1
Exhibit 10.26
***Text Omitted and Filed Separately
Confidential Treatment Requested
Under 17 C.F.R. Section 200.80(b)(4),
200.83 and 240.24b-2
CSUP15f.doc
November, 3rd, 1998
SUPPLY - AGREEMENT
This Agreement is made on November 3, 1998 (the "Effective Date"), by and
between
XXXXXXX PHARMACEUTICAL INC.,
whose registered office is at 000 Xxxxxxxxxx Xxxxxx, Xxxx Xxxx, Xxxxxxxxxx
00000-0000, U.S.A.
(hereinafter referred to as "XXXXXXX")
and
BOEHRINGER INGELHEIM PHARMA KG
whose registered office is at Xxxxxxxxxxxxxxxxxxx 00, 00000 Xxxxxxxx an der
Riss, Federal Republic of Germany
(hereinafter referred to as "BI PHARMA KG").
WITNESSETH
WHEREAS the parties have previously entered into the Contract Research and
Development Agreement (as such term is defined below) regarding the research and
development of a method to produce ANTI B1 in a commercial scale; and
WHEREAS BI PHARMA KG has developed and is the owner of the Process, and
WHEREAS XXXXXXX has all rights to the Product, and
WHEREAS XXXXXXX wishes BI PHARMA KG, and BI PHARMA KG agrees, to manufacture and
supply XXXXXXX with Product for commercial use, manufactured in accordance with
the Process.
NOW THEREFORE, the parties hereto agree as follows:
1. DEFINITIONS
In this Agreement the following terms shall have the meanings indicated:
1.1 "ANTI B1" means the murine antibody directed against B-cells expressing
the B-lymphoma phenotype.
1.2 "BI PHARMA KG Confidential Information" means all technical and other
information relating to the Process and to BI PHARMA KG's facilities and
associated technologies, excluding the XXXXXXX Confidential Information,
that is disclosed or supplied to, or used
1.
2
on behalf of, XXXXXXX by BI PHARMA KG pursuant to this Agreement or the
Contract Research and Development Agreement, whether patented or
unpatented, including without limitation, trade secrets, know-how,
processes, concepts, experimental methods and results, business and
scientific plans.
1.3 "BLA" means a Biologics License Application, as defined by the
regulations promulgated under the FD&C Act and the PHS Act and any
supplements thereunder, as amended from time to time.
1.4 "Bulk Product" means ANTI B1 which has been purified to a concentrated
form and can be stored in a liquid or frozen form under appropriate
conditions in accordance with the Specifications.
1.5 "Capacity" means BI PHARMA KG'S total production capacity per year based
on the basic production assumptions (see APPENDIX 1) of [...***...] per
run, reserved for manufacture of Bulk Product, Final Product and
Finished Product in accordance with the Process. Capacity shall be
sufficient to produce a maximum of [...***...] of Bulk Product per
calendar year, unless otherwise jointly agreed upon by the parties. The
Capacity shall be subject to an increase to [...***...] according to BI
PHARMA's option as laid down in Article 3.1.4 below.
1.6 "Cell Line" means the novel and proprietary cell line [...***...]
developed by XXXXXXX and provided to BI PHARMA KG pursuant to the terms
of the Contract Research and Development Agreement.
1.7 "Certificate of Analysis" shall mean a document describing testing
methods and results, the accuracy of which has been certified by the
issuing party.
1.8 "Certificate of Compliance" shall mean a document (a) listing the
expiration date and quantity of a particular batch of Bulk Product,
Final Product and/or Finished Product, (b) certifying that such batch
was manufactured in accordance with all Specifications, GMP, the
BLA/EMEA dossier for the Product (as applicable), and (c) certifying
that such batch is acceptable for manufacturer release. The agreed upon
format is attached hereto as APPENDIX 6.
1.9 "Compliance Policy of BI PHARMA KG for Biopharmaceutical Contract
Manufacturing for the U.S." means BI PHARMA KG's guidelines and
procedures for Product quality and Product release as set forth in
APPENDIX 7.
1.10 "Contract Research and Development Agreement" means the agreement
between XXXXXXX and Xx. Xxxx Xxxxxx GmbH dated October 22, 1997
regarding the development of the Process, which agreement was assigned
to Bl Pharma KG as of 01.01.1998.
