaning ascribed to it in the MPL License
and Supply Agreements.
(t) "Report" shall have the meaning ascribed to it in Section 3 (a) (ii)
of this Amendment.
(u) "Transfer Request Period" shall have the meaning ascribed to it in
Section 3 (e) (ii) of this Amendment.
(v) "Work Plan" shall have the meaning ascribed to it in Section 3 (b)
(i) of this Amendment.
3. TERMS OF AMENDMENT
(a) Evaluation of Corixa's Hamilton, MT MPL Manufacturing Facility (the
"Xxxxxxxx Facility").
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(i) The parties hereby agree that Corixa shall engage [*] of [*]
as a consultant for the evaluation of the Xxxxxxxx Facility
for licensability to produce MPL bulk drug substance,
according to current United States Food and Drug
Administration ("FDA") regulations and guidelines (the
"Evaluation").
(ii) The [*] all costs related to the Evaluation, up to a maximum
of USD[*], with [*] responsible for a maximum of [*]. Any
costs related to the Evaluation above USD[*] shall be [*].
Both parties shall have access to [*] written report resulting
from the Evaluation ("Report").
(iii) In the event the Evaluation determines that the Xxxxxxxx
Facility is licensable for the production of MPL bulk drug
substance, according to current FDA regulations and
guidelines, or upon Corixa warranting in writing to GSK that
[*] it will promptly implement the modifications defined in
writing during the Evaluation and recorded in the Report as
necessary for the Xxxxxxxx Facility to be so licensable ("the
Facility Modifications"), and further warranting to make any
further necessary modifications that may from time to time be
required in order to maintain the Xxxxxxxx Facility in
compliance at all times with FDA and European Union regulatory
authorities regulations and guidelines, then the parties shall
proceed in accordance with the terms and conditions set forth
in Sections 3 (b) through 3 (f) below.
(b) Scale-Up of MPL Production
(i) Promptly after issuance of the Report and in parallel with
making the Facility Modifications, if any, Corixa shall
initiate the efforts described in Stage I and Stage II of the
work plan attached hereto as Exhibit IIIA, which is
incorporated herein by this reference (the "Work Plan"), as
may be amended from time to time by written agreement of the
parties. The parties shall establish a Collaboration Steering
Committee (the "CSC") in accordance with Exhibit IIIB, which
Exhibit is incorporated herein by this reference, to oversee
the performance of the Work Plan. Corixa shall keep GSK
apprised in writing of the progress accomplished in
implementing the Facility Modifications and in performing the
Work Plan through quarterly written progress reports to GSK.
FTE Costs associated with progress report generation are
included in the Work Plan.
(ii) GSK shall fund fifty percent (50%) of all of Corixa's FTEs
costs involved in performing the Work Plan for Stage I and
Stage II, which funding shall be payable quarterly in advance
based upon Corixa's invoice therefore and receipt of Corixa
written report for activities performed during the preceding
quarter. Corixa shall be obligated to dedicate all of such
funding received from GSK to the performance of the Work Plan.
If such report(s) show that Corixa is not executing the Work
Plan, GSK shall have the right to withhold such funding,
provided, however, that GSK's license under Section 3 (d) (i)
shall not include any Manufacturing Patents or
*CONFIDENTIAL TREATMENT REQUESTED.
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Manufacturing Know-How developed during any period that GSK
does not fund fifty percent (50%) of all of Corixa's FTEs
costs for such period. The FTE rate applicable to the Work
Plan shall be Corixa's 2004 FTE rate of USD$[*], increased
annually by COLA. Neither Corixa nor GSK shall have an
obligation to contribute to FTE costs exceeding those outlined
specifically in Exhibit IIIA. Corixa shall be [*] incurred as
part of the Work Plan. Any modification to the Work Plan must
be agreed to in writing between the two parties. Any savings
or additional expense to be incurred as a result of Work Plan
modification shall be shared equally between the two parties.
(iii) The Work Plan shall supersede the work plan attached as
Exhibit A to the 2002 Agreement and the parties agree and
acknowledge that no further efforts shall be required of
either party pursuant to such Exhibit A.
(iv) Any process improvement and/or MPL improvement made, conceived
and reduced to practice as part of the Work Plan solely by
Corixa or GSK or made, conceived and reduced to practice
jointly by Corixa and GSK will be co-owned by Corixa and GSK,
who will each have co-exclusive (as used herein,
"co-exclusive" shall have the meaning provided in Section 3
(d) (i) hereof) rights to use such improvement(s) for any
purpose unless otherwise expressly provided in this Amendment.
No consideration other than that specified in this Amendment
shall be due by either party to the other for use of such
improvement(s). Any patent application claiming such
improvement(s) will be filed in the joint names of Corixa and
GSK. For the avoidance of doubt, any modification of MPL
fermentation, extraction, purification, characterization or
analytical processes that is made, conceived or reduced to
practice as a result of experimentation carried out under the
Work Plan or outside of the Work Plan but jointly by or on
behalf of Corixa or its employees and by or on behalf of GSK
or its employees, including by or on behalf of GSK or its
employees with input from Corixa or its employees, whether at
laboratory bench-scale or pilot plant scale manufacturing but,
if made, conceived or reduced to practice by or on behalf of
GSK other than jointly with Corixa, in no event later than the
date the CSC determines the Work Plan to be completed or
terminated, shall be deemed to have been made, conceived and
reduced to practice, as applicable, as part of the Work Plan
and shall be co-owned and co-exclusively licensed by Corixa
and GSK as described above.
Subject to Section 3 (d) (ii) following successful completion
of the Work Plan such that Corixa is able to produce at least
1.8kg of MPL per year and that the terms of Section 3 (c) (v)
hereof apply, any process improvement and/or MPL improvement
made, conceived and reduced to practice solely by GSK or
Corixa thereafter shall be solely owned by the party that
made, conceived and reduced to practice such improvement
subject to the following:
*CONFIDENTIAL TREATMENT REQUESTED.
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(x) Any such improvements made, conceived and reduced to
practice solely by Corixa before expiration of GSK royalty
obligation pursuant to Section 3 (d) (iii) (a) shall be part
of MPL Know-How or MPL Patents.
(y) Any such improvements made, conceived and reduced to
practice solely by Corixa after expiration of GSK royalty
obligation pursuant to Section 3 (d) (iii) (a) shall not be
part of MPL Know-How or MPL Patents provided, however that if
GSK so requests in writing, Corixa and GSK shall negotiate in
good faith commercially reasonable terms for a license from
Corixa for GSK to use such improvement(s) in the manufacture
by GSK of MPL for use as a prophylactic and/or therapeutic
vaccine adjuvant.
(z) Without prejudice to Section 3 (d) (ii) below, GSK shall
have exclusive rights to such improvements which are solely
owned by it and no obligation to provide a license to such
improvements to Corixa.
(v) In addition to the performance of the Work Plan and only after
GSK has paid the Exercise Fee pursuant to Section 3 (d) (ii), GSK
shall have the right to perform MPL process development work on its
own and/or to sub-contract to third parties MPL process development
work and shall be the sole owner of any developments resulting from
such work; provided that any such subcontractor(s) shall be subject
to nondisclosure and nonuse restrictions, at least as stringent as
those applicable to GSK as set forth in the MPL License and Supply
Agreements, in respect of all Manufacturing Know-How and any other
know-how related to the manufacture of MPL.
(vi) Corixa and GSK agree that the Patent Committee set-up under the
Multi-Field Vaccine Discovery Collaboration and License Agreement,
effective September 1, 1998, between Corixa and GSK, as amended,
will oversee the prosecution of any patents resulting from the Work
Plan and the 2002 Agreement. For purposes of clarification, if GSK
exercises its Option it will have co-exclusive rights to manufacture
MPL under any patent claiming any Inventions under the 2002
Agreement.
(c) Long-Term MPL Supply
(i) GSK shall order from Corixa guaranteed minimum annual orders
of MPL to be delivered in quarterly amounts by Corixa in
accordance with the following schedule:
2004 = [*]
2005 = [*] ([*] each quarter)
2006 = [*] ([*] each quarter)
2007 = [*] ([*] each quarter)
2008 = through 2012 = 1.8 kgs per year (450 grams each quarter)
*CONFIDENTIAL TREATMENT REQUESTED.
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and under the terms of the Quality Agreement attached hereto
as Exhibit IV, which is incorporated herein by this reference,
provided, however, that:
(x) if, in any calendar quarter, Corixa supplies GSK with at
least [*] percent ([*]%) of the quantity to be delivered
during that quarter according to the schedule above and Corixa
supplies GSK with the full annual guaranteed minimum order of
MPL to be delivered according to the schedule above during
that calendar year, GSK shall not invoke Corixa's failure to
supply under Section 3 (c) (iii) below.
(y) if the Facilities Modifications, if any, are not complete
by [*] for any reason other than Force Majeure, GSK shall be
entitled to apply a [*] percent ([*]%) reduction to the price
set forth in Section 3 (c) (iv) for MPL produced and accepted
by GSK during the time period beginning [*] and ending upon
completion of the Facilities Modifications, and to the
applicable royalty due, if any, under the MPL Supply and
License Agreements until [*] or the applicable royalty set
forth in Section 3 (d) (iii) (b) after [*], for the next
Product that will be sold by GSK during the time period
equivalent to the number of months beginning [*] and ending
upon completion of the Facilities Modifications; or
(z) if delivery to GSK of consistency lots of MPL which is
FDA-compliant after implementation of Stage I of the Work Plan
is not complete by [*] for any reason other than Force
Majeure, GSK shall be entitled to apply a [*] percent ([*]%)
reduction to the price set forth in Section 3 (c) (iv) for MPL
produced and accepted by GSK during the time period beginning
[*] and ending upon delivery to GSK of consistency lots of MPL
which is FDA-compliant, and to the applicable royalty due, if
any, under the MPL Supply and License Agreements until [*] or
the applicable royalty set forth in Section 3 (d) (iii) (b)
after [*], for the next Product that will be sold by GSK
during the time period equivalent to the number of months
beginning [*] and ending upon delivery to GSK of consistency
lots of MPL which is FDA-compliant.
