EXHIBIT 10.4
CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY WITH
THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO THE
OMITTED PORTION.
AGREEMENT
FOR
MANUFACTURING AND SUPPLY OF BNP7787
Made as of February 10, 2004 (the "Effective Date")
by and between
BIONUMERIK PHARMACEUTICALS, INC.,
(hereinafter referred to as "BioNumerik"),
a corporation duly organized and validly existing under the laws of the State
of Texas with its principal offices at Suite 1250, 0000 Xxxxxxxxx Xxxxx,
Xxx Xxxxxxx, XX 00000, XXX
and
RHODIA PHARMA SOLUTIONS INC.
,
a corporation duly organized and validly existing under the laws
of Delaware, with its principal offices at 000 Xxxxxxxx Xxxxxx Xxxx, Xxxxxxxx,
XX 00000-0000, XXX (Rhodia Pharma Solutions Inc., together
with its subsidiary Rhodia Pharma Ltd., are hereinafter
collectively referred to as "RPS")
1 DEFINITIONS
Unless otherwise specifically set forth herein, the following terms
shall have the meanings set forth below:
1.1 Compound
Shall mean the compound 2,2'-Dithio-Bis-Ethane sulfonate, disodium
salt, also known as BNP7787 or Tavocept (TM).
1.2 Confidential Information
Shall mean all information, whether technical or non-technical, trade
secrets, discoveries, data, drawings, techniques, documents, models,
samples and know-how, whether or not patented or patentable, owned or
possessed by a Party on the date of this Agreement or later developed
by them.
1.3 Party
Shall mean BioNumerik or RPS, and when used in the plural form both
BioNumerik and RPS.
1.4 Product(s) or Finished Dosage Form
Shall mean any pharmaceutical composition or formulation containing the
Compound as the pharmacologically active ingredient.
1.5 Specifications
Shall mean the specifications for the Compound attached on Annex 2
hereto.
2 AGREEMENT SCOPE AND MANUFACTURE AND SUPPLY OF COMPOUND
2.1
(a) Phase 1 - Technology Transfer and Familiarization.
Upon the signing of this Agreement by the Parties, RPS will undertake
receipt of the technology transfer from BioNumerik and laboratory
familiarization with the BNP7787 process as necessary to prepare the
Compound in accordance with the Specifications, all as described in the
Project Description (the "Project Description") attached hereto as Annex 1.
The price for this Phase 1 material will be as described in the Project
Description attached hereto as Annex 1 to be paid as described in Section
2.3 hereof.
(b) Phase 2 - Site Qualification.
Upon successful completion of Phase 1 and following receipt of written
authorization from BioNumerik to proceed with Phase 2, RPS will complete
Phase 2: Site Qualification, during which RPS will prepare under current
U.S. Food and Drug Administration ("FDA") Good Manufacturing Practices
(cGMP) a number of [**] target batch size qualification batches in order
to assure meeting the critical success criteria (the "Success Criteria")
included in Annex 10 hereto. Should the first qualification batch be
prepared under conditions deemed successful based on the Success Criteria,
then the second batch may be eliminated and BioNumerik shall only be
required to pay for such first batch. Should more than two batches be
required in order to meet the Success Criteria, all batches prepared in
excess of the first two batches will be done so at the expense of RPS
without additional cost to BioNumerik. The price for these Phase 2 batches
will be as described in the Project Description attached hereto as Annex 1
to be paid as described in Section 2.3 hereof.
(c) Phase 3 - Validation Batches.
Upon successful completion of Phase 2, RPS will complete Phase 3:
Validation Batches, during which RPS will prepare under cGMP three (3)
[**] validation
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WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
batches as described in the Project Description. The price for these Phase
3 batches will be as described in the Project Description attached hereto
as Annex 1 to be paid as described in Section 2.3 hereof.
(d) Phase 4 - Commercial Batches.
Upon successful completion of Phase 3, RPS will prepare under cGMP
commercial batches of the Compound with quantities and delivery schedule to
be agreed between BioNumerik and RPS. The price for the commercial batches
will be as described in the Project Description attached hereto as Annex 1.
It is expected that if BioNumerik gives RPS [**] prior notice of a need for
a commercial batch, RPS will do its best to fulfill the order within such
time frame. However, RPS cannot guarantee delivery of Compound [**] prior
notice, but in any event RPS will deliver Compound within a maximum of six
months after notification by BioNumerik, except in the event of an
occurrence of a Force Majeure event described in Section 9.4.
2.2 (a) All Compound shall be manufactured and delivered in accordance with
the Compound Specifications indicated in Annex 2. These Specifications
will be obtained from BioNumerik, or will be developed in conjunction
and with the approval of BioNumerik. Any changes in the Specifications
will be agreed between BioNumerik and RPS prior to scale-up or
commencing the production. In addition, manufacturing of all Compound
by RPS (other than Compound manufactured as part of the Phase 1 Work)
will be conducted in compliance with relevant current U.S. Food and
Drug Administration ("FDA") Good Manufacturing Practices ("cGMP") and
International Conference on Harmonisation ("ICH") guidelines.
(b) Unless otherwise already specified in the Annexes hereto, the batch
records; specifications for raw materials, intermediates and final
products; and analytical test methods for all materials will be
delivered to RPS by BioNumerik subsequent to the signing of this
Agreement or BNPI will develop in conjunction with RPS any additional
requirements. All batch records and production documentation specific
to the Compound must be approved in writing by BioNumerik prior to use.
Any changes in the production flow steps, analytical methods,
production records, test methods, Specifications, or equipment used by
RPS will require prior written approval by BioNumerik. RPS will provide
a Certificate of Analysis and executed batch record with each shipment
that describes product specifications and results.
(c) All starting material and other raw materials necessary for the
work hereunder will be supplied by RPS without additional charge to
BioNumerik. RPS will have back-up starting material and raw materials
available should BioNumerik decide to proceed with an additional batch
of Compound in the event a batch fails. If a batch fails to meet
Specifications due to factors under the control of RPS or is rejected
by BioNumerik or
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THE OMITTED PORTIONS.
RPS due to critical failure to be manufactured in accordance with cGMP,
and BioNumerik requests RPS to manufacture an additional batch of
Compound or reprocess the batch that is out of specification ("OOS"),
then RPS will conduct such manufacturing or reprocess at no additional
charge to BioNumerik and will schedule the manufacture of such
additional batch of Compound as soon as practical (and in any event
within 30 days of BioNumerik's request, unless the manufacture within
such time period is prevented by catastrophic equipment failure or
other Force Majeure event described in Section 9.4). The specifications
of the starting materials for manufacture of the Compound are as set
forth on Annex 3 to this Agreement.
(d) Procedures for release of the Compound have been agreed to by
BioNumerik and RPS and are attached on Annex 5 hereto. The procedures
to be followed upon the occurrence of an Out of Specification (OOS) or
Out of Trend (OOT) event are contained in the standard operating
procedures (SOPs) for the RPS [**] facility. Current copies of such
SOPs have been previously provided by RPS to BioNumerik and RPS will
promptly provide BioNumerik with any changes to such SOPs. These
procedures contain specific timelines for investigation of OOS and OOT
events. Timelines to be followed for a batch failure due to
circumstances other than OOS and OOT events are also contained in the
SOPs for the RPS Annan, Scotland facility. RPS will retain samples of
each API batch of Compound and samples of all solid raw materials and
intermediates used in the manufacturing for a period of at least 5
years following completion of the manufacturing, provided that
commodity solid raw materials will be maintained for a period of at
least one month following completion of the manufacturing.
(e) RPS shall be responsible for conducting an audit program for
vendors (including testing facilities) utilized by RPS in connection
with manufacturing of the Compound as required to comply with cGMP and
ICH Guidelines (including ICH guideline Q7A). RPS will provide
BioNumerik with a copy of RPS' audit procedures and analytical approval
process, and any updates or amendments to such procedures and process.
BioNumerik has the right, during any audits of RPS conducted by
BioNumerik, to review the records for all raw material and starting
material vendor audits conducted by RPS with respect to raw materials
and starting materials (as defined by ICH guidelines) for the Compound.
In addition, BioNumerik shall also have the right to review the
qualification records (as required by cGMP) of the vendors for the
starting materials for the Compound, provided the starting materials
are produced under cGMP. RPS shall promptly inform BioNumerik in the
event of a concern with the quality or manufacturing compliance with
respect to a raw material used in the manufacture of the Compound and
RPS will coordinate with BioNumerik to assure a prompt resolution of
any such concern. The results of all audits that have occurred that
relate to the materials to be used in the manufacture of the Compound
have previously been provided to BioNumerik, and RPS will promptly
provide to BioNumerik the results of
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WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
all such audits conducted in the future. BioNumerik and RPS agree that
the materials listed on Annex 9 are the critical raw materials in
connection with the manufacture of the Compound.
2.3 BioNumerik will pay RPS the payment amounts described in the Project
Description in the following manner:
(i) [**] of the Phase 1 payment amount will be paid upon commencement
of the Project (as such term is defined in the Project
Description) with the remainder to be paid upon completion of
Phase 1, provided that if Phase 1 in not completed within eight
(8) weeks of commencement (not including time necessary for
receipt of raw materials), then the remaining Phase 1 amount
shall be paid upon receipt of Phase 2 Compound amount satisfying
the required Specifications; and
(ii) [**] of the Phase 2 payment amount will be paid upon commencement
of Phase 2 of the Project with the remainder to be paid upon
receipt by BioNumerik of Phase 2 Compound satisfying the required
Specifications and meeting the Success Criteria; and
(iii) Assuming receipt by BioNumerik by the end of 2004 of Phase 3
validation batches satisfying the required Specifications,
payment for the Phase 3 work will be paid in January, 2005,
except that payment for the development work in support of Phase
3 will be paid upon receipt by BioNumerik of Phase 3 material
satisfying the required Specifications in the amounts required
for such Phase 3 batches; and
(iv) Notwithstanding the Project Description and unless otherwise
agreed in writing by BioNumerik in an amendment to this
Agreement, (a) the price for Phase 1 of the Project shall not
exceed [**] and (b) the total price for Phase 2 of the Project
shall not exceed [**] provided that RPS shall promptly notify
BioNumerik at such time as the costs incurred for Phase 2 of the
Project exceed [**] and any expenditures or work by RPS in excess
of such [**] amount shall only be incurred following the written
approval of BioNumerik.