1.11 "XXXXXXX Confidential Information" means the Cell Line, Product and all
technical and other information relating thereto, excluding BI PHARMA
KG's Confidential Information, that is disclosed or supplied to BI
PHARMA KG by XXXXXXX pursuant to this Agreement or the Contract Research
and Development Agreement, whether patented or unpatented, including,
without limitation, trade secrets, know-how, processes, concepts,
experimental methods and results, business and scientific plans.
1.12 "FDA" means the United States Food and Drug Administration and any
successor thereto.
*CONFIDENTIAL TREATMENT REQUESTED
2.
3
1.13 "FD&C Act" means the United States Federal Food, Drug and Cosmetic Act,
as amended.
1.14 "Final Product" means Bulk Product that has been processed, compounded
and formulated and placed in unlabeled final containers.
1.15 "Finished Product" means Final Product that has been labeled with
commercial labels affixed to the final containers and packaged under
appropriate conditions and is ready for shipment to XXXXXXX or its
designees.
1.16 "GMP" means the current regulatory requirements for good manufacturing
practices promulgated by the FDA under the FD&C Act, 21 C. F. R. et seq
and 21 C. F. R. Section 600-610, as applicable.
1.17 "Manufacturing Project Manager" shall have the meaning as specified in
Article 2.1 hereof.
1.18 "Manufacturing Project Team" shall have the meaning as specified in
Article 2.2 hereof.
1.19 "Process" means BI PHARMA KG's generic process for manufacturing Bulk
Product, Final Product and Finished Product, which has been adapted to
Product-requirements and agreed by the parties before producing Product
under this Agreement.
1.20 "Process [...***...] Agreement" means that agreement as further
described in Article 4.4 hereof.
1.21 "Product" means any product containing non-radiolabeled ANTI B1 as its
sole or combined active ingredient and produced according to the Process
whether as Bulk Product, Final Product or Finished Product.
1.22 "Product Price" means BI PHARMA KG's prices for Bulk Product, Final
Product and/or Finished Product (as the case may be) to be calculated on
the basis of the basic production assumptions set forth in APPENDIX 1.
1.23 "Project" means the activities performed under this Agreement.
1.24 "Specifications" means the specifications for Bulk Product, Final
Product and Finished Product as applicable and the respective test
methods attached hereto as APPENDIX 3 on the basis of the specifications
provided by XXXXXXX.
Such Specifications may be amended from time to time by mutual agreement
of XXXXXXX and BI PHARMA KG according to further development of the
Process and Product (e.g. according to the results of the Process
[...***...] Agreement). The Specifications may vary from country to
country as agreed upon by the parties.
2. COOPERATION BETWEEN THE PARTIES / PROJECT TEAM
2.1 DESIGNATION OF MANUFACTURING PROJECT MANAGER
Promptly after the Effective Date, BI PHARMA KG and XXXXXXX shall each
identify a Manufacturing Project Manager who will be responsible
exclusively for communicating all instructions and information
concerning the Project to the other party.
*CONFIDENTIAL TREATMENT REQUESTED
3.
4
Each Manufacturing Project Manager will be available on an agreed upon
[...***...] basis for consultation (e.g. face to face meetings,
telephone-conference, videoconference) at [...***...] times during the
course of the Project. In the absence of the Manufacturing Project
Manager of a party, a substitute shall be appointed by such party in due
time.
Additional modes or methods of communication and decision making may be
implemented with the mutual consent of each party.
2.2 MANUFACTURING PROJECT TEAM
Promptly after the Effective Date, BI PHARMA KG and XXXXXXX shall each
name representatives to a Manufacturing Project Team which shall consist
of knowledgeable specialists in appropriate disciplines who shall be
responsible for overseeing all activities of the parties under this
Agreement.
During the term of this Agreement, the Manufacturing Project Team shall
meet [...***...] in a face to face meeting, for the purpose of
communicating updates and providing a forum for decision making and
rapid resolution of issues arising under this Agreement. Additional
meetings (if required) of the Manufacturing Project Team may be
conducted by telephone-conference, videoconference and/or face to face
meetings.