Furthermore Corixa agrees to use commercially reasonable
efforts to complete the Facility Modifications and to deliver
the consistency lots by no later than [*] but in the event
that the Facilities Modifications are not completed by [*] for
any reason other than Force Majeure, or if the delivery of
consistency lots does not take place before [*] for any reason
other than Force Majeure, GSK may at its option upon written
notice to Corixa [*] and, if GSK has not yet exercised the
Option, [*] from Corixa for [*] as opposed to the [*] payment
called for in Section [*] or, if GSK has previously exercised
the Option, Corixa shall, at GSK's option, [*] or provide [*]
and any royalty due Corixa thereafter hereunder [*].
*CONFIDENTIAL TREATMENT REQUESTED.
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The MPL supplied by Corixa shall meet the specifications set
forth in the Quality Agreement attached hereto as Exhibit IV
and all requirements of the FDA and European Union regulatory
authorities and shall be suitable for use in Products to be
sold in the United States and the European Union.
(ii) If GSK orders the minimum quantities above, GSK will be deemed
to have satisfied all its combined minimum transfer price and
royalty obligations under all MPL License and Supply
Agreements. Starting in 2006, upon request of GSK, Corixa
agrees that in the event it has the manufacturing capacity, it
shall make all reasonable commercial efforts to supply GSK
with quantities in excess of the quantities specified in
Section 3 (c) (i) above, up to a capacity of minimum 1.8 kg
per year in 2006 and 2007 and up to a capacity which exceeds
1.8 kg in 2008 and each year thereafter during the term of
this Amendment. GSK agrees to inform Corixa of any such
additional request at least twelve (12) months in advance.
(iii) Corixa will use commercially reasonable efforts to supply GSK
with MPL ordered by GSK. Upon Corixa becoming aware of its
inability to supply MPL to GSK in accordance with the supply
schedule set forth in Section 3 (c) (i), Corixa shall promptly
notify GSK in writing of such inability and the date by which
Corixa reasonably anticipates being able to supply in
accordance with such schedule. Except as set forth in Section
3 (c) (vi) or if the failure to supply is due to Force
Majeure, if Corixa is unable to supply in accordance with such
schedule for more than [*] days but less than [*] days, then
[*]. If in a given year, Corixa was [*] the amount of the [*]
will be deemed to be [*] of [*]. If the contracted amount to
be purchased by GSK in that year was [*], the amount of MPL
associated with [*]. Assuming that there are [*] per dose of
Product (or that [*] of Product if there are different
Products with different amounts of MPL), [*]. However, if once
Corixa returns to production, Corixa is able to become current
with the supply schedule in terms of total material shipped to
GSK, then [*].
Except as set forth in Section 3 (c) (vi) or if the failure to
supply is due to Force Majeure, if Corixa is unable to supply
in accordance with such schedule for more than [*] but less
than [*], then [*]. If in a given year, Corixa was [*], the
amount of the [*] deemed to be [*]. If the contracted amount
to be purchased by GSK in that year was [*], the amount of MPL
associated with [*]. Assuming that there are [*] of Product
(or that [*] of Product if there are different Products with
different amounts of MPL), [*]. However, if once Corixa
returns to production, Corixa is able to become current with
the supply schedule in terms of total material shipped to GSK,
[*].
Except as set forth in Section 3 (c) (vi) or if the failure to
supply is due to Force Majeure, if Corixa is unable to supply
in accordance with such
*CONFIDENTIAL TREATMENT REQUESTED.
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schedule for more than [*] days, GSK shall have the right to
terminate the supply provisions of this Amendment and the MPL
License and Supply Agreements for breach of Corixa and: (x)
there will be [*] on sales of that number of Products that [*]
as calculated in accordance with the following example. If in
a given [*] period, Corixa was unable to supply product for
[*] days, the amount of the [*] of that year plus the [*]. If
the contracted amount to be purchased by GSK in that year [*],
the amount of MPL associated with [*]. Assuming that there are
[*] of Product (or that [*] of Product if there are different
Products with different amounts of MPL), [*] of Product
(calculated as [*] x [*] grams). Such [*] shall apply [*].
(iv) The pricing for all MPL ordered by GSK following the date of
this Amendment shall be USD[*] per gram, with an annual
increase based on COLA as reported by the United States Social
Security Administration.
(v) Notwithstanding the foregoing, if the Work Plan has been
successfully completed and in any calendar year following such
completion GSK orders more than 1.8 kg of MPL from Corixa, the
price in such year for such excess MPL shall be [*] of the
price set forth in Section 3 (c) (iv).
(vi) In the event the Xxxxxxxx Facility is shut down during 2005
due to process development activities required by the Work
Plan[*] of MPL that [*], provided that Corixa shall [*] Corixa
will provide GSK with [*]
(vii) GSK shall be committed to purchase the quantities of MPL set
forth in Section 3 (c) (i) above through 2008. From 2009, GSK
shall have the right to cancel its guaranteed minimum annual
orders of MPL upon prior written notice of [*] to Corixa (e.g;
by no later than [*] in case GSK wishes to cancel its
guaranteed minimum annual orders of MPL for [*]) and payment
of the following cancellation fee to Corixa on the day of said
notification: for [*] a cancellation fee of USD[*] [*]. In
addition, if GSK cancels its guaranteed minimum annual orders
of MPL according to this Section 3 (c) (vii), effective
immediately on the day of notification of such cancellation:
[*] and any further supply of MPL by Corixa at quantities
lower than those indicated in Section 3 (c) (i) above and/or
supply following the lapse of the [*] cancellation notice
period, will require a new supply agreement between GSK and
Corixa, (y) the royalty described in Section 3 (d) (iii) b.
shall be replaced by a flat royalty of [*]% ([*] percent) on
Net Sales of all Products for a Product-by-Product period of
[*] years post applicable Product introduction, (z) all MPL
license rights of GSK pursuant to the MPL License and Supply
Agreements [*] and GSK shall have [*] for any new vaccine
application and (xx) all MPL intellectual property, including
without limitation improvements and other know-how, developed
by or on behalf of GSK shall be promptly provided
free-of-charge to Corixa and Corixa shall have no obligation
to contribute any further MPL improvements to GSK.
(d) Co-Exclusive License to Manufacture MPL
*CONFIDENTIAL TREATMENT REQUESTED.
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(i) Subject to all terms and conditions of this Amendment, Corixa
hereby grants to GSK an option (the "Option") for a
co-exclusive, perpetual, non-sublicensable license under the
Manufacturing Patents and Manufacturing Know-How to
manufacture MPL (x) solely to meet any GSK annual requirements
after 2008 and through 2012 for MPL in excess of 1.8 kg and
after 2012 solely to meet GSK's requirements and (y) solely
for use in accordance with the applicable license grants set
forth below:
AGREEMENT APPLICABLE PROVISION(S)
------------------ -------------------------
The 1991 Agreement Sections 3.1 and 3.2
The 1992 Agreement Section 3.1
The 1995 Agreement Sections 3.1, 3.2 and 3.3
The 1996 Agreement Sections 3.1, 3.4 and 3.5
The 1999 Agreement Sections 3.1 and 3.2
and for use in any other human vaccine application licensed to
GSK on a non-exclusive basis.
Co-exclusive license under this clause means that only Corixa
and GSK will be entitled to manufacture MPL for use as a
prophylactic and/or therapeutic vaccine adjuvant. No license
is hereby granted to GSK to manufacture MPL for any other
purpose. During the term of this co-exclusive license Corixa
shall promptly disclose to GSK and/or supply GSK with all
Manufacturing Know-How. Corixa shall retain exclusive rights
to manufacture MPL for any purpose other than use of MPL as a
prophylactic and/or therapeutic vaccine adjuvant. GSK and
Corixa shall each have the right to use subcontractors
(including Corixa, in the case of GSK) to make MPL for use as
a prophylactic and/or therapeutic vaccine adjuvant, provided
that such subcontractor(s) shall be subject to nondisclosure
and nonuse restrictions, at least as stringent as those
applicable to GSK and/or Corixa as set forth in the MPL
License and Supply Agreements, in respect of all Manufacturing
Know-How and any other know-how related to the manufacture of
MPL and provided that Corixa shall remain liable for all its
obligations hereunder. In the event GSK determines to engage a
subcontractor to manufacture MPL, GSK shall inform Corixa in
writing and Corixa shall have the right to make an offer for
the subcontract, provided that GSK shall have no obligation to
negotiate with Corixa. Nothing in this agreement shall be
interpreted as to prevent Corixa from transferring its MPL
manufacturing operations and business to a Corixa subsidiary
or any other Corixa affiliate provided that such affiliate or
subsidiary shall remain bound by all obligations, terms and
conditions applicable to Corixa under this Amendment. In the
event
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Corixa determines to dispose of its MPL manufacturing
operations and business, whether directly if held by Corixa or
by disposing of all or a majority ownership in any Corixa
affiliate or subsidiary to which it has transferred its MPL
manufacturing operations and business, Corixa shall inform GSK
in writing and GSK shall have the right to make an offer for
the available operations and business, or interest in such
affiliate or subsidiary, as applicable, provided that Corixa
shall have no obligation to negotiate with GSK.