(v) Notwithstanding any other provision of the Agreement or the
Project Description, BioNumerik shall have no obligation to pay
for (and RPS shall promptly refund to BioNumerik amounts paid to
RPS for) any Phase 2 Compound amount, any Phase 3 Compound
amount, or any Phase 4 Compound amount unless such Compound
amount (i) is manufactured by RPS in compliance with current U.S.
FDA Good Manufacturing Practices (cGMP), ICH guidelines, the
manufacturing procedures specified herein, and in accordance with
the other manufacturing procedures and information provided by
BioNumerik to RPS, and (ii) is manufactured by RPS in accordance
with the Specifications.
2.4 Except as otherwise specified above, payment for all Compound purchased
from RPS by BioNumerik in accordance with this Agreement shall be made
within 30 days after goods satisfying the required Specifications are
shipped, by wire transfer in accordance with Annex 6.
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WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
2.5 RPS shall maintain all of the appropriate specifications and standard
operating procedures related to the manufacturing of the Compound.
These will be treated as controlled documents and will be maintained
utilizing a suitable document control procedure to ensure proper
issuance and change, respectively. During the term of this Agreement
and for a period of at least five years thereafter, RPS shall maintain
records of inspection and testing, lab notebooks and procedures made in
connection with the manufacturing work conducted under this Agreement.
In addition, RPS is in a position to either (i) prepare a Drug Master
File (DMF) for BNP7787 for the United States, the European Union, and
Japan, or (ii) provide BioNumerik with the necessary information so
that the same information that would be included in the DMF can be
included in the NDA or equivalent filing in the United States, the
European Union, and Japan. RPS will prepare a DMF for BNP7787 upon
request by BioNumerik and after reaching agreement with BioNumerik on
the amount to be paid to RPS for preparing the DMF (which amount is
roughly estimated by RPS to be approximately [**] for a U.S. DMF). If,
instead of requesting RPS to actually prepare a DMF, BioNumerik
requests RPS to simply provide the information to BioNumerik for
inclusion in the NDA or equivalent filing in the United States, the
European Union, and Japan as described in clause (ii) of the fourth
sentence of this paragraph, then RPS will provide such information
without additional charge to BioNumerik.
2.6 RPS shall keep BioNumerik regularly informed of the status and progress
of all stages of Phases 1, 2, 3, and 4, including manufacturing,
through regular telephone or e-mail updates and through written
summaries. During all periods that RPS is conducting any manufacturing
for BioNumerik, RPS shall perform an annual product review, including a
review of production history, deviations (if any), out of specification
events, investigation programs adopted and the outcome of any
investigations, any reprocessing conducted, ongoing stability results
if generated at an RPS site, and site availability for the upcoming
year. RPS shall communicate the results of its review to BioNumerik in
writing.
2.7 RPS shall be responsible for complying with all transport regulations
applicable to the provision of the Compound to BioNumerik in accordance
with this Agreement.
2.8 The Compound will be produced in the A3 plant at RPS's [**] facility.
2.9 RPS shall promptly provide BioNumerik with written proof of any
destruction of intermediates or API either upon reaching the expiry
date or in the event RPS is requested by BioNumerik to destroy any such
materials.
2.10 In the event of any disqualification of an RPS site relating to the
manufacturing by any regulatory agency, RPS shall be responsible for
the cost of any raw materials, intermediates or API produced up to such
time.
3 INSPECTIONS AND CONTROLS
3.1 Subject to confidentiality obligations contained in Section 7, RPS
agrees, without additional charge to BioNumerik, to allow inspections
of its manufacturing facilities in which the Compound is being
manufactured, analyzed or tested, by representatives of BioNumerik or
its agents (including inspections by regulatory authorities) during
normal working hours upon prior written notice to RPS, which notice
will occur at least three days in advance of the inspection, unless not
possible with respect to an inspection by a regulatory agency. RPS
shall grant access to such premises and to the documentation necessary
for or appropriate to the manufacturing and quality control of the
Compound. During such visits, RPS shall make sure that at least one
technical person from each of Quality Assurance, Quality Control,
project teams, and, if reasonably possible, business
development/coordination is present to answer questions or discuss
matters of concern with the BioNumerik personnel conducting such audit
or inspection.
3.2 RPS shall ensure all relevant and/or critical manufacturing, test and
inspection equipment is maintained under a documented calibration and
maintenance program. This includes providing equipment calibration
certifications as required.
3.3 RPS will maintain environmental controls, including particulate and
bioburden monitoring, pest controls and housekeeping procedures in
accordance with FDA cGMP and ICH guidelines. The use of supplies of
process water, air and particulate handling, etc., for cGMP manufacture
of the Compound, shall be consistent with relevant FDA cGMP
specifications and ICH guidelines.
3.4 RPS shall maintain a quality control department, which is a distinct
department separate from manufacturing. RPS quality control/quality
assurance will perform incoming, in-process and finished product
inspections, review records, perform line clearance inspections,
maintain batch history records, provide batch history records for
review and accuracy and completeness and provide product release
services. RPS
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will promptly inform BioNumerik of any changes in management control
related to the work conducted hereunder.
3.5 The conditions to be maintained for the storage of API, raw materials,
and intermediates are set forth on Annex 7.
3.6 RPS will promptly notify BioNumerik of any FDA or other material
regulatory inspection of RPS related to the Compound, and will promptly
provide BioNumerik with a copy of documentation relating to such
inspection. BioNumerik shall have the right to communicate at any time
with the FDA or any regulatory agency or body regarding such matters,
provided any communication with the FDA regarding potential inspection
of RPS' plants should be done in coordination with RPS. BioNumerik will
provide appropriate support for any such inspection, including data and
information relating to critical parameters and justification for the
process for manufacturing the Compound.
3.7 At all times during the term of this Agreement, each of the parties
shall carry and keep in force a general liability Insurance policy, in
support of their liability obligations to one another hereunder. The
policy maintained by RPS shall afford limits of not less than [**] for
each occurrence and not less than [**] in the annual aggregate in
respect of products and completed operations liability. The policy
maintained by BioNumerik shall afford limits of not less than [**] for
each occurrence and not less than [**] in the aggregate. In the event
that such policy is written on a claims-made basis, such policy shall
provide no less than twelve (12) months extended reporting period from
the date of termination of this Agreement. A Certificate of Insurance
evidencing RPS's coverage and a Certificate of Insurance evidencing
BioNumerik's coverage are attached hereto as Annex 8 hereto.
4 PRODUCT WARRANTIES
4.1 RPS warrants and represents that the Compound manufactured by RPS and
delivered to BioNumerik, its affiliates or sub-licensee(s) hereunder
shall conform to the Specifications (except as otherwise provided in
Section 2.2 hereof) when delivered and, when expressly required by the
Project Description, be manufactured in accordance with all applicable
laws and regulations relating to the manufacture of the Compound,
including but not limited to, current U. S. FDA Good Manufacturing
Practices (cGMP) and ICH guidelines. RPS will maintain at least 25 to
50 grams of the Compound from each batch produced as a retained sample.
Such retained sample will be maintained at RPS' facility and RPS will
store such retained sample under suitable storage conditions adequate
for the purpose of development as specified by BioNumerik. RPS further
represents and warrants that RPS is not aware that the manufacturing
process for the Compound or the Product or the use of such process
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infringes or will infringe the claims under any patent or other
intellectual property right of RPS or any third party; RPS will
immediately inform BioNumerik if it should become aware of any such
infringement or potential infringement.
EXCEPT FOR THE FOREGOING, RPS MAKES NO WARRANTY OR REPRESENTATION OF
ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, THE
WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE AND
ANY REPRESENTATION OR ANY WARRANTY THAT USE OF THE PROCESS FOR
MANUFACTURE OF THE PRODUCT OR USE OR SALE OF PRODUCT, WHETHER OR NOT
SUCH PRODUCT IS MADE BY THE PROCESS FOR MANUFACTURE OF THE PRODUCT,
WILL NOT INFRINGE THE CLAIMS UNDER ANY PATENT OR OTHER INTELLECTUAL
PROPERTY RIGHT OF RPS OR ANY THIRD PARTY.