Meeting minutes shall be prepared jointly by the Manufacturing Project
Team to record all issues discussed and decisions made. The present list
of the members of the Manufacturing Project Team is attached hereto as
APPENDIX 4.
The members of the Manufacturing Project Team may be changed from time
to time as appropriate.
2.3 COOPERATION.
In the course of the Project, BI PHARMA KG will at all times take into
consideration and implement the recommendations of XXXXXXX as long as
they do not adversely affect BI PHARMA KG's ability to perform other BI
PHARMA KG biotech operations and are agreed upon by the Manufacturing
Project Team. In the absence of explicit instructions from XXXXXXX, BI
PHARMA KG shall be entitled to employ its reasonable judgment in
carrying out the Project consistent with BI PHARMA KG's overall
obligations under this Agreement and consistent with the BLA and the
EMEA application.
2.4 FDA OR OTHER AUTHORITIES INTERACTION.
BI PHARMA KG has the express right to send representatives to any
meeting of or on behalf of XXXXXXX with the FDA for discussions
(regarding the CMC-part of BLA) involving the Product or BI PHARMA KG's
facilities. BI PHARMA KG shall have reasonable advance notice, if
possible, of at least 30 (thirty) days before any meeting scheduled with
the FDA. Any FDA and EMEA correspondence regarding the Product or
facilities shall be approved by BI PHARMA KG prior to submission, such
approval not to be unreasonably withheld.
2.5 ACCESS TO FACILITIES.
*CONFIDENTIAL TREATMENT REQUESTED
4.
5
BI PHARMA KG shall permit XXXXXXX and its representatives or
consultants, upon reasonable prior notice to BI PHARMA KG, to audit and
to review the originals of all batch records and other primary documents
at its facilities [...***...] as set forth in APPENDIX 7.
While at any facility, the respective XXXXXXX personnel and its
representatives or consultants shall comply with all security and safety
policies and procedures of the facility owner.
3. SUPPLY
3.1 SUPPLY / PURCHASE OBLIGATIONS
3.1.1 Provided the Product is approved by the FDA to be biologically
equivalent to Anti-B1 product produced by Lonza, BI PHARMA KG will
manufacture and supply Product to XXXXXXX [...***...] (where and as
approved by appropriate regulatory authorities) during the full term of
this Agreement. XXXXXXX agrees to use all commercially reasonable
efforts to secure such approval by the FDA and other appropriate
regulatory authorities.
In case the Product is not approved by the FDA to be biologically
equivalent XXXXXXX shall use all commercially reasonable efforts
(including if necessary a clinical study required by the FDA) to apply
for a BLA in order to qualify the BI PHARMA KG Product to be equivalent.
With respect to manufacturing issues BI PHARMA KG shall use all
commercially reasonable efforts to secure biological equivalence of the
Product on the basis of the Process. In this case [...***...] shall be
valid as of the time FDA approval of equivalence has been made.
Except as set forth in Articles 3.1.2, 3.1.3 and 3.2.2 below and
provided, the parties execute a Process [...***...] Agreement, XXXXXXX
will purchase and [...***...] to purchase [...***...] of Product from BI
PHARMA KG throughout the world for the period of this Agreement
provided, however, XXXXXXX may, after agreement with BI PHARMA KG which
shall not be unreasonably withheld, enter into an agreement with
[...***...] to have such [...***...].
XXXXXXX will collaborate with BI PHARMA KG as appropriate, with respect
to the manufacturing and control section of each regulatory filing in
determining the detailed regulatory filing strategy. The parties agree
to a single BLA, unless mutually agreed upon otherwise. Further the
parties agree to cooperate in seeking regulatory approval from the
appropriate regulatory authorities in the US and with EMEA.
3.1.2 In case BI PHARMA KG is not able, despite its reasonable efforts to
supply [...***...] according to the forecast system set forth in Article
3.3 below and within its respective Capacity, then XXXXXXX shall have
the right to establish and maintain [...***...] for additional material.
3.1.3 Notwithstanding anything in this Agreement, XXXXXXX shall [...***...] to
have [...***...] for [...***...] of [...***...] to be [...***...] for a
[...***...].
In case registration of BI PHARMA KG as manufacturer of Product at the
FDA has [...***...], the [...***...] of XXXXXXX shall [...***...] to
[...***...] for [...***...] the respective [...***...].