(ii) After GSK has exercised the Option, any process improvement
and/or MPL improvement made, conceived and reduced to practice
by GSK other than jointly with Corixa which is not as part of
the Work Plan will be solely owned by GSK. Subject to the
provisions of Section 3 (c) (i) above, the Option shall be
exercised by GSK paying to Corixa USD$[*] (the "Exercise Fee")
in immediately available funds at any time during the period
commencing on the date of this Amendment and terminating
thirty (30) days following written notification by Corixa to
GSK that the CSC has determined that Corixa has completed the
Facility Modifications (the "Option Period"). In the event GSK
does not exercise the Option, this Amendment shall immediately
terminate and neither party shall have any further obligations
hereunder, provided that GSK shall not be relieved of any then
outstanding payment obligations pursuant to Section 3 (a)
(ii), pursuant to 3 (b) (ii) solely for any work performed as
of the date of termination under the Work Plan, or pursuant to
Section 3 (c) (iv) for any MPL produced by Corixa and
delivered to GSK hereunder as of the date of termination.
(iii) Royalty.
a. In consideration for the grant of the license
hereunder and other good and valuable
consideration, GSK shall pay Corixa a royalty on
all Net Sales generated on or after June 30, 2008,
which royalty obligation shall expire for all
Products, ten (10) years after the first
commercial sale in the United States or Europe of
GSK's Product for the prevention and/or control
and/or treatment of human papilloma virus in
humans or fifteen years (15) after the first
commercial sale in the United States or Europe of
GSK's Product for the prevention and/or control
and/or treatment of herpes simplex virus in humans
if GSK does not launch a Product for the
prevention and/or control and/or treatment of
human papilloma virus in humans, provided,
however, that if the first commercial sale of such
Product occurs after June 30, 2008, GSK shall
continue to pay royalties in accordance with the
applicable MPL License and Supply Agreement on all
Net Sales of other Products until such first
commercial sale, after which only the royalty due
under this Amendment shall be payable on Net
Sales.
*CONFIDENTIAL TREATMENT REQUESTED.
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b. Royalties shall be payable on a Product-by-Product
basis according to the following schedule:
Aggregate Annual Net Sales of the
applicable Product Royalty
--------------------------------- -------
< or = USD$[*] [*]%
> USD$[*] and < or = USD$[*] [*]%
>USD$[*] [*]%
As an example, if a particular Product has aggregate Annual
Net Sales of USD$1billion, the first USD$[*] of such Net Sales
shall bear a [*]% royalty, the next USD[*] of such Net Sales
shall bear a [*]% royalty and the remaining USD$[*]n of such
Net Sales shall bear a [*]% royalty. If in the same year
another Product has aggregate annual Net Sales of USD[*], all
of such Net Sales shall bear [*]% royalty.
The royalty rates under this Amendment shall not be subject to
reduction or offset for any reason.
During any period of time during which GSK will be paying a
royalty to Corixa under the applicable MPL License and Supply
Agreement(s) or, after June 30, 2008, under this Amendment.
Corixa shall not grant any rights to MPL, nor supply MPL, to
any third party for use as a prophylactic and/or therapeutic
vaccine adjuvant in products exclusively licensed to GSK under
the MPL Supply and License Agreements.
(e) Technology Transfer
(i) In the event GSK has exercised the Option in accordance with
Section 3 (d) (ii) of this Amendment, then, subject to the
terms and conditions of this Section 3 (e), Corixa shall
transfer to GSK on a co-exclusive basis all Manufacturing
Know-How for GSK's use solely in connection with the practice
of the license set forth in Section 3 (d) (i).
(ii) GSK shall have the right to request the foregoing transfer of
Manufacturing Know-How by providing written notice to Corixa
therefor during the period that commences upon exercise of the
Option and terminates on the later of December 31, 2007 and
the date the CSC determines that the Work Plan is fully
completed (the "Transfer Request Period"). GSK shall have no
right to a transfer of the Manufacturing Know-How if GSK has
not provided Corixa a written request therefore during the
Transfer Request Period.
*CONFIDENTIAL TREATMENT REQUESTED.
12
(iii) In the event GSK requests such transfer in writing in
accordance with Section 3 (e) (ii), the parties shall
negotiate in good faith a Manufacturing Know-How transfer work
plan, which work plan shall include the FTE rate for Corixa's
FTEs who will perform such work plan and which work plan will
be appended to this Amendment as Exhibit V and thereupon shall
be incorporated into this Amendment.
(iv) Following agreement to the Manufacturing Know-How transfer
work plan, Corixa shall transfer to GSK all then existing
Manufacturing Know-How in accordance with such work plan. GSK
shall fund Corixa's efforts in performing such work plan as
set forth therein, which funding shall be payable quarterly in
advance based upon Corixa's invoice therefore.
(f) Term; Termination for Breach; No Termination for Convenience
(i) GSK and Corixa hereby agree that after June 2008 the licenses
granted to GSK under all MPL License and Supply Agreements
will be fully-paid-up for any and all human vaccine
applications meaning that (x) subject to Section 3 (c) (vii),
GSK shall have perpetual exclusive, co-exclusive or
non-exclusive licenses according to the level of exclusivity
under the current License and Supply Agreements and
non-exclusive license rights to use MPL in any other human
vaccine application, (y) Corixa shall be entitled to supply
MPL to a single third party for use in Products for which GSK
will have co-exclusive licenses in perpetuity, shall be
entitled to supply MPL to third parties on a non-exclusive
basis for use in Products for which GSK will have
non-exclusive licenses in perpetuity and shall not be entitled
to supply MPL to any third party for use in Products for which
GSK will have exclusive rights in perpetuity, and (z) GSK
shall have no financial obligation whatsoever to Corixa other
than as specifically provided under this Amendment and that
GSK shall be free to use MPL as an adjuvant in any and all
human vaccine applications, provided, however, that if the
first commercial sale of GSK's Product for the prevention
and/or control and/or treatment of human papilloma virus in
humans occurs after June 30, 2008, or in the case GSK does not
launch a Product for the prevention and/or control and/or
treatment of human papilloma virus in humans if the the first
commercial sale of GSK's Product for the prevention and/or
control and/or treatment of herpes simplex virus in humans
occurs after June 30, 2008, GSK shall continue to pay
royalties in accordance with the applicable MPL License and
Supply Agreement on all Net Sales of other Products until such
first commercial sale. GSK and Corixa further acknowledge and
agree that the terms of this Amendment, including but not
limited to the obligation of GSK to pay a royalty in
accordance with Section 3 (d) (iii) above, incorporate the
negotiated terms of continued supply of MPL by Corixa to GSK
after June 2008. GSK and Corixa further acknowledge and agree
that after the expiration of the royalty obligation under
Section 3 (d) (iii) above, GSK's license under Section 3 (d)
(i) above shall be fully paid-up for any and all human vaccine
applications.
13
Unless extended as provided for herein, this Amendment shall
terminate on December 31, 2012. GSK shall have the right to
extend the term of this Amendment for successive period(s) of
three (3) years by providing Corixa (a) thirty-six months
written notice(s) of extension. GSK's guaranteed annual
minimum order of MPL during each year of such extension, if
applicable, shall be 1.8 kg unless otherwise mutually agreed
to by the parties.
(ii) Each party shall have the right to terminate this Amendment
based on the other party's material breach, which termination
shall be effective ninety (90) days following written notice
of such breach to the breaching party, provided that this
Amendment shall not terminate if the breaching party cures
such breach within such ninety (90) day period.
(iii) Except as set forth in Section 3 (c) (vi) or if the failure to
supply is due to Force Majeure, in case Corixa is unable to
supply GSK minimum annual orders as specified in Section 3 (c)
(i) for more than [*], GSK shall have the right upon written
notice to Corixa to terminate the supply provisions of this
Amendment and the MPL License and Supply Agreements and there
will be [*] on sales of that number of Products that [*], as
calculated in accordance with the example set forth in
subsection (x) of the third paragraph of Section 3 (c) (iii),
and for subsequent sales, GSK's obligation to pay royalties to
Corixa shall continue in accordance with Section 3 (d) (iii)
(b), provided, however, that such royalties on all subsequent
sales of Product by GSK shall be reduced to [*] of the rates
set forth in Section 3 (d) (iii) (b). If GSK has not exercised
its Option at the time GSK terminates the supply provisions
under this Amendment and the MPL License and Supply Agreement,
there will be [*] on sales of any Product after such
termination.
(iv) Except if the failure to meet the applicable due date is due
to Force Majeure, if Corixa does not complete the Facilities
Modifications or does not deliver to GSK consistency lots of
FDA-compliant MPL by [*] as further described in Section 3 (c)
(i), then the terms and conditions of Section 3 (c) (i)
related to exercise of the Option and the Exercise Fee shall
apply and if GSK has exercised the Option, GSK shall have the
right upon written notice to Corixa to terminate the supply
provisions of this Amendment and the MPL License and Supply
Agreements and the royalties on all subsequent sales of
Product by GSK shall be reduced by [*] of the rates set forth
in Section 3 (d) (iii) (b).
(v) In the event of either of the foregoing terminations of the
supply provisions of this Amendment and the MPL License and
Supply Agreements described in Sections 3 (f) (iii) and (iv),
Corixa shall immediately [*] and [*] under this Amendment or
any of the MPL License and Supply Agreements other than [*] to
effect the Manufacturing Know-How transfer under Section 3 (e)
(iv) above.
*CONFIDENTIAL TREATMENT REQUESTED.