Limitations. RPS'S SOLE LIABILITY AND BIONUMERIK'S EXCLUSIVE REMEDY IN
THE CASE OF PRODUCT DELIVERED HEREUNDER TO BIONUMERIK THAT DOES NOT
MEET PRODUCT SPECIFICATIONS SHALL BE, AT RPS'S OPTION, TO USE
COMMERCIALLY REASONABLE EFFORTS TO REPLACE THE DEFECTIVE PRODUCT WITH
PRODUCT THAT CONFORMS WITH THE PRODUCT SPECIFICATIONS OR TO REFUND THE
FEES AND CHARGES PAID TO RPS FOR THE SERVICES RELATED TO SUCH
NON-CONFORMING PRODUCT. EXCEPT IN THE CASE OF GROSS NEGLIGENCE OR
INTENTIONAL MISCONDUCT ON THE PART OF RPS, RPS'S LIABILITY FOR ANY
CLAIM OF BIONUMERIK RELATED TO THIS AGREEMENT SHALL NOT EXCEED THE
AGGREGATE FEES AND CHARGES PAID TO AND RECEIVED BY RPS FOR THE SERVICES
PERFORMED TO WHICH ANY SUCH CLAIM RELATES. IN NO EVENT SHALL EITHER RPS
OR BIONUMERIK BE LIABLE TO THE OTHER FOR INDIRECT, SPECIAL,
CONSEQUENTIAL (INCLUDING WITHOUT LIMITATION LOST PROFITS), PUNITIVE,
INCIDENTAL OR SIMILAR DAMAGES IN ANY WAY ASSOCIATED WITH THIS
AGREEMENT, REGARDLESS OF THE FORM OR BASIS OF ANY CLAIM OR ACTION. ALL
CLAIMS CONCERNING PRODUCT DELIVERED TO BIONUMERIK HEREUNDER MUST BE
MADE IN WRITING RECEIVED BY RPS WITHIN NINETY (90) DAYS AFTER THE DATE
OF DELIVERY, FAILING WHICH CLAIM NOTICE SUCH PRODUCT SHALL BE DEEMED
ACCEPTED BY BIONUMERIK "AS IS" AND ALL CLAIMS BY BIONUMERIK IN RELATION
TO SUCH DELIVERED PRODUCT SHALL BE DEEMED WAIVED. NOTWITHSTANDING THE
FOREGOING, NOTHING CONTAINED IN THIS ARTICLE 4 IS INTENDED TO LIMIT THE
INDEMNIFICATION OBLIGATIONS OF THE PARTIES CONTAINED IN ARTICLE 9.
5 DEBARMENT CERTIFICATION
5.1 RPS warrants that it will not knowingly use in connection with the
services rendered under this Agreement in any capacity the services of
any person
debarred under the U.S. Food, Drug & Cosmetic Act or any other similar
law or regulation governing drug manufacturing.
6 INDEPENDENT CONTRACTOR STATUS
6.1 Each of the Parties in performing this Agreement shall be and be deemed
to be acting as an independent contractor and not as the agent or
employee of the other. Neither RPS nor BioNumerik shall have any
authority whatsoever to act as agent or representative of the other
party nor any authority or power to contract or create any obligation
or liability on behalf of the other party or otherwise bind any other
party in any way for any purpose.
7 CONFIDENTIALITY
7.1 Each Party shall hold all Confidential Information received from the
other Party in strictest confidence and shall use the same level of
care to prevent any unauthorized use or disclosure of such Confidential
Information as it exercises in protecting its own information of
similar nature. A Party shall not disclose any Confidential Information
received from the other Party to any third party without the prior
written consent of the other Party.
7.2 The Confidential Information shall be supplied to the Parties in
written form and shall be identified as being confidential and
disclosed under the provisions of this Agreement. Any information that
is disclosed in oral form shall be confirmed in writing within sixty
(60) days after disclosure and be deemed included within the scope of
this Agreement.
7.3 Each Party shall have the right to disclose the Confidential
Information of the other Party to the minimum number of those officers
and employees of such receiving Party who need to know it for the
purposes of this Agreement. Such disclosure is allowed only on
condition that the persons to whom the Confidential Information will be
disclosed shall be, by law, contract or other binding undertaking,
under confidentiality obligations corresponding to those set out in
this Agreement.
7.4 The disclosing Party retains all rights to its Confidential
Information.
7.5 The confidentiality obligations of this Agreement shall not apply to:
a) Confidential Information which at the time of the disclosure
is in the public domain; or
b) Confidential Information which, after disclosure, becomes part
of the public domain otherwise than by breach of this
Agreement; or
c) Confidential Information which can be established by
reasonable and competent proof to have already been in the
receiving Party's possession prior to disclosure and was not
acquired, directly or indirectly, from the disclosing Party;
or
d) Confidential Information which a receiving Party shall receive
from a third party who has the legal right to disclose it and
who would by disclosure not breach, directly or indirectly,
any confidentiality obligation to either Party; or
e) Confidential Information which is released for disclosure by
prior written consent of the disclosing Party; or
f) Confidential Information which has been independently
developed by a Party hereto without the use or benefit of
Confidential Information received from the other Party; or
g) Confidential Information which is required to be disclosed by
law or by order of court of competent jurisdiction, provided
that due advance notice is given to the other Party of such a
requirement and also such disclosure is then made only to the
minimum extent so required.
h) In addition to the foregoing, the existing Confidentiality
Agreement (the "Confidentiality Agreement), dated as of June
25, 2003, among BioNumerik, Xxxxxx Oncology GmbH, and RPS
shall remain and continue in full force and effect after the
date hereof in accordance with its terms.
All obligations under Section 7 of this Agreement shall terminate 5
years after the termination of this Agreement.
7.6 The burden of proving that any of the above exceptions is applicable to
a Party to relieve it of its liability or obligations hereunder shall
be upon the Party claiming such exception(s).
8 INTELLECTUAL PROPERTY RIGHTS
8.1 a) As used herein "Intellectual Work Product" means all inventions,
modifications, discoveries, improvements (including, without
limitation, process improvements and improvements in analytical
methods), processes, techniques, documentation, scientific and
technical data, drawings and other information (other than the RPS
Technology) that is generated as a result of any of the manufacturing
services and other projects performed for BioNumerik by RPS. "RPS
Technology" means all present and future documentation, scientific and
technical data, processes, test procedures and other information and
techniques that are owned, developed or licensed by RPS relating to the
development, formulation or manufacture of chemical and pharmaceutical
substances and that are not developed hereunder or in connection with
the manufacturing or other projects performed for BioNumerik by RPS.
BioNumerik shall not own any of the RPS Technology. RPS will, however,
use know-how and experience of RPS to facilitate the efficient
manufacture of the Compound.
b) The parties hereto understand and agree that no rights are being
conveyed to RPS (or any of their affiliates) to use any BioNumerik
Technology (as hereafter defined) for any purpose other than the sole
purpose of preparing the Compound for the benefit of BioNumerik in
accordance with the terms of this Agreement. As used herein,
"BioNumerik Technology" means all present and future documentation,
scientific and technical data, processes, test procedures, information,
techniques, technology, patents, patent rights, inventions and other
intellectual property rights that are owned, developed, or licensed by
BioNumerik.
8.2 a) RPS acknowledges that BioNumerik shall be the sole and exclusive
owner of all Intellectual Work Product (except the RPS Technology, as
described above in Section 8.1). In consideration of the covenants
contained herein, and for other good and valuable consideration set
forth herewith, RPS hereby assigns and transfers to BioNumerik and its
successors and assigns all right, title and interest that RPS has or
may later acquire in and to the Intellectual Work Product under
copyright, patent, trade secret and trademark law. Such assignment
includes the assignment of the entire right, title and interest in and
to all applications for letters patent and any and all letters patents
in the United States of America and all foreign countries which may be
granted on and in connection with the Intellectual Work Product. Upon
request by RPS, BioNumerik will meet with RPS to discuss the
possibility of providing RPS with a non-exclusive, royalty free,
non-sublicensable license to practice the Intellectual Work Product
described in 8.1(a) above for the purpose of manufacturing compounds
other than the Compound that are not similar to or related to the
Compound and that do not complete in any way with the business and
planned business of BioNumerik or BioNumerik's strategic alliance
partners. BioNumerik will have no obligation to grant such a license
and any determination to grant such a license will be made in the sole
discretion of BioNumerik and will be based upon such considerations as
BioNumerik deems appropriate.
b) RPS agrees to cooperate with BioNumerik so that BioNumerik may enjoy
to the fullest extent the entire right, title and interest in and to
the Intellectual Work Product. In connection therewith, RPS agrees to
execute, if necessary, additional papers and documents and to take all
actions requested by BioNumerik in order to (a) further evidence
ownership of the Intellectual Work Product by BioNumerik and its
successors and assigns and (b) allow BioNumerik to procure, maintain
and enforce all letters patent and intellectual property rights to the
Intellectual Work Product. BioNumerik agrees to reimburse RPS all
reasonable costs in relation to the production of additional papers and
documents.
c) In addition, for the purpose of the work conducted by RPS for the
BNP7787 manufacturing project as described in the Project Description,
RPS will not incorporate any of its proprietary technologies toward a
synthesis or manufacturing process.
d) RPS is hereby granted a worldwide, nonexclusive, royalty-free
license to practice the Intellectual Work Product solely for the
purpose of preparing Compound on behalf of BioNumerik in accordance
with this Agreement and the Project Description.
e) BioNumerik warrants and represents that the Products manufactured
and delivered by RPS under this Agreement will be used solely by
BioNumerik or its designated assignees, licensees, representatives or
alliance partners for legally permissible purposes. BioNumerik further
represents and warrants that it has the right to disclose its
Confidential Information to RPS, including without limitation all
technology made available by BioNumerik to RPS for the manufacture of
the Compound subject to and in accordance with the provisions of this
Agreement, and that BioNumerik has the right to license such technology
to RPS for such purpose and RPS may use it accordingly, all free and
clear of any intellectual property or other rights of third parties,
all subject to and in accordance with the provisions of this Agreement.
8.3 Except as specifically described in this Agreement, no right, title,
interest, or license in or to any trademark, patent, copyright or
service xxxx or symbol or any other intellectual property right of a
party is granted to the other party under this Agreement.