In case XXXXXXX [...***...] XXXXXXX shall use all commercially
reasonable efforts to ensure that and be solely responsible for a
[...***...] of BI
*CONFIDENTIAL TREATMENT REQUESTED
5.
6
PHARMA KG Product [....***....] containing ANTI
B1 from one source with respect to treatment of an individual patient
(i. e., [...***...] of product per patient).
XXXXXXX shall indemnify and hold harmless BI PHARMA KG from any and all
damages resulting from such [...***...].
3.1.4 Subject to Article 3.2 below BI PHARMA KG undertakes to use all
commercially reasonable efforts to supply XXXXXXX with the quantities of
Product ordered by XXXXXXX according to Article 3.3 below within the
Capacity.
BI PHARMA KG shall use reasonable efforts to manufacture and deliver to
XXXXXXX all quantities of the Product beyond the binding forecasts
within its Capacity.
BI PHARMA KG shall have the option to increase the Capacity up to
[...***...] (taking effect [...***...]) by giving written notice to
XXXXXXX not later than [...***...]. This option is subject to XXXXXXX'x
agreement in case the forecasts laid down in Appendix 5 hereto (for the
entire world) are decreased by XXXXXXX before [...***...] by more than
[...***...] for the [...***...] and the following year.
3.1.5 If there is any loss of Product because of reasons which are out of the
reasonable control of the parties, then BI PHARMA KG shall use all
commercially reasonable efforts to manufacture within its Capacity the
missing quantities of Product at XXXXXXX'x cost.
The Product Price shall be according to the scheme laid down in APPENDIX
1 (the quantity of lost Product not to be added to the quantity per
year).
3.1.6 All manufacture of Product hereunder will be made in accordance with the
Process, GMP, BLA and EMEA requirements and will be delivered in agreed
form suitably packed as specified in the Specifications.
3.2 PRODUCTION FACILITY
3.2.1 All quantities of Product will be produced in a BI PHARMA KG production
facility that has received regulatory approval by the FDA and EMEA for
commercial scale production and deliveries. BI PHARMA KG shall take all
commercially reasonable efforts to secure approval of BI PHARMA KG's
production facility by the FDA and the EMEA and BI PHARMA KG's
obligations under Article 3.1 above are subject to such approval as the
case may be.
BI PHARMA KG will not contract out to a third party any part of the
manufacturing or the testing of Product without prior written approval
from XXXXXXX which shall not be unreasonably withheld.
3.2.2 To the extent that XXXXXXX requests that BI PHARMA KG participate in
securing regulatory approval of the manufactured Product in other
countries, then BI PHARMA KG shall seek regulatory approval of its
production facility unless such approval would require significant
change in the production facility and/or the respective SOP's used in
the manufacture of the Product.
XXXXXXX shall pay any additional costs for such approval, subject to
XXXXXXX'x prior written approval.
*CONFIDENTIAL TREATMENT REQUESTED
6.
7
If significant changes to the production facility are required by the
respective authority and if BI PHARMA KG does not agree to make such
changes at XXXXXXX'x expense, then XXXXXXX shall have the right to
[...***...].
No changes relating to the Process shall be made without the prior
written consent of XXXXXXX, such consent not to be unreasonably withheld
or delayed.
3.3 ROLLING PRODUCTION FORECASTS
3.3.1 Beginning as of [...***...] and the [...***...] XXXXXXX will provide BI
PHARMA KG with a [...***...] Product forecast planning horizon for Bulk
Product or an update thereof. The planning horizon shall start the first
day of the [...***...] which shall be [...***...] or an [...***...]
thereof.
The forecasts for the [...***...] of the planning horizon [...***...]
have to be given as Final Product forms [...***...] and/or Bulk Product
for the remaining forecast period.
3.3.2 The forecast for [...***...] are firm orders and cannot be changed. This
forecast has to be broken down to single months.
The forecast for [...***...] is a partly binding forecast which means
that the forecast can fully be changed within this period as follows:
the forecast may be increased within the Capacity, but is limited to the
following restrictions when decreased:
[...***...]
[...***...]
The forecast for [...***...] is a non-binding forecast.
The forecasts for [...***...] of the planning horizon have to be broken
down quarterly.