14
(vi) No Termination for Convenience. The following provisions
of the MPL License and Supply Agreements are hereby deleted in
their entirety:
AGREEMENT APPLICABLE PROVISION(S)
--------- -----------------------
The 1991 Agreement Section 7.3
The 1992 Agreement Section 7.3
The 1995 Agreement Section 14.6
The 1996 Agreement Section 7.3
The 1999 Agreement Section 14.6
(g) Fulfillment and Termination of 2000 Agreement; Repayment of Credit
Line
(i) Fulfillment and Termination of 2000 Agreement. Corixa shall
deliver to GSK three (3) lots of MPL, with each lot being [*]
to [*] of MPL prepared using bacterial [*] master seed [*].
GSK shall pay to Corixa USD$[*] per gram for each such lot.
Corixa shall have no further obligation to supply to GSK and
GSK shall have no further obligation to purchase from Corixa,
any MPL pursuant to the 2000 Agreement and the 2000 Agreement
is hereby terminated and of no further force or effect,
provided, however, that Paragraph 2 thereof shall survive this
termination and provided further that GSK shall have no
further obligation under Section 4.7 of the 1991 Agreement.
(ii) Repayment of Credit Line. When Corixa has implemented all
Facility Modifications and has warranted in writing to GSK
that it will make all other necessary investments to upgrade
the Xxxxxxxx Facility as necessary to produce GSK's
requirements of MPL in accordance with regulations and
guidelines of regulatory authorities in the United States and
the European Union, Corixa shall be entitled to repay the
credit line described in Section 6 (b) (C) of the Multi-Field
Vaccine Discovery Collaboration and License Agreement,
effective September 1, 1998, between Corixa and GSK, as
follows. Corixa shall issue to GSK that number of shares equal
to USD$5,000,000.00 divided by the average per share closing
price of Corixa Common Stock on the Nasdaq National Market as
reported in the Wall Street Journal for the thirty (30) day
trading period immediately preceding but not including the
date of this Amendment, and such issuance shall be payment in
full for such credit line. Following receipt of the Report
described in Section 3 (a) (ii), the parties shall negotiate
in good faith and agree upon a reasonable date by which the
Facilities Modifications, if any, should be implemented. In
the event the Facilities
*CONFIDENTIAL TREATMENT REQUESTED.
15
Modifications have not been completed by one hundred and
twenty (120) days following such agreed date, the credit line
shall not be repayable using Corixa common stock and the
USD$5,000,000.00 shall be due and payable in full fifteen (15)
days thereafter.
(h) Miscellaneous Terms
(i) Notices. All notices required or permitted to be given under
this Amendment or any of the MPL License and Supply Agreements
shall be addressed when to Corixa:
Corixa Corporation
0000 Xxxxxxxx Xxxxxx, Xxxxx 000
Xxxxxxx, XX 00000
Attn: Chairman and Chief Executive Office
With a copy to: General Counsel
(ii) Full Force and Effect. Except with respect to supply,
royalties and financial obligations and except as
amended or terminated hereby, the licenses under the MPL
License and Supply Agreements shall remain in full force
and effect in accordance with their respective terms and
conditions, which terms and conditions are hereby
incorporated by this reference. In the event of any
conflicts or inconsistencies between this Amendment and
the applicable MPL Agreement, this Amendment shall
prevail.
[THIS SPACE LEFT INTENTIONALLY BLANK]
16
By your execution of this Amendment as indicated below and delivery of a
signed counterpart to my attention, GSK shall agree to the terms and conditions
set forth above.
Best regards.
CORIXA CORPORATION
/s/ XXXXXX XXXXXX
______________________________________________
By: Xxxxxx Xxxxxx
Its: Chairman and Chief Executive Officer
AGREED TO AND ACCEPTED BY:
SMITHKLINE XXXXXXX PLC
/s/ JEAN STEPHENNE
______________________________________________
By: Jean Stephenne
Its: Attorney-in-fact
17
EXHIBIT I
MANUFACTURING PATENTS
CASE APPLICATION NUMBER PATENT NUMBER
NUMBER COUNTRY FILING DATE FILING DATE STATUS
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[*]
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* [*] patent family included in both Exhibit I and II as the claims include [*]
*CONFIDENTIAL TREATMENT REQUESTED.
18
EXHIBIT II
PATENTS
CASE APPLICATION NUMBER PATENT NUMBER
NUMBER COUNTRY FILING DATE FILING DATE STATUS
---------------------------------------------------------------------------
[*]
---------------------------------------------------------------------------
*CONFIDENTIAL TREATMENT REQUESTED.
19
EXHIBIT IIIA
WORK PLAN
[*]
*CONFIDENTIAL TREATMENT REQUESTED.
20
EXHIBIT IIIB
COLLABORATIVE STEERING COMMITTEE (CSC)
Corixa and GSK shall agree on the installation of a Collaborative Steering
Committee (CSC) with [*] members from Corixa and [*] members from GSK. The CSC
is charged with considering and adopting or rejecting changes to the attached
Work Plan as required by the practice of good business judgment and high
scientific standards. In addition, the committee shall represent the respective
companies for current technical operations issues (MPL manufacturing, MPL
expanded capacity plans and process validation) and subsequent phase activities
as outlined in the Work Plan.
Composition: The CSC shall be comprised of [*]) named representatives of Corixa
and [*] named representatives of GSK. Each of the representatives will have one
(1) vote on matters that come before the CSC and will be entitled to vote
through proxy vote if he/she is unable to attend in person. The initial named
representatives to the CSC are as follows:
Corixa Representatives GSK Representatives
[*] [*]
Each Party may replace one (1) or more of its named representatives from
time-to-time with the consent of the other Party, which consent shall not be
unreasonably withheld. One (1) of the representatives of Corixa shall be the
chairman of the CSC, and in such capacity, such representative shall be
responsible for setting the agenda for meetings of the CSC, with input from the
other members, and for conducting the meetings of the CSC. Each Party shall be
entitled to have further representative(s) attending CSC meetings on an ad-hoc
basis provided that such Party informs the other at least five (5) working days
prior to the concerned CSC meeting and provided that such additional
representative(s) shall have no vote on matters that come before the CSC.
Meetings: The CSC shall meet not less than four (4) times per calendar year
alternatively at Seattle, Washington, USA, Xxxxxxxx, Montana, USA and Rixensart,
Belgium or alternatively through video conferences as the CSC may agree. Subject
to the preceding sentence, the CSC shall meet on such dates and at such times
and places as agreed to by the members of the CSC. Each Party shall be
responsible for all of its own expenses relating to attendance at or
participation in CSC meetings. Within thirty (30) days following each CSC
meeting, the chairman shall cause to be prepared and shall provide to the other
Party a draft of reasonably detailed written minutes describing all matters
reviewed or considered by the CSC and all determinations or decisions made and
actions taken by the CSC and a summary of the reasons therefore stated by the
members of the meeting. The minutes of any meeting of the CSC shall be final
upon approval by the members of the CSC at any subsequent meeting. The minutes
and the drafts of any minutes shall be the confidential information of the
Parties.
Actions: For the transaction of business, a quorum consisting of at least [*] of
GSK's members and at least [*] of Corixa's members must be present at a meeting.
Decisions of the CSC, unless
*CONFIDENTIAL TREATMENT REQUESTED.
21
otherwise stated herein, shall be made by majority vote of the members, provided
that a quorum is present and at least one (1) representative of each Party votes
in favor of such action.
22
EXHIBIT IV
Quality Agreement
*
CORIXA - GSK BIO
*
Supply of Bulk MPL(R) Adjuvant (MPL) for use
in Human Vaccine Manufacture
23
This document contains confidential, proprietary information intended for the
sole use of GlaxoSmithKline Biologicals, Inc. (GSKBio) and Corixa Corporation.
(Corixa). Disclosure of this information without the express written consent of
GSKBio and Corixa is prohibited.
Upon agreement by responsible heads of the Quality Assurance Departments for
GSKBio (Global Head Quality Assurance) and Corixa, this Quality Plan will be
revised as needed and distributed to appropriate GSKBio and Corixa personnel.
This Quality Agreement will be annexed to the supply contract and reviewed and
revised as needed.
_______________________________ _______________________________
Global QA Representative QA Representative
GlaxoSmithKline Biologicals, SA Corixa Corporation
_______________________________ _______________________________
Date Date
24
TABLE OF CONTENTS
1. Introduction............................................. 26
2. Quality Statement........................................ 26
3. Standard Operating Procedures............................ 27
4. Personnel Training....................................... 28
5. Production of Intermediates and Finished Products........ 29
6. Labeling and Packaging................................... 33
7. Storage and Shipping..................................... 34
8. Stability Testing and Sample Retention................... 35
9. Lot Recall............................................... 36
10. Change Control and Change Notification.................. 36
11. Quality Assurance....................................... 38
12. Regulatory Issues....................................... 39
13. Responsible Contacts.................................... 40
TABLE OF APPENDICES
Appendix 1: Corixa Documents Provided as Controlled Documents to GSK Bio
Appendix 2: [*]
Appendix 3: [*]
Appendix 4: Change Notification Form
Appendix 5: [*]
Appendix 6: Supply Agreement Responsibilities
*CONFIDENTIAL TREATMENT REQUESTED.
25
1. INTRODUCTION
This Quality Agreement is intended to provide GSKBio, a customer of bulk MPL(R)
Adjuvant (MPL) manufactured by Corixa, with information concerning Corixa's
Quality Program. Aspects of the Quality Program that are related specifically to
the preparation, control, and handling of MPL are described within this Quality
Agreement.
The Quality Program is the responsibility of Corixa's Vice President, Quality
Systems and Compliance and involves representatives from the production,
release, control, engineering and development of Corixa's products. The VP
Quality Systems and Compliance is also the Chairman of the Specifications
Committee, which is responsible for establishing product release specifications,
and the Material Review Board, which determines the disposition of lots with
indications of possible non-conformance with established quality criteria. The
VP Quality Systems and Compliance reports to the Senior Vice President, Clinical
Development.