9 INDEMNIFICATION PROVISIONS; FORCE MAJEURE; ARBITRATION
9.1 BioNumerik will indemnify and hold harmless RPS, its affiliates, any
present or future parent or subsidiary of them, and their respective
officers, directors, employees, counsel, agents and affiliates (the
"Indemnified RPS Parties") against any and all losses, liabilities,
damages, costs and expenses including, but not limited to, reasonable
attorney fees and any and all reasonable expenses incurred in defending
against any litigation, commenced or threatened, or any claim, and any
and all amounts reasonably paid in settlement of any claim or
litigation, commenced or threatened ("Losses"), arising out of (i)
product liability and patent and trademark infringement suits regarding
any active pharmaceutical ingredient or raw materials relating to the
projects hereunder, including but not limited to, any bulk drug, or the
Compound, (ii) any failure by BioNumerik to comply with any applicable
governmental regulation (including, without limitation, any applicable
environmental laws), (iii) the breach of any representation, warranty,
or covenant of BioNumerik contained in this Agreement, (iv) the use by
RPS of any raw or component material(s) supplied by BioNumerik to RPS
or by a third party on BioNumerik's behalf, or (v) the promotion,
marketing, distribution and sale, whether directly or through
distributors, of BNP7787; PROVIDED, HOWEVER, THAT IN NO EVENT SHALL
BIONUMERIK INDEMNIFY OR HOLD HARMLESS ANY OF THE INDEMNIFIED RPS
PARTIES IN THE EVENT RPS OR ANY INDEMNIFIED RPS PARTY, IS IN ANY WAY
RESPONSBILE BY NEGLIGENCE OR WILLFUL ACT FOR SUCH LOSSES, LIABILITIES,
DAMAGES, COSTS AND EXPENSES.
9.2 RPS will indemnify and hold harmless BioNumerik, its affiliates, any
present or future parent or subsidiary of any of them, and their
respective officers, directors, employees, counsel, agents and
affiliates (the "Indemnified BioNumerik Parties") against any and all
Losses arising out of (i) any breach of any representation, warranty,
covenant or agreement of RPS contained in this Agreement, (ii) any
failure by RPS to comply with any applicable governmental regulation
(including, without limitation, any applicable environmental laws), or
(iii) any product recalls or withdrawals,
personal injury, product liability or property damage relating to or
arising from any Compound supplied by RPS under this Agreement, BUT
ONLY TO THE EXTENT SUCH RECALLS OR WITHDRAWALS, PERSONAL INJURY,
PRODUCT LIABILITY OR PROPERTY DAMAGE REFERRED TO WITHIN (iii) OF THIS
PARAGRAPH IS ATTRIBUTABLE TO RPS'S BREACH OF THIS AGREEMENT, OR RPS'S
FAILURE TO MANUFACTURE ANY PRODUCT IN CONFORMANCE WITH THE
SPECIFICATIONS AND REQUIREMENTS SET FORTH IN THIS AGREEMENT; provided
further that RPS will not indemnify or hold harmless Indemnified
BioNumerik Parties for any losses arising out of BioNumerik's
negligence.
9.3 Conditions of Indemnification: With respect to any indemnification
obligations of either Party to the other Party under this Agreement,
the following conditions must be met for such indemnification
obligations to become applicable:
a) The indemnified Party shall notify the indemnifying Party promptly
in writing of any claim which may give rise to an obligation on the
part of the indemnifying Party hereunder;
b) The indemnifying party shall be allowed to timely undertake the sole
control of the defense of any such action and claim, including all
negotiations for the settlement, or compromise of such claim or action
at its sole expense;
c) The indemnified Party shall at its sole expense render reasonable
assistance, information, cooperation and authority to permit the
indemnifying Party to defend such action.
9.4 Force Majeure. Neither party shall be liable to the other for damages
of any sort arising from any delay or default in such party's
performance hereunder caused by events or conditions beyond such
party's reasonable control and which such party is unable through the
exercise of due diligence to prevent, including, but not limited to,
acts of nature, government or regulatory action, war, civil commotion,
destruction of synthesis or production facilities or materials by
earthquake, fire, flood or storm, or public utilities ("Force
Majeure"). Each party agrees promptly to notify the other party of any
event of Force Majeure and to employ all reasonable efforts toward
prompt resumption of its performance when possible. If Force Majeure
prevents performance by one party of its obligations hereunder in whole
or in part for more than thirty (30) days, the other party shall have
the right to terminate any remaining Phase or Phases of the Project or
the remainder of this Agreement upon written notice to the
non-performing party. In no event shall Force Majeure affecting RPS
obligate RPS to procure supplies of Product for BIONUMERIK from
alternate suppliers, or to allocate its available manufacturing
resources and product supplies in other than a fair and reasonable
manner giving equal consideration to the internal manufacturing needs
of RPS and its affiliates and to the needs of BioNumerik and RPS'
regular customers whether or not they are then under contract.
9.5 Arbitration. Any controversy or claim arising under this Agreement or
the breach thereof which cannot be settled amicably within a period of
[**] after the date of notification, by registered mail, of the
controversy or claim by one party to another shall be settled
exclusively by arbitration in San Antonio, Texas in accordance with the
rules of the American Arbitration Association ("AAA") then in effect,
such arbitration to occur before a single arbitrator mutually agreeable
to both parties; provide however that, in urgent situations in which
times is of the essence to obtain proper remedies, the rights of the
parties to bring claims or actions in Courts of law shall remain
unimpaired. The arbitrator shall render his/her decision within [**] of
the completion of the hearing, and may, in his/her discretion, award
costs and expenses (including attorney's fees) to the winning party.
The judgement and award of the arbitrator shall be final and binding
and may be entered in any court having jurisdiction thereof, or
application may be made to such court for judicial acceptance of any
award or an order of enforcement, as the case may be. RPS and
BioNumerik shall share equally the fees and expenses of the arbitrator.
It is further understood between the parties that both the arbitration
proceeding and the arbitration award will be confidential and kept
confidential by the arbitrator, the AAA and the Parties, except for
such disclosure as may be required to comply with legally required
corporate disclosure and disclosure to shareholder's, investors,
alliance partners, accountants, attorneys and financial advisors of the
disclosing party.
10 TERM AND TERMINATION
10.1 This Agreement shall enter into force as of the Effective Date of the
Agreement and unless earlier terminated, shall continue in full force
and effect until one year after completion of the projects described in
the Project Description. Sections 4, 8, 9, and 13 shall survive any
termination of this Agreement. The obligations under Section 7 of this
Agreement shall terminate 5 years after the termination of this
Agreement.
10.2 Either Party shall have the right, without prejudice to any other
rights or remedies available to it, to terminate this Agreement for
cause with immediate effect by written notice to the other Party in any
of the following events:
a) The other Party defaults in the performance of any of its
obligations under this Agreement and such default continues
unremedied for thirty (30) days from notice to the defaulting
Party;
b) The other Party intentionally makes (or is discovered to have
intentionally made) any material false representations,
reports or claims in connection with the business
relationships of the Parties;
[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
c) Any of the representatives of the Parties engages in (or is
discovered to have engaged in) fraudulent, criminal or
negligent conduct in connection with the business
relationships of the Parties;
d) The other Party files a petition in bankruptcy, is adjudicated
bankrupt, files for reorganization, is placed in liquidation,
makes a general assignment for the benefit of its creditors,
becomes insolvent or is otherwise unable to fulfill its
business obligations.
10.3 BioNumerik may also terminate this Agreement at any time with or
without cause upon 30 days written notice to RPS, provided that, upon
termination of this Agreement by BioNumerik without cause, BioNumerik
will pay to RPS the price as agreed in the Project Description up to
the costs incurred at the point of termination of the Agreement.
10.4 RPS may terminate this Agreement upon 6 months written notice to
BioNumerik if, as a result of the services performed by RPS prior to
such termination and RPS's findings relevant thereto, RPS has
determined that, after expending diligent efforts towards the
manufacture of the Compound, it simply cannot make the Compound
required for future phases of this Agreement within the Specifications
(as defined in this Agreement), such written notice to include an
explanation of the basis for any such decision by RPS. In the event of
any such termination of this Agreement by RPS, BioNumerik shall only be
responsible for the payment of fees and charges for services performed
by RPS hereunder through the termination date specified in RPS's
termination notice, and then only to the extent that BioNumerik is able
to utilize the Compound resulting from such services.
11 CRITICAL INTERFACES AND NOTICES
11.1 All notices referred to herein shall be sent by prepaid registered
mail, by recognized courier service (such as Federal Express), or by
facsimile and shall be deemed delivered if sent to the addresses of the
respective Parties hereinbelow indicated, or such other address as is
furnished by such notice to the other Party.
Notices and payments to RPS shall be made in accordance with the RPS
contact information contained in the Project Description:
Notices and invoices to BioNumerik shall be made to:
BIONUMERIK PHARMACEUTICALS, INC.
Suite 1250,
0000 Xxxxxxxxx Xxxxx,
Xxx Xxxxxxx, XX 00000, XXX
Attn: Xx. Xxxxx Xxxxxx, Senior Manager
Chemistry & Manufacturing Operations
Fax: x0 000 000 0000
Phone: x0 000 000 0000
e-mail: xxxxx.xxxxxx@xxxx.xxx
with a copy to:
Xxxxxxxxx X. Xxxxxxxx, M.D.,
Chairman and CEO
BioNumerik Pharmaceuticals, Inc.,
Suite 1250,
0000 Xxxxxxxxx Xxxxx
Xxx Xxxxxxx, XX 00000, XXX
Fax: x0 000 000 0000
Phone: x0 000 000 0000
11.2 STATUS UPDATES.
RPS shall keep BioNumerik regularly informed of the status and progress
of all stages of the Phase 1, 2, 3, and 4 work, including
manufacturing, through regular telephone or e-mail updates and through
written summaries.