The rolling forecast system (including firm orders) for Bulk Product and
Final Product are laid down in APPENDICES 2 a/b.
3.3.3 Whilst the rolling forecast system is not applicable (see Article 3.3.1
above) XXXXXXX shall place all requirements for Bulk Product and Final
Product as firm orders.
3.4 [...***...] QUANtity
Beginning [...***...] for each calendar year during which Finished
Product is approved for commercial sale in the United States for the
entirety of such year, the [...***...] of Bulk Product to be bought by
XXXXXXX [...***...] shall be [...***...]. If the [...***...] the
[...***...] of Bulk Product BI PHARMA KG will [...***...] according to
Article 8.2 below.
3.5 DELIVERY / RISK OF LOSS
3.5.1 BI PHARMA KG shall make deliveries by the 10th day of the month for
which a firm purchase order is made unless mutually agreed upon
otherwise.
*CONFIDENTIAL TREATMENT REQUESTED
7.
8
BI PHARMA KG shall deliver or arrange for the delivery of the Product
purchased by XXXXXXX to a carrier designated by XXXXXXX on the basis of
EXW BI PHARMA KG's plant in Biberach, in accordance with Incoterms 1990
as published by the International Chamber of Commerce.
3.5.2 Title to the Product sold hereunder shall pass to XXXXXXX upon payment
of invoices for Bulk Product by XXXXXXX to BI PHARMA KG pursuant to
Article 8.3.2 hereto. In the event, that BI PHARMA KG maintains
inventory of Bulk Product ("Inventory") at a BI PHARMA KG facility after
XXXXXXX has been invoiced and has paid for such Bulk Product, BI PHARMA
KG shall maintain such Inventory in appropriate storage conditions for
Bulk Product as set forth under the BLA for Product and as laid down in
the Specifications regarding shelf-life.
After establishing the mutually agreed stability program BI PHARMA KG
shall be [...***...] as a result of damage that occurs prior to the
expiration of the shelf-life of such Inventory while such Inventory is
being stored by BI PHARMA KG. BI PHARMA KG [...***...], if applicable,
for [...***...] as a result of damage described in the preceding
sentence [...***...]. BI PHARMA KG's liability as to risk of loss or
damage during transportation of Product shall cease upon delivery of the
Product in good condition to the carrier designated by XXXXXXX at BI
PHARMA KG's plant in Biberach for shipment to XXXXXXX'x designee.
3.6 SUPERIORITY
No provision on XXXXXXX'x purchase order forms or in BI PHARMA KG's
General Conditions of Sale which may purport to impose different
conditions upon XXXXXXX or BI PHARMA KG, nor any other modification of
this Agreement, will be of any force and effect, unless in writing and
signed by both parties claimed to be bound thereby. In the event of any
inconsistencies, the terms of this Agreement shall govern.
4. RECORDS / DOCUMENTATION
4.1 RECORDS
BI PHARMA KG shall maintain all records necessary to evidence compliance
with all its obligations under this Agreement and relating to the
manufacture of the Product. All such records shall be maintained for a
period of not less than 3 (three) years from the date of expiration of
each batch of Product to which such records pertain, or such longer
period as may be required by law, rule, or regulation.
Prior to the destruction of any record, BI PHARMA KG shall give written
notice to XXXXXXX which shall have the right to request, receive and
retain such records with no further compensation to BI PHARMA KG.
4.2 DOCUMENTATION
BI PHARMA KG shall certify in writing, that each shipment lot of
Product, was produced and tested in compliance with (i) the
Specifications (including the respective test methods), (ii) GMP
requirements, (iii) all other applicable regulatory documents filed with
the BLA and the European regulatory filings with the EMEA, if any, in
accordance with procedures agreed between BI PHARMA KG and XXXXXXX. BI
PHARMA KG shall provide XXXXXXX upon
8.
9
request with a copy of the master batch records in English as submitted
with the BLA and one copy of one executed German-language batch record
of one representative lot.
A Certificate of Analysis appropriately signed and a Certificate of
Compliance appropriately signed by BI PHARMA KG's quality assurance
representative, as are necessary to demonstrate BI PHARMA KG's
compliance with this Article 4.2 for each shipment lot, shall be
provided to XXXXXXX with each shipment lot from BI PHARMA KG's
manufacture site.