The objectives of Corixa's Quality Program are:
- To assure that Corixa products are prepared in compliance with corporate,
contractual, and national GMP regulatory standards;
- To establish procedures that guarantee QA-oversight over product
manufacture, testing and distribution.
- To establish quality control procedures that enable consistent preparation
and testing of products through control of raw materials, processes,
equipment, personnel and test methods;
- To establish procedures to document the performance of quality control
measures;
- To establish procedures to ensure the accountability of generated data,
i.e., that the data as reported applies to the indicated processes
measured and/or to samples submitted;
- To establish traceability procedures for information related to product
preparation, testing, and distribution;
- To establish validation procedures for information related to product
preparation, testing and distribution
- To establish procedures that minimize the possibility of loss, damage or
tampering with materials produced for distribution by Corixa.
2. QUALITY STATEMENT
The assurance of quality is fundamental for all work undertaken and is practiced
by all Corixa employees.
Quality is enhanced through the use of formalized procedures designed to
eliminate product deficiencies. To promote uniformity of work methods,
procedures fundamental to the production of quality materials are in effect at
all times, without significant deviation. It is the responsibility of individual
Department Managers and/or Directors to compile, implement and integrate these
26
procedures into regular working methods and to ensure that all such methods are
clearly defined and documented. It is also the responsibility of Department
Managers and/or Directors to ensure through training that employees understand
and follow procedures and to document that training.
It is the responsibility of Corixa's management to ensure that these procedures
are implemented and reviewed on a minimum of a biannual basis to assure that
they adequately reflect Corixa philosophy.
It is the responsibility of Quality Systems and Compliance to monitor the
implementation of the Quality program, to verify that necessary systems,
procedures and policies exist, or, in the absence of such, to initiate the
development of the same and to verify implementation and adherence by regular
auditing procedures.
Quality Systems and Compliance is organized such that it is free to make
decisions regarding matters of internal compliance and is not influenced either
by internal sources or by contractual sources.
3. STANDARD OPERATING PROCEDURES
Formalized documents have been developed at Corixa in the form of Standard
Operating Procedures (SOPs). These SOPs have been designed to instruct operators
on the use of equipment and the performance of specific tasks, and to describe
in-house policies intended to assure consistency of product manufacture. SOPs
have been categorized into departmental areas in which specific pieces of
equipment are used, a particular process is carried out, or in which the policy
applies. An index of the departmental sections and a brief description of the
types of SOPs contained within each section are listed below.
Animal Care (AC) - Contains SOPs describing care, use and handling of
laboratory animals. Animals within the facility are used both for testing
of finished products and for research purposes by discovery and
development departments. Quality Control maintains a separate area within
the animal facility for housing of animals used for product testing
purposes.
Administration/Documentation (AD) - Contains one SOP that describes
employee health assessments.
Clinical/Regulatory (CR) - Contains SOPs relating to the conduct of
clinical studies and maintenance of regulatory documentation by the
Clinical Development Department.
Central Supply (CS) - Contains SOPs concerning equipment used in the
Central Supply area and policies describing the movement of materials both
entering and leaving the Central Supply area.
Engineering (E) - Contains SOPs describing use of metrology equipment and
calibration of Production and Quality Control equipment with traceability
to NIST standards. Also includes SOPs concerning operation of HVAC
systems, water systems, electrical systems, building pressurization
systems, and compressed gas systems. Operation of major pieces of
production-related equipment such as autoclaves, lyophilizers and
27
depyrogenating ovens are also covered under Engineering SOPs, as are
procedures for equipment validation and validation of Production
processes.
Preventative Maintenance (PM) - Contains SOPs designed to ensure the
continued efficient operation and care of equipment through preventive
maintenance programs.
Production - Contains SOPs covering cleaning and operation of equipment,
cleaning of the Production facility, use of specialized areas within the
Production facility, and additional instruction for processes described
within manufacturing documents.
Quality Control - Contains SOPs describing handling and preparation of
samples, test methods, use and operation of equipment, and documentation
of test results.
Quality Assurance - Contains SOPs describing internal and external audit
procedures, deviation reporting systems, product release, review and
disposition of non-conforming raw materials and products, training
policies, responding to customer complaints, customer notification of
changes, and specification development.
Security - Contains SOPs relating to security systems in use at Corixa.
Shipping and Receiving - Contains SOPs describing processing and handling
of both incoming and outgoing shipments of materials.
Validation - Contains SOPs describing validation of computer-related
equipment, as well as procedures related to the validation of
manufacturing processes, testing methods and shipment procedures.
GSKBio is responsible for document control of SOPs received from Corixa. A
representative list is provided in Appendix 1.
4. PERSONNEL TRAINING
In order to ensure that personnel have the necessary education, background,
training, and experience to assure correct performance of their job functions,
Corixa selects its employees based upon education, aptitude, and experience in
the particular area for which a vacancy exists. All Corixa employees are
provided with an orientation program upon initiation of employment which covers
OSHA regulations, safety training, and GMP compliance. Orientation is tailored
for each job function by providing additional exposure in areas that are
critical to successful completion of specific job functions.
Training is an ongoing process to ensure that personnel have a thorough
understanding of their jobs. A permanent training record is kept for all
employees by each departmental Manager and/or Director. The training record
documents the in-house training as well as off-site training that an employee
has received relating to their particular job function. Job function training is
conducted both through group training sessions as well as through one-on-one
sessions with qualified trainers. Job function training is tied directly to a
particular group of SOPs as well as to the process for which the employee is
being trained. An employee is given responsibility for the
28
performance of a particular job function only after training has been completed
successfully and is documented by both the employee and the trainer.
5. PRODUCTION OF INTERMEDIATES AND FINISHED PRODUCTS
Several formalized systems have been created at Corixa to control all aspects of
the production and release of intermediates and finished products. These systems
are described by policy-related SOPs and include raw materials control, a part
numbering system that provides complete traceability of materials, and
establishment of standardized manufacturing instructions for material
preparation.
PART NUMBERING SYSTEM
All consumable materials used in the Production area are identified through a
part numbering system. An SOP is in place describing the use of the part
numbering system for identification of raw materials, in-process materials and
finished materials. Each material is assigned a five digit part number (PN)
based upon material characteristics and a Part Number Specification sheet is
prepared for that material. The Part Number Specification sheet contains
information concerning qualified vendors, material characteristics, storage
conditions, sample retention requirements, required specifications, and testing
required for proof of specification compliance. Upon receipt of raw materials,
each shipment is assigned the appropriate five digit part number and is given a
lot number in the form of an additional nine digit number based on the month,
day, and year the material is received on site and a sequential (serial) number
for the particular material. The combination of the part number along with the
nine digit numeric lot number prevents any two lots of raw material from having
the same identifier. In the same manner, a numeric lot number is assigned to
each in-process material, prepared reagent, or finished product based upon the
month, day, year, and sequential (serial) number when the manufacturing
instruction for that particular material is given to Production personnel for
initiation of production.
Part numbering coupled with assignment of lot numbers for all consumable
materials allows for complete traceability of all consumable materials used in
the production of intermediates or finished products at Corixa. The part number
assigned to MPL(R) Adjuvant at the time of signing was PN 60039. An example of a
specific lot number for MPL(R) Adjuvant is PN 60039-070999001.
RAW MATERIALS
All raw materials intended for use in production are quarantined upon their
arrival in a locked area that is accessed only by authorized Shipping and
Receiving and Quality Control personnel. An initial receiving inspection is
conducted and documented by Shipping and Receiving staff to verify that the
shipment is from an authorized vendor, the quantity ordered and the quality or
grade are appropriate as per the part number specification sheet, and the
information supplied by the vendor is accurate and complete. The shipment is
also checked by Shipping and Receiving personnel for appropriate package
integrity. A Shipping Report is completed for each lot of raw material that
documents the identity of the vendor, vendor lot number, date of arrival,
quantity, condition, and indicates the assigned Corixa part number and lot
number. This part number/lot number combination is used to identify the material
throughout its use at Corixa. A quarantine label is then affixed to each
shipping container that indicates the assigned Corixa part number/lot
29
number, the material's quarantine status, the number of units in the shipment,
and the expiration date of that lot of raw material (if applicable). The raw
material is then moved to the quarantine storage area and a Raw Material Test
Request form is completed by Shipping and Receiving staff and delivered to the
Quality Control Department along with the Shipping Report. Quality Control
representatives sample the raw material and conduct appropriate testing as
specified on the Part Number Specification sheet. Test results are reviewed, the
certificate of analysis supplied by the vendor is reviewed, and the raw material
released to Production for use only after a determination has been made that the
material meets required specifications. At that time, an overlabel indicating
that the material has been released is applied to the quarantine label by a
Quality Control representative. A copy of the Raw Material Test Request Form is
submitted to representatives of Accounting as well as to the Central Supply
clerk, and the raw material is moved to the released inventory storage area by a
Quality Control representative. The raw material is added to the released
inventory by the Accounting staff and is thereafter available for use by
Production personnel.
Tests required for the release of raw materials according to written
specifications are conducted by Quality Control prior to the release of that
material for use by the Production Department. In addition to testing by the
Quality Control Department for appropriate characteristics, a certificate of
analysis (C of A) is required from the vendor for each raw material, and that C
of A is kept on file along with all other documentation concerning that raw
material and its use at Corixa.
MANUFACTURING INSTRUCTIONS
Manufacturing instructions are prepared as master documents for the manufacture
of all materials by the Production Department at Corixa. Manufacturing
instructions are maintained under a change control system in which all changes
to procedures are evaluated, justified and approved prior to implementation.
Validation may be required prior to approval for significant changes that may
produce differences in the quality, purity, safety, and/or potency of a product.