11.3 CONTACT PROCEDURES.
The following individuals shall serve as initial points of contact at
RPS and BioNumerik with respect to any questions or occurrences that
may arise with respect to the Agreement and the work conducted
hereunder:
RPS CONTACTS:
TECHNICAL MATTERS: Xxxx Xxxxxxx
PAYMENT OR FINANCIAL MATTERS: Xxxx Xxxx
BUSINESS OR CONTRACT MATTERS: Xxx Xxxxxxx (with copy to Xxxxxx
Xxxxxxxx)
BIONUMERIK CONTACTS:
TECHNICAL MATTERS:
Xx. Xxxxx Xxxxxx
Xxxxx Xxxxxxxxxx
PAYMENT OR FINANCIAL MATTERS:
Xxxxx Xxxxxx - Vice President & Chief Financial Officer
Xxxxxxx Xxxxxxx - Controller
BUSINESS OR CONTRACT MATTERS:
Xx. Xxxx Xxxxxxxx - Chief Executive Officer
Xxxxx Xxxxxxxx - Vice President, Administration & General Counsel
Xxxxx Xxxxxx - Vice President & Chief Financial Officer
11.4 CHANGE MANAGEMENT.
RPS will promptly notify BioNumerik whenever there is a change in
management or key personnel on the project for the work to be conducted
hereunder.
11.5 Complaint Procedures: Procedures to address any complaint related to
the manufacturing of the Compound are contained in the standard
operating procedures (SOPs) for the RPS Annan, Scotland facility.
Current copies of such SOPs have been previously provided by RPS to
BioNumerik and RPS will promptly provide BioNumerik with any changes to
such SOPs.
11.6 Responsibility for Regulatory Communications.
(a) BioNumerik will have responsibility for initial regulatory
communication with the FDA and other regulatory agencies regarding the
manufacture of the Compound.
(b) RPS will have responsibility for providing back-up assistance and
support as requested by BioNumerik in connection with communications
with the FDA and other regulatory agencies regarding the manufacture of
the Compound. In addition, RPS will have responsibility for regulatory
communication with the FDA and other regulatory agencies (following
coordination with BioNumerik) with respect to the process of RPS'
manufacture of the Compound up to the point that the manufactured
Compound is delivered to the U.S. main port for further shipment as
designated by BioNumerik.
12 ASSIGNMENT
12.1 This Agreement is deemed personal to BioNumerik and RPS. Neither Party
shall, without prior written consent of the other Party, assign this
Agreement or any of its rights nor delegate any of its duties or
obligations herein. Both Parties agree not to unreasonably withhold
consent if such an assignment is contemplated in connection with the
sale or merger by a Party of all or substantially all of its business
or assets to a third Party, providing the non-assigning Party receives
and accepts such written assurances of continued performance and
commitments from the assignee under this Agreement as it may reasonably
require prior to such an assignment becoming effective. Any assignment
or delegation in derogation of this provision shall be deemed null and
void.
13 MISCELLANEOUS
13.1 WAIVERS: Failure of either Party at any time to require strict
performance by the other Party of any of the provisions of the
Agreement shall in no way affect the right thereafter to enforce the
same, nor shall the waiver of any
term, provision, covenant or condition hereof be taken or held to be a
waiver of any subsequent breach hereof or as nullifying the
effectiveness of such term, provision, covenant or condition.
13.2 COUNTERPARTS: This Agreement may be executed in two or more
counterparts, which all together shall constitute one instrument.
13.3 ENTIRE AGREEMENT: This Agreement and its annexes (including, without
limitation, the Project Description) embody the entire understanding of
the Parties and shall supersede all previous communications,
representations, or understandings, either oral or written, between the
Parties relating to the subject matter hereof.
13.4 AMENDMENTS: No amendments or modifications of this Agreement will be
deemed legally binding unless made in writing and signed by both
Parties hereto.
13.5 SEVERABILITY: In case one or more of the provisions contained in this
Agreement shall, for any reason, be held invalid, illegal, or
unenforceable in any respect, such invalidity, illegality or
unenforceability shall not affect any other provision of this
Agreement, but this Agreement shall be construed by amending or
limiting such invalid, illegal, or unenforceable provision so as to
conform as closely as possible to the intent of the Parties or, if such
is not possible, by deleting such provision from this Agreement.
13.6 ANNEXES: The Annexes form an integral part of this Agreement. Should
any internal discrepancies or variances occur between this Agreement
and its Annexes (including the Project Description), this Agreement
shall take precedence.
13.7 GOVERNING LAW: THIS AGREEMENT IS MADE UNDER AND SHALL BE CONSTRUED IN
ACCORDANCE WITH THE LAWS OF THE STATE OF TEXAS, WITHOUT REGARD TO THE
CONFLICTS OF LAW PRINCIPLES THEREOF. EACH PARTY TO THIS AGREEMENT
HEREBY IRREVOCABLY CONSENTS AND SUBMITS TO THE JURISDICTION OF THE
COURTS OF THE STATE OF TEXAS AND OF THE UNITED STATES OF AMERICA FOR
ALL PURPOSES IN CONNECTION WITH ANY PROCEEDING THAT ARISES OUT OF OR
RELATES TO THIS AGREEMENT.
13.8 HEADINGS: The headings in this Agreement may not be used in the
interpretation of any provisions hereof.
13.9 USE OF NAMES: Except as expressly required pursuant to law, neither
party will without prior written consent of the other:
(a) Use in advertising, publicity, promotional premiums or
otherwise, any trade name, trademark, trade device, service
xxxx, symbol, or any abbreviation, contraction or simulation
thereof owned by the other party, or
(b) Represent, either directly or indirectly, that any product or
service of one party is a product or service of the other.
In Witness Hereof,
the Parties hereto through their authorized representatives have
executed this Agreement as of the date first written above.
RHODIA PHARMA SOLUTIONS INC.,
on behalf of itself and its subsidiary, Rhodia Pharma Ltd.
By: /s/ [ILLEGIBLE]
Title: President
Date: February 23, 2004
BIONUMERIK PHARMACEUTICALS, INC.
By: /s/ XXXXXXXXX X. XXXXXXXX
Title: Chief Executive Officer
Date: effective as of February 10, 2004
ANNEXES
Annex 1: Project Description (the Proposal)
Annex 2: Specification of Compound
Annex 3: Specification of Starting Materials
Annex 4: Form of Certificate of Analysis
Annex 5: Procedures for Release of Compound
Annex 6: RPS Wire Transfer Information
Annex 7: Validation Schedule and Timeline; Storage Conditions
Annex 8: Certificate of Insurance for RPS and BioNumerik
Annex 9: List of Critical Raw Materials
Annex 10: Qualifying Batch: Critical Success Criteria
19
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PROPOSAL
QUALIFICATION OF BNP7787
(Proposal ANNJMC20021211-A)
[GRAPH]
PREPARED FOR:
BIONUMERIK PHARMACEUTICALS, INC.
0000 XXXXXXXXX XXXXX - XXXXX 000
XXX XXXXXXX, XX 00000
Proposal #ANNJMC20021211-A November 7, 2003
[RHODIA LOGO]
CONTENTS
PAGE
----
1. EXECUTIVE SUMMARY 3
2. PROPOSAL 4
3. ESTIMATED PRICE/KEY ASSUMPTIONS 8
4. SCOPE OF WORK/DELIVERABLES 12
5. TIMELINE 12
6. COMMUNICATION 13
7. CONTACT 13
8. ACCEPTANCE 14
9. APPENDIX 15
Proposal #ANNJMC20021211-A November 7, 2003 Page 2 of 17
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1. EXECUTIVE SUMMARY
BioNumerik Pharmaceuticals, Inc. ("BioNumerik") is currently in development with
BNP7787, also known as Tavocept(TM), a chemoprotectant intended for use to
neutralize the toxic side-effects of a number of major anticancer drugs -
including platinum and taxane drugs. Currently BioNumerik has established a
long-term supply agreement with Sumika of Japan, but is interested in securing a
second supplier. The FDA has recently given BNP7787 fast-track designation, and
the clinical trial program for BNP7787 is currently in Phase III. BioNumerik has
requested Rhodia Pharma Solutions Inc. ("RPS") to provide price and timeline
estimates for lab evaluation/tech transfer, qualification batches, validation
batches, and commercial batches of BNP7787.
RPS has considered the above requests and offers the following proposal based on
the technical data and requirements supplied by BioNumerik. A firm timeline for
the activities described will be provided after approval and suitable
discussions between RPS and BioNumerik.
RPS proposes a four-phase project (the "Project") to be conducted at RPS'
[**]facility:
Phase 1: Lab familiarization, tech transfer, and hazard evaluation
Phase 2: Qualification campaign (up to 2 x [**])
Phase 3: Validation campaign (3 x [**])
Phase 4: Commercial batches
RPS has agreed that the price for Phase 1 of the project on a [**] will be:
Phase 1: Lab familiarization/Tech transfer [**]
Proposal #ANNJMC20021211-A November 7, 2003 Page 3 of 17
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WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
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RPS has agreed that the price for Phases 2-4 of the project on a [**] will be,
subject to the other provisions of this Proposal and to the terms and conditions
contained in the Agreement for Manufacturing and Supply of BNP7787 between RPS
and BioNumerik (the "Agreement"), to which Agreement this Proposal is attached
as Annex 1:
Phase 2: Qualification campaign [**]
Phase 3: Validation campaign [**]
Development support [**]
Phase 4: Commercial batches [**]
[**]
[**] [**]
Proposal #ANNJMC20021211-A November 7, 2003 Page 4 of 17
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WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTION.
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2. PROPOSAL
The process used to prepare BNP7787 is shown below:
SCHEME 1. SYNTHESIS OF BNP7787
Proposal #ANNJMC20021211-A November 7, 2003 Page 5 of 17
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RPS will conduct the Project in the phases described below:
PHASE 1: TECHNOLOGY TRANSFER AND FAMILIARIZATION
BioNumerik developed and scaled this process in-house before entering into
BioNumerik's agreement with Sumika. As part of transferring the process to RPS,
there are several necessary activities.