During the [..***..] audit according to Article 2.5 above, BI PHARMA KG
shall provide to XXXXXXX access to all documentation relating to
facilities, equipment and the Process required to enable XXXXXXX to
evaluate BI PHARMA KG's compliance with GMP and the BLA, and the
respective regulatory filing with the EMEA in the manufacture of the
Product.
4.3 ADDITIONAL WORK.
On request of XXXXXXX, BI PHARMA KG shall perform additional work not
currently covered by existing agreements between the parties to sustain
the progress of the Project on conditions in terms of money, time and
scope to be subject to mutual agreement of the parties hereto.
4.4 PROCESS [...***...] AGREEMENT
BI PHARMA KG and XXXXXXX will negotiate in good faith a Process
[...***...] Agreement, subject to mutual agreement of the parties hereto
on conditions to be reasonably agreeable (with regard to timing,
capacity, cost) relating to the performance of additional work to
sustain the progress of the Project. Such Process [...***...] Agreement
shall include, but not be limited to provisions and terms relating to
[...***...], and other [...***...], however the parties agree that a
positive outcome can't be guaranteed.
5. QUALITY / INSPECTION OF PRODUCT / DEFECTIVE PRODUCT
5.1 TESTS OF THE PRODUCT AND AGREED UPON AUDITS
XXXXXXX shall have the right to carry out agreed upon customary tests of
the Product and agreed upon annual audits (not to exceed [...***...]) at
reasonable times, of the premises and facilities where BI PHARMA KG
performs work under this Agreement, and of the premises where it stores
raw materials, auxiliary materials, intermediates, packing materials for
the Product and the Product itself. The agreed upon tests of the Product
shall be included in APPENDIX 3 hereto.
5.2 LOT NUMBERING
BI PHARMA KG shall be responsible for lot numbering of Bulk Product,
using BI PHARMA KG's lot number system. BI PHARMA KG shall be
responsible for lot numbering of all Final Product and Finished Product
using BI PHARMA KG's lot numbers and lot numbering system.
All details of lot numbering will be provided by BI PHARMA KG to XXXXXXX
as needed. XXXXXXX'x lot number will also be included as needed.
*CONFIDENTIAL TREATMENT REQUESTED
9.
10
5.3 QUALITY CONTROL PROGRAM
BI PHARMA KG shall maintain a quality control program consistent with
GMP and as agreed by the parties, with respect to BI PHARMA KG's
manufacture of the Product hereunder.
5.4 PRODUCT RELEASE AND QUALITY MANAGEMENT POLICY
BI PHARMA KG shall be responsible for manufacturer release of Bulk
Product, Final Product and Finished Product according to APPENDIX 3.
Final release shall be made by and in the responsibility of XXXXXXX,
subject to the Compliance Policy of BI PHARMA KG for Biopharmaceutical
Contract Manufacturing for the U.S. as described in APPENDIX 7.
5.5 RETENTION OF SAMPLES
BI PHARMA KG shall retain a sufficient quantity of Product from each
batch to perform [...***...] quality control tests as described IN
APPENDIX 3. Retained repository samples shall be maintained in a
suitable storage facility for a period of [...***...] from the date of
expiration of each batch of the Product. All such samples shall be
available for inspection and testing by XXXXXXX or, at XXXXXXX'x
request, XXXXXXX'x designee at reasonable times and upon reasonable
notice.
BI PHARMA KG shall not use these samples except for the purposes of this
Agreement.
5.6 COMPLAINTS AND ADVERSE REACTIONS
BI PHARMA KG shall notify XXXXXXX immediately by telephone and not later
than 5 (five) working days in writing after receipt by BI PHARMA KG's
quality assurance department of any and all complaints, adverse reaction
reports, safety issues or toxicity issues relating to Product (each an
"Adverse Event Report"), regardless of the origin of such information,
BI PHARMA KG shall advise XXXXXXX of such Adverse Event Report.
XXXXXXX shall be responsible for adverse event notification to the
respective regulatory authorities regarding all such Adverse Event
Reports.