Copies of these master documents are prepared by a representative of Quality
Assurance upon formal request by Production to initiate the preparation of
reagents, containers, closures, components, or finished products. Each
manufacturing instruction provides information concerning the requirements for
raw materials, the necessary equipment, and the procedure. In addition, the
manufacturing instructions require the operator to provide information
concerning the identification of equipment and materials used, the persons
performing the operations, the date that the operations were performed, the
yields obtained from the operation, and any further information required to
provide complete traceability of the manufacture of that material. Manufacturing
instructions are divided into four categories based upon the type of material
being prepared, as summarized below:
Equipment Preparation Records (EPRs) provide instructions for the cleaning
and preparation of equipment in the Production area;
Reagent Preparation Records (RPRs) provide instructions for the
preparation of various reagents such as media, buffers, and organic
solvents that are used in the Production area during the manufacture of
intermediates and/or finished products;
30
Container/Closure Preparation Records (CPRs) provide instructions for the
preparation of containers and closures that are used as either final
product containers or containers for in-process materials;
Master Batch Records (MBRs) provide instructions for the manufacture of
intermediates and/or finished products. An individual MBR may yield an
in-process material, or may yield the final product.
Each manufacturing instruction in place at Corixa corresponds to a part number
that identifies the resulting product. A part number specification sheet is
prepared for each part number assigned that contains all information regarding
the material manufactured (see above). As copies of manufacturing instructions
are issued by Quality Assurance to Production personnel for the initiation of a
manufacturing procedure, a lot number is assigned to that copy of the
manufacturing instruction according to the day of the month and the year that
the work order is processed by Central Supply personnel. That part number/lot
number combination is used to identify the manufactured material and to trace it
throughout its existence.
Completed manufacturing instructions for each reagent, in-process intermediate,
container/closure preparation, intermediate, or finished product are reviewed by
a representative of Quality Assurance as the material is submitted to Central
Supply for quarantine. Once reviewed, the manufacturing instruction document is
stamped to indicate completion of the review and initialed by the reviewer. If
any deviations from written instructions have occurred during the manufacturing
process, a deviation report is prepared and submitted to the QA Manager for
review. A determination as to whether that deviation might have an effect on
product quality, purity, safety, or potency is either made by Quality Assurance
or deviation reports may be forwarded to the Material Review Board for review
and determination of disposition of the material. GSKBio will be notified of any
deviation investigations carried out during the manufacture of a product that is
intended for delivery to them via the Tracking Transfer Document.
The Quality Control Department at Corixa is responsible for testing as well as
the release or rejection of raw materials, packaging materials and in-process
materials based on current specifications. Laboratory facilities and equipment
are appropriate for the required analytical procedures, and personnel have been
sufficiently trained to perform the analyses accurately. Operator training is
documented as per the requirements of the training program. Maintenance and/or
calibration procedures, including system suitability evaluations if applicable,
are included for analytical equipment and assays. Records are kept for all
reagents, culture media, and equipment used for testing purposes. Reagent
preparation is documented according to written procedures and reagents are
labeled appropriately and assigned expiration dates prior to storage in the
Quality Control laboratory.
All testing procedures carried out in the Quality Control Laboratory are
conducted according to SOPs (see Section 3). Any deviations from SOPs are
reported and investigated according to set procedures and time frames. QA is
responsible for review of such investigations, for determinations as to whether
product quality may be affected by the deviation, and for final disposition of
the product affected by the deviation.
31
MANUFACTURING DEVIATIONS
Manufacturing deviations are documented and investigated based on Corixa
controlled documents on the handling of deviations. Deviations are consistently
evaluated for any impact on the quality, purity, safety, and/or potency of the
product.
Deviation and Observation Reporting System Forms (DORS) provide details of
any deviation or observation of unusual manufacturing conditions (also
provides details of any deviation/observation outside of manufacturing
area. and includes documentation of all assessments, investigations,
decisions and subsequent corrective actions. The DORS Event number is
referenced on the batch record documentation. The original document is
stored in the associated DORS Event file.
Out of Specification Reports (OOS) provide details of any failure of the
product to meet defined specifications and includes documentation of all
assessments, investigations, decisions and subsequent corrective actions.
Environmental Deviation Reports (EDR) provide details of any failure of
the production environment to meet defined specifications and includes
documentation of all assessments, investigations, decisions and subsequent
corrective actions.
None of these documents (DORS, OOS, EDR) become permanent parts of the
associated batch record Corixa standard operating procedures prohibit the
release of materials until all deviations have been resolved.
Corixa QA is to decide the final status of the materials following
appropriate investigations and assessments. GSKBio QA requires full
transparency around any individual deviation affecting MPL- product,
testing or shipment.
LOT RELEASE TESTING
Final products are tested according to current release specifications as listed
on part number specification sheets for each material requiring testing. Quality
Control personnel analyze the material, document the test results on the Quality
Control Analysis Report form, and attach all hard data to the form. Once testing
is completed, the Quality Control Analysis Report form and all hard data are
reviewed by the Quality Control Manager. The testing data is forwarded to the
Quality Assurance Manager for final accept/reject decisions based upon testing
results as well as review of all manufacturing documentation including
deviations from procedures. If the final product meets all release
specifications and has been manufactured according to required procedures with
no significant deviations, a notification of release is provided to Central
Supply by Quality Assurance to indicate release. Finished product is then
removed from the Central Supply quarantine area to the finished goods area by
Central Supply personnel.
If the finished product does not meet release specifications, a procedure (SOP)
is in place to track the disposition of the rejected material. A Material
Rejection Report is completed by Quality Assurance and that report is circulated
to representatives of Production, Adjuvant Development, Purchasing and Quality
Control for signature. A copy of the completed Material
32
Rejection Report indicating disposition of the rejected material, is provided to
Accounting and the rejected material is disposed of appropriately.
GSKBio will perform lot release testing upon receipt of MPL materials, according
to GSKBio Quality Control Procedure 10026402 (Appendix 5). GSKBio will make
their acceptance criteria and methods for determining acceptability available to
Corixa. They will also advise Corixa of any changes in their requirements or
methods.
If the received bulk materials are found to not comply with the agreed
specifications, GSK will notify Corixa immediately, advising Corixa of the batch
number(s) and such details of the test failure as are available. After
confirmation of the GSKBio testing result, Corixa shall retest samples from the
same bulk retained. If Corixa finds that, based on the retested sample, the bulk
does not comply with the specifications set forth in the Corixa material
specifications, it will be treated as if no lot had been delivered and a
replacement lot will be scheduled in accordance with the supply agreement.
In the case that Corixa results and GSKBio results on the suspect lot do not
match, and after a reasonable investigation on the reason for the opposing
results Corixa, a mutually agreed third party shall continue testing of the
suspect lot and decide on the questioned compliance with the set specifications.
Corixa and GSKBio will share equally the costs associated with the third party
testing including any costs associated with the necessary technology transfer.
At the discretion of either party, this requirement may be waived and the
opposing parties position accepted without any admission of fault.
6. LABELING AND PACKAGING
Labeling of materials is strictly controlled through a series of SOPs that
describe the requirements for documentation and control, label accountability,
performance of labeling operations, and inspection of labeling areas prior to
and following labeling operations. All incoming labeling materials are placed in
quarantine by Shipping and Receiving personnel pending examination of
representative samples against an approved master copy of that item by Quality
Control. A record of receipt, examination or testing, acceptance or rejection,
and disposition is kept for each shipment of labeling materials. Each individual
type of labeling material has been assigned a part number and a part number
specification sheet prepared with appropriate information including a master
copy of the labeling material. A lot number is assigned to the labeling material
based upon the date that it arrives on site.
All labeling materials are stored in a secured storage area with labels for
different products stored separately.
A labeling operation is initiated by a request from a Production representative
for labeling materials. A "Label Accountability" form is prepared that documents
the number of labels issued, 100% inspection of those labels by two persons for
conformity to master label stock, and use of those labels during labeling
operations. Labeling operations themselves are controlled by SOPs requiring
documentation of the use of the labels as well as requiring inspections of pre-
and post-labeling operations by a representative of Quality Control.
Corixa will notify GSKBio of labeling changes affecting MPL.
33
7. STORAGE AND SHIPPING
MPL final product is filled and lyophilized in 1 L screw top bottles composed of
USP Type 1 borosilicate uncolored glass. The fill quantity is 2 g per bottle and
the bottles are stoppered under a nitrogen gas overlay. The bottles are closed
with 43 mm lyophilization stoppers made of xxxx butyl rubber (4416/60 xxxx
formulation). Bottles plus stoppers are capped with plastic screw caps and are
sealed with tamper-proof seals.
MPL is also provided in 10 mL vials with 5 mg per vial for Quality Control
testing at Corixa and GSKBio. The vials are made of USP Type 1 borosilicate
uncolored glass and are closed with 20 mm lyophilization stoppers consisting of
xxxx butyl rubber (formulation 850). Vials plus stoppers are capped with 20 mm
aluminum tear-off seals.
A shipment of MPL is initiated with receipt of a purchase order from GSKBio and
is based upon availability of inventory as well as prior agreements between
GSKBio and Corixa. MPL is delivered to GSKBio FOB from the Corixa facility in
Hamilton, MT, or at other locations as Corixa may specify. Title to and risk for
the MPL shipment passes to GSKBio upon delivery to the freight carrier.
Shipments of MPL are handled by Federal Express International carrier or
equivalent and will be designated as "international priority" mail.
All shipping procedures for MPL are described and controlled in SOPs (see
Section 3). The specified shipping containers hold up to 6 x 2 g bottles of
MPL,. The bottles are wrapped individually with protective packing material
prior to placement in the container. Frozen ice packs are included with each
shipping container to maintain a specified temperature range throughout the
course of the shipment. Corixa will use validated shipping configurations to
guarantee the temperature and seal of the materials during their transfer to
GSK-premises.