RPS would expect to receive copies of all batch records and process development
/ hazard evaluation reports for review along with analytical standards, markers,
and analytical methods used in the manufacturing process. This will allow the
technical team from RPS to become familiar with the process and permit the
analytical method transfer to commence. A technical exchange with a team from
BioNumerik originally involved in the development /operation of this process
would allow RPS to assess and highlight to BioNumerik any significant deviations
from the original scope before commencing manufacture.[**].
NOTE: Should the tech transfer information received from BioNumerik be, in RPS'
opinion, insufficient to enable RPS to safely and efficiently transfer the
process to the RPS plant, a new work plan going forward will be discussed
(including tasks and appropriate charges) and agreed by RPS and BioNumerik with
the goal of getting the process into the plant.
RPS has sourced raw material suppliers. If so desired, BioNumerik may wish RPS
to procure raw materials from these suppliers or find other suppliers.
Proposal #ANNJMC20021211-A November 7, 2003 Page 6 of 17
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WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
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PHASE 2: SITE QUALIFICATION
Based on the process flow sheet, BioNumerik's preferences, and the need to
isolate an API at scale in a Class 10,000 isolation area, [**] is the site of
choice for qualification with respect to the Project. RPS believes that the
BioNumerik process is a good fit for the A3 plant at [**]. This site has also
been considered as the site that could accommodate the possible manufacture of
up to [**] of BNP7787 if desired by BioNumerik in the future.
After completion of Phase 1, the following qualification strategy would be
implemented (timing subject to change based on BioNumerik's strategic plan):
- Qualification campaign - cGMP preparation of up to 2 batches of
approximately [**] each to be used to support Phase III clinical
trials. [NOTE: should RPS feel that more than two batches of BNP7787
need to be prepared to meet the acceptance criteria, all batches
prepared above and beyond the first two will be prepared at RPS'
expense]. Target batch size is [**]. Development necessary to
support the campaign is included in Phase 1. Should the first batch
be prepared under conditions deemed successful based on critical
success criteria (included in Appendix 10 to the Agreement), the
second batch may be eliminated. Pricing for this work will be [**]
with a maximum BioNumerik spend of [**] for the total qualification
material.
Hazard Evaluation studies would also be undertaken by RPS to ensure the process
will be as safe as possible during scale-up.
As BioNumerik will require [**] of stability data prior to initiation of the NDA
submission, RPS has the option of generating material in 2004 with a view toward
obtaining [**] stability data which would satisfy BioNumerik's timeline and
which could be included with the BNP7787 submission document (currently
estimated for as early as approximately [**]. This program of work is based on
the expectation of carrying out full stability studies (5-year study to ICH
guidelines) on the final API (BNP7787). The assumption is that there will be no
intermediate stability studies required since this is a "one-pot" process where
no intermediates are isolated.
Details of the 2 x [**] qualification campaign are summarized below.
TABLE 1. DETAILS FOR 2 X [**] BNP7787 QUALIFICATION CAMPAIGN IN 2004
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COMMISSIONING/CLEANOUT
STAGE DAYS PROCESSING DAYS
----- ---------------------- ---------------
API 12 12
PHASE 3: VALIDATION BATCHES
Upon successful completion of the 2 x [**] batch qualification campaign, RPS
would then validate the process according to BioNumerik's timeline. RPS will
prepare three validation batches of [**] each to prepare a total of approx.
[**]. Target batch size is [**] RPS will endeavor to complete the three
validation batches during late [**] but cannot guarantee the precise timing. In
the event RPS is not able to prepare such batches by late [**], RPS will so
advise BioNumerik and RPS will then work expeditiously to complete such batches
as soon thereafter as reasonably possible within a time-frame described to and
coordinated with BioNumerik. Before these are initiated, however, an additional
round of development work may be required to address any issues identified in
the process after the qualification campaign. The effect of these changes and
their impact on registration would need to be agreed between RPS and BioNumerik
before any additional work by RPS occurred.
Pricing for the Phase 3 validation batches will be [**] and BioNumerik will be
invoiced for this work in [**], with payment deferred until [**]. An
additional [**] will be charged for chemist support for the validation campaign.
BioNumerik will be invoiced for this chemist support work in 2004, with payment
expected in [**].
Details of the validation campaign are summarized below.
TABLE 2. DETAILS FOR 3 X [**] BNP7787 VALIDATION CAMPAIGN IN 2004
COMMISSIONING/CLEANOUT
STAGE DAYS PROCESSING DAYS
----- ---------------------- ---------------
API 7 18
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THE OMITTED PORTIONS.
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PHASE 4: COMMERCIAL BATCHES
Following successful completion of the validation campaign, RPS would
progress the process to commercial scale with the capability of preparing
[**][**] and [**] commercial batches based on such amounts as BioNumerik may
request in the future. Details for these commercial batches are summarized below
(potential amounts for illustration purposes only).
[**]
Note: Based on BioNumerik's requirements, RPS can offer flexibility in batch
size. Batch sizes of [**] and [**] can be generated at BioNumerik's request. In
order to achieve the [**] batch size, RPS suggests two options:
- Two successive [**] batches would be combined on a large Rosenmund
filter, then slurried together to form the [**] batch.
-
- Replacement of key vessels to allow the preparation of a discrete
[**] batch.
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THE OMITTED PORTIONS.
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3. ESTIMATED PRICE/KEY ASSUMPTIONS
PHASE 1: TECHNOLOGY TRANSFER AND FAMILIARIZATION
[**]
PHASE 2: QUALIFICATION CAMPAIGN
[**]
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THE OMITTED PORTIONS.
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PHASE 3: VALIDATION CAMPAIGN
[**]
PHASE 3: DEVELOPMENT SUPPORT
[**]
PHASE 4: COMMERCIAL BATCHES (POTENTIAL AMOUNTS FOR
ILLUSTRATION PURPOSES ONLY)
[**]
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THE OMITTED PORTIONS.
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SODIUM 2-BROMOETHANESULFONATE TARGET PRICE/VOLUME INDICATIONS
[**]
THIOACETIC ACID TARGET PRICE/VOLUME INDICATIONS
[**]
TYPICAL STABILITY STUDY PRICES
[**]
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THE OMITTED PORTIONS.
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KEY ASSUMPTIONS:
- The process will operate in line with the batch records supplied (when
available) in terms of processing time and yields.
- Validated analytical methods will be supplied during the technical
transfer.
- Markers and reference standards will not have to be synthesized.
- Raw materials are readily available from sources identified to date and
safe to handle.
- 50 Kilogram heel loss on the Rosenmund vessel is assumed.
- Microbiological analysis will be conducted offsite at a rate of [**]
Endotoxin testing will be conducted onsite using a purchased-in kit.
- The high bromide and sulfur content of the aqueous waste stream will
necessitate offsite incineration. Guideline disposal price is [**] waste.
- Target prices for sodium 2-bromoethanesulfonate and thioacetic acid are
achievable.
The actual charges for BioNumerik's account will be invoiced as described in the
Manufacture and Supply Agreement, with payment due net 30 days from invoice
date. A down payment as described in the Manufacture and Supply Agreement is due
upon acceptance of this proposal. This payment will be used to purchase starting
materials, with any balance credited towards the final billable work performed
on this project. All deliveries will be FOB, U.S.A. main port basis. Shipments
will be made by air unless otherwise agreed by RPS and BioNumerik.
Prior to the start of the Phase 2 qualification campaigns, the A3 plant must be
re-engineered to accommodate the process. RPS estimates it will take
approximately four months to effect the engineering work and to complete the
validation of the USP water system in A3. The majority of the engineering work
will be required to handle the pure water system and pressurized oxygen. The
specifics of the re-engineering process can be summarized as follows:
ITEM
Pure water ring main installation and tie in to three units
Oxygen gassing station
Transfer lines, tracing, lagging, & flow control, support
Design and Maintenance support
Electrical & Instrumentation
Proposal #ANNJMC20021211-A November 7, 2003 Page 13 of 17
[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
[RHODIA LOGO]
CAPITAL RECAPTURE CLAUSE
RPS' goal is to supply approximately [**] of BNP7787 prepared and delivered at
commercial scale under cGMP conditions over a period of approximately [**]. We
hope that this will be followed by a launch stock order of at least [**] RPS
will provide the approximately [**] in capital spend required to fit the process
into our plant. This plan allows RPS to spread out our internal capital spend
over enough batches to allow us to offer BioNumerik close to commercial pricing
for qualification and validation batches. Should BioNumerik decide to change the
scope of the project and order less than [**] total within [**] after the
effective date of the Agreement (including qualification, validation, and
commercial batches), RPS will attach a capital recapture fee of [**] for the
difference in what was ordered and [**] plus an additional [**] to cover the
discount on the Phase I work (reduced from [**]), up to a maximum capital
recapture fee and additional payment of [**] in the aggregate to be paid by
BioNumerik. A worked example is displayed below. In addition, the amount of any
recapture fee and additional payment paid by BioNumerik to RPS pursuant to the
foregoing provision shall be fully credited against and applied to the
satisfaction of the cost of any order for Compound made by BioNumerik within six
months after payment of such recapture fee and additional payment. Of course, in
the event that the project proceeds as expected and a minimum of [**] is ordered
(including qualification, validation, and commercial quantities), no additional
charge is payable since all capital expenses are amortized over the campaign.
EXAMPLE:
BioNumerik cancels the project having ordered a total of [**] including
qualification, validation, and commercial quantities.