XXXXXXX'x obligation to notify BI PHARMA KG immediately by telephone and
no later than 5 (five) working days in writing of such Adverse Event
Reports of which XXXXXXX becomes aware shall extend only to those that
may have relevance to the manufacturing and supply activities conducted
by BI PHARMA KG.
The parties agree to cooperate with each other and any regulatory
authority in evaluating any Adverse Event Reports related to the
manufacture and supply of the Product.
5.7 RECALLS ETC.
XXXXXXX shall notify BI PHARMA KG immediately by telephone and within 5
(five) working days in writing if any Product is the subject of a field
alert, recall, market withdrawal or correction, and XXXXXXX and/or its
designee shall have sole responsibility for the handling and disposition
of such field alert, recall, market withdrawal or correction.
*CONFIDENTIAL TREATMENT REQUESTED
10.
11
BI PHARMA KG shall notify XXXXXXX immediately by telephone and within 5
(five) working days in writing of any information of which it becomes
aware which might reasonably be expected to require a field alert,
recall, market withdrawal or correction relating to any Product and
XXXXXXX and/or its designee shall have sole responsibility for the
handling and disposition of such field alert, recall, market withdrawal
or correction.
[...***...] shall bear the costs of all field alerts, recalls, market
withdrawals or corrections of Product unless otherwise provided for in
Article 6 hereof.
[...***...] shall solely bear the direct costs incurred in connection
with any such recall and [...***...] for any direct and reasonable costs
incurred by [...***...] in cases where such recall was caused by
[...***...] due to [...***...].
5.8 GOVERNMENTAL CONTACTS
XXXXXXX will notify BI PHARMA KG in due time but in no event later than
5 (five) working days of any governmental contact with regard to
manufacture, supply and quality control of the Product manufactured at
BI PHARMA KG and, at XXXXXXX'x discretion, regarding all other Product
and BI PHARMA KG shall have the right but not the obligation to
participate in such meetings relating to BI PHARMA KG manufacturing and
testing of the Product and approve such filings prior to submission.
BI PHARMA KG will be responsible for any reporting of matters regarding
the manufacture of Product to the FDA and EMEA in accordance with
pertinent laws and regulations of the respective countries, and will
keep Xxxxxxx informed and provide XXXXXXX with a copy of such reports
not later than the time they are filed.
BI PHARMA KG shall be responsible for handling and responding to any
appropriate German governmental agency or other regulatory authorities
inspections with respect to the manufacturing of the Product. BI PHARMA
KG shall provide to XXXXXXX any information reasonably requested by
XXXXXXX and all information correspondence and reports prepared by any
governmental agency or by BI PHARMA KG in connection with the Product.
BI PHARMA KG shall advise XXXXXXX in due time of any requests by any
governmental agency for such inspections and shall - at its sole
discretion -permit XXXXXXX or its representative to attend such
inspections/audits concerning the Product. Notwithstanding anything in
this Article 5.8 XXXXXXX shall be permitted to be onsite at BI PHARMA KG
for Product specific briefings and debriefings of the audit, if any.
5.9 DEFECTIVE PRODUCT (INCLUDING LOSS AND INACCURATE QUANTITY)
5.9.1 Claims on account of quantity, quality (i.e. compliance with
Specifications), loss or damages to the Product shall be made by XXXXXXX
in writing within [...***...] following receipt thereof, and BI PHARMA
KG's liability for damages resulting therefrom shall [...****...] for
the particular shipment with respect to which such claims are made. No
Product will be returned to BI PHARMA KG without BI PHARMA KG's written
permission.
5.9.2 If XXXXXXX claims that any shipment of Product did not at time of
delivery meet the Specifications, BI PHARMA KG shall conduct an assay of
its retained sample from such shipment. If BI PHARMA KG agrees with
XXXXXXX'x claim or if the Third Party Firm (as
*CONFIDENTIAL TREATMENT REQUESTED
11.
12
defined in Article 5.9.3 below) agrees with XXXXXXX'x claim and if BI
PHARMA KG has Product in existing stock, BI PHARMA KG shall replace such
shipment of Product [...***...] of XXXXXXX'x notice or the Third Party
Firm's determination. If BI PHARMA KG agrees with XXXXXXX'x claim or the
Third Party Firm agrees with XXXXXXX'x claim but BI PHARMA KG does not
have Product in existing stock, then at XXXXXXX'x option, BI PHARMA KG
shall [...***...].