Depending on the quantity of MPL that has been ordered, a shipment may comprise
more than one shipping container and more than one lot of MPL. The container
designated as "#1 of N" will contain the following items:
1. For each lot of MPL in the shipment, a Release Protocol that provides
testing results and release authorization by the Quality Assurance Manager
(Appendix 2);
2. For each lot of MPL in the shipment, a Tracking Transfer Document that
contains a deviation summary, as well as a summary of any manufacturing
changes, information on lot numbers, yields, and test results for the
in-process intermediates used in manufacture of the lot, along with
process information on key steps (Appendix 3);
3. For each lot of MPL in the shipment, 30 x 5 mg vials for Quality Control
testing and retention. In the event that a lot of MPL has been shipped
previously to GSKBio, no 5 mg sample vials will be included unless prior
arrangements have been made by GSKBio;
4. Standard shipping documentation for international shipment of materials as
required by the carrier as well as the appropriate customs office.
A TempTale monitor will also be included in each container along with
instructions for returning the monitor(s) to Corixa. The monitor(s) will be
programmed to record temperature at 5 minute intervals throughout the entire
shipping period.
34
'
Upon arrival of the shipment at the premises of GSKBio or of their specified
agent, the following procedures will be performed:
1. Containers will be inspected for damage and enclosed documentation
evaluated for completeness;
2. The TempTale monitor will be removed from each container, date stamped (by
depressing the date stamp button on the end of the unit without the
silver ring), and the data will be downloaded. The monitor(s) are to be
returned to Corixa, and must be received by Corixa within 20 working days
from delivery of the shipment;
3. The Receiving Report form from container #1 will be filled out and filed
by GSKBio;
4. The Transfer Document(s) and Certificate of Analysis(es) will be removed
from container #1 and distributed to the appropriate personnel at GSKBio;
5. The 5 mg sample vials will be removed from container #1 and given to a
representative of Quality Control;
6. Bottles containing MPL will be removed from the shipping containers and
placed in storage at 2(degrees)-8(degrees)C.
Temperature data from the TempTale monitors are to be reviewed by a designated
representative of GSKBio. Should it be determined that a temperature excursion
involving exposure to temperatures outside the specified range of for a period
exceeding one hour has occurred, GSKBio will notify Corixa and the disposition
of the affected container(s) will be determined by joint discussions. GSKBio is
responsible for archiving the temperature data for all shipments.
8. STABILITY TESTING AND SAMPLE RETENTION
The Quality Control Department at Corixa will maintain and execute a master
stability protocol for MPL, as described in SOP QC-10039, "Master Stability
Protocol for MPL(R) Bulk Drug Substance." According to this protocol, expiration
dating for MPL is established by real time stability testing on three lots of
MPL. Thereafter, one lot of MPL per year is selected at random to be enrolled in
the stability program. The first three lots manufactured after marketing
approval is received will also be placed on real time stability, followed by one
lot per year in subsequent years.
GSKBio will be notified in the event that any lot of MPL received by them fails
a real time stability test. Such test failures require an investigation to
determine if the test result is valid, and notification of GSKBio will occur
within 3 days of completion of such determination. GSKBio will also be notified
if information emerges which indicates that the shelf life for MPL is incorrect.
These communications will occur through GSKBio Quality Assurance.
The Quality Control Department at Corixa will retain a supply of 5 mg and 10 mg
sample vials from each released lot of MPL. These retention samples will be
stored at 2(degree)-8(degree)C, in the same manner as for the product, and will
be used in the event that unanticipated questions arise requiring further
testing and/or characterization. If adequate supplies are available, retention
samples may be provided to GSKBio as necessary to assist in their investigation
of lot-related questions.
35
9. LOT RECALL
The procedure for recall of marketed products by Corixa is described in SOP
QA-9900, "Marketed Product Recall." This SOP describes the process for making
product recall decisions, and also delineates the actions following a recall
decision, including retrieval of distribution data, notification of customers,
receipt/segregation/inspection of returned product, investigation/reporting of
returned product, and reporting of corrective actions.
Recall decisions are initiated by a recommendation from the Material Review
Board, which is chaired by the VP Quality Systems and Compliance or their
designee. This recommendation is reviewed by a senior management team at Corixa.
In the event that there is a recommendation to recall one or more batches of MPL
or to recall other formulations of MPL that could implicate the MPL, GSKBio QA
will be notified the same working day.
Final responsibility for all recall decisions resides with the CEO/President of
Corixa. The Regulatory Affairs Department is responsible for coordinating recall
actions.
GSKBio is responsible for the recall of any affected lot(s) of their product(s)
that contain the recalled lot of MPL. GSKBio is also responsible for notifying
the appropriate regulatory authorities of the recall actions related to their
products.
10. CHANGE CONTROL AND CHANGE NOTIFICATION
Changes to procedures, processes, equipment, test methods, and specifications
related to MPL manufacture, testing and shipment as well as other GMP products
made by Corixa are strictly controlled by Corixa's change control and change
notification policies. GSKBio will have access to Corixa`s Change control policy
procedure. As a customer of Corixa, GSKBio will be notified of any changes
related to the manufacture, testing and shipment of MPL. Procedures related to
Corixa's change control policy are described in SOPs E-1004 (equipment), QA-100
(controlled documents), and QA-3501 (specifications), and the customer change
notification policy is described in SOP QA-104. These SOPs are incorporated by
reference in this Quality agreement, and controlled copies of these documents
will be provided to GSKBio and maintained in accordance with Corixa's document
control procedures. The main elements of the customer change notification policy
(SOP QA-104) are summarized in this section.
POLICY STATEMENT
Corixa recognizes the value of its customer, GSKBio, and the importance of
communication in maintaining a satisfactory business relationship. In
recognition of Corixa's commitment to customer satisfaction, Corixa agrees to
notify GSKBio in a timely and appropriate manner of all changes relating to the
manufacture and release of MPL. The timing and manner of notification, as well
as the level of involvement by GSKBio prior to implementation, will be
determined by the category of change as specified in this policy.
PURPOSE
As a producer of MPL, Corixa must occasionally make changes in its processes to
ensure that this product continues to meet the needs of its customer, GSKBio. At
the same time, GSKBio must be confident that such changes will not compromise
the performance and suitability of
36
MPL for use in its applications. The purpose of this policy is to provide a
mechanism for addressing the needs of both Corixa and GSKBio regarding changes
affecting MPL. This policy defines procedures by which GSKBio will be informed
of all changes in the manufacture, release, and control of MPL.
PROCEDURE
The FDA recognizes that changes differ with respect to their potential to
adversely affect the safety, purity, and/or potency of a product, and
accordingly have established different reporting requirements for changes
depending on their level of importance. Corixa applies the reporting
requirements for the FDA to notification of GSKBio to changes related to MPL.
The change notification categories and procedures used by Corixa are summarized
below (additional detail is provided in SOP QA-104):
Category 0 - Editorial Changes - This category involves changes that do
not alter the process or product per se but relate only to documentation
changes that are considered editorial. Such changes will generally not be
reported to the regulatory authorities unless they involve the Drug Master
File or other regulatory filings. Category 0 changes will be communicated
to GSKBio by notation on the documentation that accompanies the first
affected lot. GSKBio approval is not required for implementation of
Category 0 changes.
Category I - Minor Changes - These changes include modifications to
procedures, process parameters, components, manufacturing methods,
reagents, equipment and facilities that are intended to tighten control(s)
on the product or process and yet are not associated with a potential
adverse impact on product safety, purity or potency. Limited qualification
or validation may be required for Category I changes. Such changes will
typically be reported to the regulatory authorities in the form of routine
annual reports, and it may be necessary to amend regulatory filings as a
result of such changes. All Category I changes will be communicated to
GSKBio via the Change Control Form (see Appendix 4). GSKBio approval is
not required for implementation of Category I changes.
Category II - General Changes - Changes in this category include
modifications that do not change the manufacturing process for MPL but
have the potential to adversely affect product safety, purity and/or
potency. Changes in test methodology or product specifications intended to
tighten control are also included in this category. Corixa will notify
GSKBio of Category II changes. Notification will be made via a package
comprising the Change Notification Form, supporting documentation, and
test samples as appropriate. Implementation of Category II changes
requires written agreement by GSKBio within 30 days of receipt of the
change notification package unless alternative arrangements have been
made. It is the responsibility of GSKBio to obtain required authorities
approval for implementation of proposed changes. Final approval of a
change by competent authorities will be communicated by GSKBio to Corixa
in a timely manner.
Category III - Major Changes - Changes in this category are considered
significant and will require process validation. The implementation plan
for such changes will typically be discussed in advance with GSKBio and
should include provisions for process validation and demonstration of
product/process consistency. Corixa will provide
37
GSKBio with a package comprising the Change Notification Form, supporting
documentation, and test samples as appropriate. Implementation of Category
III changes requires written agreement by GSKBio within 90 days of receipt
of the change notification package unless alternative arrangements have
been made. It is the responsibility of GSKBio to obtain required
authorities approval for implementation of proposed changes. Final
approval of a change by competent authorities will be communicated by
GSKBio to Corixa in a timely manner.
Category IV - Unanticipated Manufacturing Changes - Such changes may occur
due to equipment failure, damage to facility, loss of suppliers of
critical raw material, and other unforeseen events. Such changes will be
communicated to GSKBio at the earliest possible time and in all cases in
advance of product shipment. Changes involving general and routine
equipment maintenance are not included in this category.