Material delivered to date: [**]
Minimum total order required: [**]
Capital Recapture fee and additional payment is:
[**]
Proposal #ANNJMC20021211-A November 7, 2003 Page 14 of 17
[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
[RHODIA LOGO]
4. SCOPE OF WORK/DELIVERABLES
RHODIA PHARMA SOLUTIONS WILL:
- Perform tech transfer, laboratory evaluation and familiarization
experiments on the process.
- Execute the qualification campaign to prepare up to 2 x [**] of BNP7787
under cGMP conditions (and all other applicable requirements described in
the Agreement) in the A3 plant at the RPS [**] facility.
- Execute a validation campaign to prepare three validation batches
(approximately) [**] of BNP7787 under cGMP (and all other applicable
requirements described in the Agreement) in the A3 plant at the RPS [**]
facility.
- Prepare commercial batches, quantity to be selected by BioNumerik.
- Provide written status reports on a monthly basis with teleconferences
and/or meetings to be organized as agreed appropriate.
- Provide copies of master batch records used in the plant.
- Provide written reports summarizing all phases of the work undertaken on
the project.
- Provide a hazard evaluation report.
- Comply with all other obligations of RPS described in the Agreement.
BIONUMERIK WILL:
- Subject to the provisions of the Agreement, BioNumerik shall purchase from
RPS and RPS shall supply, at the prices contained in the Agreement and
this Proposal, a minimum of [**] of BioNumerik's annual actual commercial
requirements of the Compound beginning with commercial launch of the
Product (as defined in the Agreement) and continuing for not less than
five years after commercial launch of the Project.
- Agree to a final product release specification prior to scale-up
activities.
- Provide any relevant health, safety, and environmental information.
- Provide any hazard information pertaining to the process that BioNumerik
has available.
- Provide any samples that are available to assist RPS in polymorph
determinations and analytical support.
- Provide batch records / development reports for the process and arrange
for technical discussion / transfer of information from Sumika.
- Comply with all other obligations of BioNumerik described in the
Agreement.
Proposal #ANNJMC20021211-A November 7, 2003 Page 15 of 17
[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
[RHODIA LOGO]
5. TIMELINE
Work on Phase 1 could begin immediately at RPS upon acceptance of this proposal
and receipt of suitable starting materials. RPS expects work on Phase 1 to be
complete within approximately 8 weeks of initiation. Prior to scale-up in the A3
plant at [**] a four-month lead time will be necessary to complete needed
re-engineering to accommodate the process.
6. COMMUNICATION
An RPS technical project manager will be appointed to handle technology transfer
and technical interface issues for the project. An RPS product manager will
coordinate all timeline and financial aspects of the project with BioNumerik.
7. CONTACT
For additional information or questions, please contact:
Xxxx Xxxxxxx
Manager, Business Development
Rhodia Pharma Solutions
0000 Xxxxxxx Xxxxx
Xxxx, XX 00000
Phone: 000.000.0000
Mobile: 000.000.0000
Fax: 000.000.0000
Email: xxxx.xxxxxxx@xx.xxxxxx.xxx
Proposal #ANNJMC20021211-A November 7, 2003 Page 16 of 17
[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
[RHODIA LOGO]
8. ACCEPTANCE
Please indicate BioNumerik's acceptance of this proposal by returning a signed
copy or a purchase order, referencing Proposal #ANNJMC20021211-A to Xxxx
Xxxxxxx. This proposal is valid for 30 days.
BIONUMERIK PHARMACEUTICALS, INC.
By: XXXXXXXXX X. XXXXXXXX
------------------------------- Date: effective as of February 10, 2004
Title: Chief Executive Officer
RHODIA PHARMA SOLUTIONS, INC.,
On behalf of itself and its subsidiary, Rhodia Pharma Ltd.
By: [ILLEGIBLE] Date: February 23rd, 2004
-------------------------------
Title: President
Proposal #ANNJMC20021211-A November 7, 2003 Page 17 of 17
[RHODIA LOGO]
9. APPENDIX
QUALIFICATION BATCH: CRITICAL SUCCESS CRITERIA
[**]
[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
ANNEX 2: SPECIFICATION OF COMPOUND
[**]
[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
ANNEX 3: SPECIFICATION OF STARTING MATERIALS
[**]
[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
ANNEX 4: FORM OF CERTIFICATE OF ANALYSIS
CERTIFICATE OF ANALYSIS
Product Name:
Material No.
Inspection Lot No:
Batch No:
Date of Analysis:
Retest Date:
Manufacturer: Rhodia Pharma Solutions [**]
Tested by: Rhodia Pharma Solutions [**] unless indicated otherwise
TEST SPECIFICATION RESULTS
Prepared by:____________________ ____________________
Date: Approved by: Date:
[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
ANNEX 5: PROCEDURES FOR RELEASE OF COMPOUND
STANDARD OPERATING PROCEDURE
Page 1 of 8
OPERATING PROCEDURE FOR FINAL PRODUCTS FOLLOWING
COMPLETION OF PROCESSING
REFERENCE NO: ASOP008C/057 REV 1
REVISED: DECEMBER 2003
REPLACES: ASOP008C/46; ASOP008C/51; ASOP008C/54; AGMP3; AGMP58; AGMP59
REVIEW PERIOD: 2 YEARS (UNLESS SUPERSEDED)
EFFECTIVE DATE: 19 DECEMBER 2003
Prepared by: _____________________________________ Date ________________
Operational Quality Manager [E Xxxxxx]
Reviewed by: _____________________________________ Date ________________
Operational Quality Manager [A Xxxxx]
Approved by: _____________________________________ Date ________________
Laboratory Manager [J Xxxxxxx]
Approved by: _____________________________________ Date ________________
Process Manager [S R Xxxxxxxx]
Approved by: _____________________________________ Date ________________
Quality Manager [I R Lisle]
ASOP008C/057 REV 1 Page 2 of 8
CONTENTS
1.0 INTRODUCTION............................................ 3
2.0 DEFINITIONS............................................. 3
3.0 RESPONSIBILITIES........................................ 3
4.0 PROCEDURE............................................... 3
4.1 MANUFACTURING ACTIVITIES....................... 3
4.2 ANALYTICAL ACTIVITIES.......................... 3
4.3 OQ ACTIVITIES.................................. 4
5.0 DOCUMENT REVISION HISTORY............................... 6
6.0 DISTRIBUTION LOCATION................................... 7
TRAINING NEEDS MATRIX FOR DOCUMENT INTRODUCTION.................. 8
ASOP008C/057 REV 1 Page 3 of 8
1.0 INTRODUCTION
This procedure applies to all final products made at Rhodia Pharma Solutions,
[**]. It specifies how batches are off-loaded, sampled, labelled, analysed and
sentenced.
2.0 DEFINITIONS
QC - Quality Control
OQ - Operational Quality
3.0 RESPONSIBILITIES
See details within the individual parts of the procedure section.
4.0 PROCEDURE
4.1 MANUFACTURING ACTIVITIES
Manufacturing inform the Quality Department when a batch of final product is to
be off-loaded. The Quality Department reserve the right to be present during
off-loading to ensure that the correct procedures are followed.
Final product is off-loaded under controlled conditions via suitable off-loading
equipment e.g. glove-box, containment booth or cleanroom. Specific sampling and
off-loading requirements for each product are detailed in the relevant
manufacturing logsheet/manufacturing guide. The samples are clearly labelled and
delivered to the QC department for analysis.
When off-loaded, the filled containers have a unique sequentially numbered
product label attached to them by manufacturing which specify the identity,
batch number, container number, gross, Tare and nett weights.
Following offloading and sampling, the containers are sealed by manufacturing
using uniquely numbered metal security seals. The seal numbers are recorded on
the ancillary logsheet. The containers are then transferred to the S12
warehouse, or the drum park as appropriate. The logsheet is signed to indicate
that the off-loading activities are complete. Note: should a container need to
be re-sampled it will be checked for cleanliness and returned to the off-loading
area. Sealed containers may only be opened with the permission of the OQ
Department in line with POP 01/00.
Manufacturing enters the batch weight into SAP, which automatically transfers
the batch to QI status.
4.2 ANALYTICAL ACTIVITIES
On receipt of the product samples from manufacturing, QC will designate (as
labelled) one sample as a keeping sample, which will be stored for possible
future reference.
The QC analyst will then generate "inspection Instructions" from SAP and the
remaining sample will be analysed according to the correct method reference.
Note that if an MGA is operative, extra testing may be required (see
ASOP015C/007 - Manufacturing Guide Amendment Procedure).
[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
ASOP008C/057 REV 1 Page 4 of 8
As the analytical tests are carried out the results are calculated and then
checked by a second person. Test results will be evaluated against an approved
specification. Any tests, which fail to meet the defined acceptance criteria,
are dealt with in accordance with SOP016A/001 - Out of Specification Procedure.
When analysis on the batch is complete, the results are entered onto the SAP
system. An Inspection Report is then generated by SAP, signed by the analyst and
the data checked by a second person. The analyst, checker or third person signs
to indicate that the analysis has been completed correctly.The inspection report
is then passed to Operational Quality.
4.3 OQ ACTIVITIES
The correct usage decision (or sentence) for any batch depends on both its
manufacturing history and analysis. Rhodia Pharma Solutions Operational Quality
are responsible for carrying out the checks specified below and for ensuring
that the correct usage decision is made.
OQ carry out the following checks:
- Check batch documentation in line with the requirements of the relevant
part of ASOP008F/002. If satisfactory, sign the SAP Inspection Report to
indicate that the manufacturing documentation has been completed
correctly.
- Check whether the batch was subject to an MGA and confirm that all
outstanding actions which impact the usage decision have been assessed and
closed out.
- Confirm that any records associated with the manufacture of the batch are
present, e.g. in-process analysis.
- Review any PDRs associated with the batch and assess their impact on the
usage decision with particular reference to the likely impact on quality,
any violations of regulatory submissions and impact on validation and
critical parameters.