All official communications relating to changes will be conducted between the
respective QA representatives at Corixa and GSKBio. The QA representatives are
responsible for transmitting all change notification issues to appropriate
personnel at their respective companies for input and/or action, and for
notifying the other company of any further actions required as a result of these
communications.
For changes requiring prior notification, Corixa will discuss the proposed
changes with GSKBio in a time frame that encourages cooperation and allows for
the needs of both parties to be met. These discussions will establish the
category of the change, the necessary level of documentation, the appropriate
degree of involvement by GSKBio in the approval process, and the inventory
requirements for "pre-change" product. A detailed implementation plan may be
developed that defines the testing and validation required for approval of the
change. All contractual obligations of Corixa regarding the supply of MPL to
GSKBio will remain in effect throughout any change period, unless specific
exceptions have been agreed to by Corixa and GSKBio.
Corixa's change control procedures require that documentation be maintained in
support of all changes in manufacturing processes, equipment, test methods and
product specifications. Corixa will allow access to such documentation related
to MPL during facility audits conducted by GSKBio. GSKBio maintains a "right to
audit" of Corixa developmental documents and validation reports prior to
acceptance (approval) of general and major changes that affect MPL, or
retrospectively in the case of unanticipated changes.
11. QUALITY ASSURANCE
Upon request from GSKBio, the Quality Systems and Compliance Department at
Corixa will provide information necessary to demonstrate that appropriate
quality systems are in place and are adhered to during the manufacture and
release of MPL. GSKBio may gather such information in part through scheduled
audits of the Corixa facility.
The Quality Systems and Compliance Department at Corixa has responsibility for
the review and release of all finished lots of MPL. All lots of MPL must be
released before shipment to GSKBio or its agent. All product complaints related
to MPL should be directed to the VP Quality Systems and Compliance at Corixa.
38
Process and product deviation for any lot/batch will be notified by Corixa to
GSKBio in advance of delivery and full technical discussion will take place
between the two parties with full exchange of information to take appropriate
measures and find best solutions.
The Quality Systems and Compliance Department will prepare a Release Protocol
and a Transfer Tracking Document to accompany each lot of MPL that is shipped to
GSKBio. The Certificate of Analysis contains a summary of the test results and
indicates the date of release of the lot. The Transfer Document provides a
summary of all manufacturing changes, information on lot numbers, yields, and
test results for the in-process intermediates used in manufacture of the lot,
along with process information on key steps (See also Section 8.)
Trending of yields, process times, and analytical results will be performed on
critical process points and quantitative test results as determined by the
Quality Systems and Compliance Department at Corixa. The Quality Systems and
Compliance Department will notify GSKBio of results from any trend analysis that
indicate that the MPL manufacturing process is operating outside of historical
ranges.
A GMP statement signed by Quality Assurance representative has to be provided
with every lot together with the certificate of analysis.
12. REGULATORY ISSUES
Corixa maintains a Type II Master File (MF) with the Center for Biologics
Evaluation and Research at the FDA. This MF was initially submitted on October
29, 1992, and is identified as BB-MF 4809, "Manufacture and Control of
Monophosphoryl Lipid A, a Drug Substance." BB-MF 4809 has been amended as needed
to accurately document the manufacture and control of MPL. The most recent
amendment to the MF was Amendment #5 and was submitted on June 20, 2003. The
Regulatory Affairs Department at Corixa will provide GSKBio Regulatory Affairs
with an updated copy of BB-MF 4809 as well as any amendments to this MF.
The Regulatory Affairs Department at Corixa will provide GSKBio with regulatory
support as necessary for development and licensure of GSKBio final products in
which MPL is a constituent. Corixa Regulatory Affairs will respond to requests
from the FDA and other regulatory authorities for information related to MPL,
and will notify GSKBio Regulatory Affairs in a timely manner of any such
discussions that potentially affect the use of MPL by GSKBio. Corixa Regulatory
Affairs will cooperate with GSKBio Regulatory Affairs in support of all
regulatory filings involving MPL, including participation in meetings with
regulatory authorities as appropriate.
GSKBio is ultimately responsible for ensuring the accuracy of any information
related to MPL that is contained in its regulatory filings.
39
13. RESPONSIBLE CONTACTS
[*]
*CONFIDENTIAL TREATMENT REQUESTED.
40
APPENDIX 1. CORIXA DOCUMENTS PROVIDED AS CONTROLLED DOCUMENTS TO GSKBIO
SOPs
#CS-400 Assigning Lot Numbers
#CS-551 Label Documentation and Control
#E-1004 GMP Equipment Change Control
#P-530 Labeling Operation Procedure
#QA-100 Controlled Document Change Control
#QA-104 Customer Change Notification Procedure
#QA-2000 Deviation and Observation Reporting System
#QA-2001 Material Rejection
#QA-2002 Customer Complaint Procedures
#QA-6000 Material Review Board Operation
#QA-9000 Batch Record Review and Product Release
#QA-9001 Issuance, Distribution and Control of Manufacturing Instructions
#QA-9003 Preparation of GlaxoSmithKline Tracking/Transfer Documents
#QC-981 Raw Material Quality Control Procedure
#SR-001 Receiving Procedures
41
APPENDIX 2. [*]
*CONFIDENTIAL TREATMENT REQUESTED.
42
APPENDIX 3. [*]
*CONFIDENTIAL TREATMENT REQUESTED.
43
APPENDIX 4. CHANGE NOTIFICATION FORM
[ILLEGIBLE] 03/27/02
SOP #QA-104.01
ATTACHMENT #1
Date: 03/02
Supersedes: #NA
Page 6 of 7
CHANGE NOTIFICATION FORM
PART A - NOTIFICATION BY CORIXA CORPORATION
Notification ID Number: Change Control ID No.:
Change Category: Change Control Date: First Affected Lot:
AFFECTED COMPONENT(S) [include Corixa ID number(s) and brief description(s)]
DESCRIPTION OF CHANGE(S)
REASON FOR CHANGE(S)
VALIDATION/QUALIFICATION
[ ] Necessary - describe validation/ [ ] Not Necessary - provide
qualification study and results (attach justification
relevant materials)
CORIXA QUALITY ASSURANCE
Name: __________________________________________________________________________
Title: _________________________________________________________________________
Signature/Date: ________________________________________________________________
"CONTROLLED COPY" (Red Print)
44
[ILLEGIBLE] 03/27/02
SOP #QA-104.01
ATTACHMENT #1
Date: 03/02
Supersedes: #NA
Page 7 of 7
PART B - RESPONSE BY CUSTOMER(CATEGORY II AND III CHANGES ONLY)
Notification ID Number: Change Control ID No.
Change Category: Change Control Date: First Affected Lot:
CUSTOMER RESPONSE AND COMMENTS
[ ] Approved [ ] Not Approved - please provide detailed explanation
CUSTOMER REPRESENTATIVE
Name: __________________________________________________________________________
Title: _________________________________________________________________________
Signature/Date: ________________________________________________________________
"CONTROLLED COPY" (Red Print)
45
APPENDIX 5: [*]
*CONFIDENTIAL TREATMENT REQUESTED.
46
APPENDIX 6: SUPPLY AGREEMENT RESPONSIBILITIES
Responsibility
1.
Responsibility
--------------
Clause Corixa GSK
------------------------------------------------------------------------------------ ------ -----
1 Manufacture of the MPL Bulk Product and release for use in GSK vaccines X
2 Starting raw materials are purchased, tested and released by X
3 Expiry dating, batch numbers and storage conditions will be provided by X
4 Safety information to be provided by X
5 Starting raw materials retention samples held by X
6 Final bulk product retention samples held by X
7 Stability testing on bulk products to be done by X
Stability testing on final vaccines to be done by X
8 Records of manufacturing and testing of bulk to be held by X
9 Certificates of analysis and GMP statement of bulk product to be prepared by X
10 Final inspection and reconciliation of bulk product by X
11 Storage in Corixa warehouse X
12 Packaging and placing of suitable shipment monitoring devices by X
13 Validation of shipment operations by X
14 Storage in GSKBio warehouse X
15 Recall decision on unsuitable bulk X X
16 Shipment of recalled bulk by X
17 Investigation on pharmaceutical technical complaints (PTC's) relating
to bulk product: Initial complaint X
Manufacturing and testing of bulk X
Effectiveness stability and safety of bulk X
Reply to complainant X
18 Investigation on Medical Complaints relating to bulk product:
Initial complaint X
Clinical Investigation X
Technical Investigation X
Serious and unexpected adverse Events to Corixa within 7 d X
Vaccine product recall and report to Corixa X
Investigation of complaints related to the bulk MPL product X
19 Recall or market withdrawal
Initiation of recall related to the vaccine product X
Notification to Corixa within three working days X
Disposition of lots for further technical investigation X X
20 Error and Accident Reporting
Report to Corixa of inadvertant storage or transport of bulk X
Decision regarding further disposition of affected bulk product X X
47
Responsibility
--------------
Clause Corixa GSK
------------------------------------------------------------------------------------ ------ -----
21 Lot Tracing
Generation of comprehensive traceability records for bulk X
Generation of comprehensive traceability records for vaccine X
22 Where manufacture of vaccine finished product is carried out by third parties,
GMP-responsibility is assumed by X
23 Alterations to the contract, specifications and manufacturing or testing
procedures shall be agreed in writing X X
24 Master packing and labeling instructions
Provided by X
Prepared by X
Agreed by X X
25 Annual Quality Report of Product Quality Review including production X
overview, quality results overview, stability, complaints to be provided to GSK. X
26 Receipt testing and acceptance of bulk MPL adjuvant after shipment X
Signed on behalf of Corixa/ date
Signed on behalf of GSKBio/date
48
EXHIBIT V
MANUFACTURING KNOW HOW TRANSFER WORK PLAN
(LEFT BLANK)
49