- Ensure that the analytical data and inspection report are available and
have been reviewed and approved by the Analytical Department.
- Check whether the batch is within specification.
- Review any Out of Specification Reports and ensure that a full and
thorough investigation has been made and the correct conclusions drawn.
- If the batch is out of specification ensure an OOSIR has been completed
(see above). Also, ensure that a process investigation report (PIR) has
been completed, which identifies the cause of the failure, corrective
action to prevent recurrence and which recommends from a technical
viewpoint how the batch should be sentenced. Assess the regulatory,
validation and cGMP aspects of such a recommendation prior to making a
usage decision. OQ sign off the PIR.
- Inform the customer of significant deviations/issues as required by the
relevant agreements.
- Ensure that any issues affecting inputs to the batch are fully accounted
for.
ASOP008C/057 REV 1 Page 5 of 8
The Operational Quality Manager then sentences the batch, taking into account
all of the above information. The correct usage decision is entered on the SAP
inspection report and the report then signed and dated. The Operational Quality
manager then enters the usage decision into SAP.
A batch release checklist is used to facilitate and record the OQ checking
associated with each batch of final product. (See Appendix 1).
Analytical data is available to Manufacturing via the SAP system. The Inspection
Instructions, computer output and ancillary logsheet are filed in the Quality
Department archives.
ASOP008C/057 REV 1 Page 6 of 8
5.0 DOCUMENT REVISION HISTORY
DATE SEQUENTIAL CODE ALTERATIONS, ADDITIONS, OMISSIONS
December 2003 ASOP008C/057 REV 1 First Issue - a general SOP for final product
operations following processing replaces
specific products SOP's.
ASOP008C/057 REV 1 Page 7 of 8
6.0 DISTRIBUTION LOCATION
File Locations [**]
A Operational Quality (Masters of all documents)
B Analytical Services (shift lab)
C Pilot Plant
D [**] 1 (Manufacturing/Engineering)
E [**] 2 (Manufacturing/Engineering)
F ADG
G R&D Main office (to hold documents for
Safety/Engineering/Finance/Accounts/ Human
H Resources/Purchasing/Planning/Commercial/Customer Services
I Central Engineering
J Warehouse
K PPG
K 1. Point of Use [specify]
2. Point of Use [specify]
3. Point of Use [specify]
File Locations [**]
A Operational Quality File
B Shift Managers Office
C General Admin Building (Master)
D S12 Stores
E Engineering Records Office
F 1. S3
2. QC Labs
3. Point of Use [specify]
File Locations [**]
A Quality Assurance (copy from [**])
B Engineering
C GPP
D Orion
E Building 44
F Lyra
G 1. Point of Use [specify]
2. Point of Use [specify]
3. Point of Use [specify]
File Locations [**]
A Quality Assurance (copy from [**])
B 4. Point of Use [specify]
5. Point of Use [specify]
6. Point of Use [specify]
[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
ASOP008C/057 REV 1 Page 8 of 8
TRAINING NEEDS MATRIX FOR DOCUMENT INTRODUCTION
DOCUMENT STAFF GROUP
-------- -----------
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Key-Staff Group Requirements Code
1. QC
2. OQ NC No changes to document after two yearly review, training not relevant.
3. Validation NAR No awareness required. Document is not directly relevant to the staff group.
4. Production Shift Managers A Individuals have read the updated or new document but no demonstration of competency is
required.
5. Process Operators B Individuals have been briefed by local/line manager ie overview with changes highlighted.
6. Pilot Plant Technicians C Off job training in SOP with knowledge assessed.
7. Production Team Leaders D Off job training with knowledge and skills competency assessed
8. Plant Eng/Plant Mgrs/Ops Mgrs
9. Maintenance staff -
Inst/Elec/Mech
10. Projects
11. Engineer Projects
12. Project Managers
13. PPG
14. SHE
15. Supply Chain/Purchasing DATE EFFECTIVE:__________________________________________________________________
16. R&D Chemists
17. IT SIGNED:___________________________________________DATE:____________________________________
18. Accounting
APPENDIX 1 TO ASOP008C/057 REV 1
FINAL PRODUCT BATCH RELEASE CHECKLIST
PRODUCT:___________________________ BATCH NO:_________________________
INITIALS DATE COMMENTS/NUMBERS
Logsheet reviewed and approved by OQ? Y N
Computer report reviewed and approved by
OQ? Y N N/A
Trends reviewed and satisfactory? Y N N/A
In-process analysis available and
satisfactory? Y N
Do any MGAs apply?
If YES are all actions relating to
batch complete? Y N N/A
Any controlled MGAs? Y N
PDRs raised as necessary and signed off by
OQ? Y N N/A
INITIALS DATE COMMENTS/NUMBERS
Analytical data available? Y N
Batch in specification? Y N
Analytical investigations completed? Y N N/A
Any other investigations completed? Y N N/A
Process investigations completed? Y N N/A
Check inputs for market restrictions and
issues affecting the usage decision Y N N/A
DETAILS COMMENTS
Batch weight/yield
Usage decision
Signed: ____________________________________ Date: ___________________________
Containers Labelled: _______________________ Date: ___________________________
(if stored in drum park)
53
ANNEX 6: RPS WIRE TRANSFER INFORMATION
HSBC
Newcastle upon Tyne City Branch
Account Number: 00000000 (605-480771-130)
IBAN CODE: XX00 XXXX 0000 0000 0000 00
Swift Code: XXXXXX00
ANNEX 7 (2 Pages): VALIDATION SCHEDULE AND TIMELINE; STORAGE CONDITIONS
Graphic image of Timeline for tasks for calendar years 2004 through 2006
[**]
[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
ID TASK NAME
--- ----------------------------------------
1 Engineering Activity [**]
2 Project Kick Off [**]
3 CAR Approval [**]
4 CAR preparation [**]
5 CAR review [**]
6 CAR Submission [**]
7 CAR Approval [**]
8 Process development [**]
9 Lab Evaluation [**]
10 Hazard Evaluation [**]
11 Fixed process outlines for HAZOP [**]
12 Detailed Design [**]
13 ELD generation [**]
14 Process safety review (HAZ 2) [**]
15 Material of construction review [**]
16 DQ1/GMP review [**]
17 Process HAZOP [**]
18 Revised ELD's [**]
19 Frozen ELO's [**]
20 IPPC Application [**]
21 Process Mass Balance [**]
22 Emission Calculations [**]
23 BAT Defination [**]
24 Application Preparation [**]
25 Application Submission [**]
26 Application Approval Process [**]
27 Application Approved [**]
28 Layouts/Plot Plan [**]
29 Isometric Production [**]
30 Issue lsometrics-Building [**]
31 Software [**]
32 Phase Defination [**]
33 Recipe Preparation [**]
34 Hardware [**]
35 Recipe testing [**]
36 Procure/Order/Install/Test [**]
37 Mechanical [**]
38 Procurement of Valves and Fittings [**]
39 Previous Campaign cleanout [**]
40 Install Pipework [**]
41 First tag for tracing [**]
42 Trace heating [**]
43 Lagging [**]
44 Testing (mechanical) [**]
45 Clad tagging [**]
46 Instruments [**]
47 Supplier enquiries [**]
48 Procure in-line Instruments [**]
Project 469 Level 1 Plan
Campaign 6
Date: 05/06/03
[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
ID TASK NAME
-- -----------------------------------------------------
49 Manufacture/Deliver In-Line Instruments [???] [**]
50 Loop lost uncommissioned equipment [**]
51 Electrical installation [**]
52 Electrical testing [**]
53 HANDOVER [**]
54 Mechanically Complete [**]
55 Equipment Qualification [**]
56 IQ [**]
57 OQ1 [**]
58 OQ2 [**]
59 Engineering Complete & ready for manufacture [**]
60 API Endotox and Micro Validation [**]
61 Set up contracts with testing houses [**]
62 Complete Validation [**]
63 Complete Validation reports [**]
64 Installation Complete [**]
65 USP Water Equipment Enotox Validation [**]
66 Complete one month Intensive study [**]
67 Complete two month weekly study [**]
68 Generate validation report [**]
69 Validation Complete & Tested [**]
70 Cleanroom Validation [**]
71 Define scope of validation [**]
72 Gneemie validation [???] [**]
73 Carry out validation exercise [**]
74 Generate validation report [**]
75 Cleanroom Validation Complete [**]
76 [**]
77 MANUFACTURE [**]
78 Run first qualification batch [**]
79 Review/Release of first qualification batch [**]
80 BioNumeric review of first batch [**]
81 Run second qualification batch [**]
82 Review/Release of second qualification batch [**]
83 Bionumeric review of second batch [**]
84 Run first validation batch [**]
85 Interbatch Cleanout/Preliminary first batch analysis [**]
86 Run second validation batch [**]
87 Interbatch cleanout/Preliminary second batch analysis [**]
88 Run third validation batch [**]
89 Interbatch Cleanout/Preliminary third batch analysis [**]
90 Run fourth validation batch [**]
91 Review/Analysis of validation batches [**]
92 Release of validation campaign material and Initiate stability studies [**]
93 Completion of Stability studies (six-month accelerated) [**]
94 NDA Submission
Project: 469 Level I Plan
Campaign 5
Date: 05/06/03
[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
ANNEX 8 (3 pages): CERTIFICATE OF INSURANCE FOR RPS AND BIONUMERIK
[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
ANNEX 9: LIST OF CRITICAL RAW MATERIALS
[**]
[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
ANNEX 10: QUALIFYING BATCH: CRITICAL SUCCESS CRITERIA
[**]
[**] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN REQUESTED WITH RESPECT TO
THE OMITTED PORTIONS.