BI PHARMA KG shall give XXXXXXX written instructions as to how XXXXXXX
should, at BI PHARMA KG's expense, either dispose of the non-conforming
material or return it to BI PHARMA KG, and such instructions shall
comply with all appropriate governmental requirements.
5.9.3 If the parties are unable to resolve their differences, then either
party may refer the matter to an independent specialized firm of
international reputation agreeable to both parties (the "Third Party
Firm") for final analysis, which shall be binding on both parties
hereto. An additional set of quality control samples will be generated
to ensure that 2 (two) full sets of retention samples are available
should the lot be released.
Any dispute resolution shall not release BI PHARMA KG from its
obligation to manufacture the required quantities of Product according
to the rolling forecast system and the Capacity.
5.10 BI PHARMA KG certifies it has not knowingly and will not knowingly use
in any capacity the services of any person, including any firm or
individual, debarred or subject to debarrment under the United States
Generic Drug Enforcement Act of 1992. BI PHARMA KG agrees to notify
XXXXXXX immediately in the event it becomes aware of any person
providing services to BI PHARMA KG under the scope of the work of this
Agreement who is debarred or becomes subject to debarrment.
6. WARRANTY / LIMITATION / INDEMNIFICATION
6.1 WARRANT
BI PHARMA KG warrants and represents that the Product to be supplied by
BI PHARMA KG hereunder including any labeling and other packaging if any
for such Product corresponds to the Specifications and shall be
produced, handled, stored, labeled, packaged according to GMP standard,
and all applicable laws and regulations of Germany, and has been
produced consistent with the Process. The Product shall be delivered
free and clear of liens and claims which affect title.
6.2 LIMITATION OF WARRANTY / LIABILITY
Except as provided in Article 6.1 above BI PHARMA KG makes no warranty
of any kind, express or implied. BI PHARMA KG shall be liable for
[...***...] and, except for [...***...], BI PHARMA KG shall [...***...].
6.3 INDEMNIFICATION BY XXXXXXX
XXXXXXX shall indemnify, defend and hold BI PHARMA KG, its affiliates,
and their respective officers, employees and agents harmless from any
damage, loss, cost or expense [...****...] relating to third party
claims or suits, including injury to persons or damage to property
arising from the packaging, use,
*CONFIDENTIAL TREATMENT REQUESTED
12.
13
marketing or sale of the Product by XXXXXXX, or its licensees or other
authorized persons or entities, which (i) [...***...], or (ii)
[...***...] and provided that upon receipt of notice by BI PHARMA KG of
any claims or suits relating to such use or sale of the Product.
BI PHARMA KG shall notify XXXXXXX thereof without delay and shall permit
XXXXXXX to handle such claims or suits at the cost and [...***...]
including but not limited to defense, settlement and compromise thereof.
6.4 INDEMNIFICATION BY BI PHARMA KG
To the extent provided for in this Article 6 BI PHARMA KG shall
indemnify, defend and hold XXXXXXX, its affiliates, licensee(s) and
their respective officers, employees and agents harmless from any
damage, loss, cost or expense [...***...] relating to third party claims
or suits, including injury to persons or damage to property arising from
BI PHARMA KG's activities under this Agreement which (i) [...***...]
(ii) [...***...] and provided that [...***...] by XXXXXXX of any claims
or suits relating to such use or sale of the Product, XXXXXXX shall
notify BI PHARMA KG thereof without delay and shall permit BI PHARMA KG
to handle such claims or suits at the cost and [...***...] including but
not limited to defense, settlement and compromise thereof.
6.5 YEAR 2000
BI PHARMA KG is currently working to ensure that the functionality and
performance of the Biberach facility and the computer systems and
computer programs which affect or may affect the manufacturing or
testing of Product hereunder will not be affected by dates prior to,
during and after the year 2000. BI PHARMA KG shall use all commercially
reasonable efforts to ensure that it will be able to fulfill the firm
orders within the Capacity under this Agreement prior to, during and
after the year 2000.
6.6 [...***...] AMOUNT
Except as set forth in Section 5.9, BI PHARMA KG's [...***...] under
this Agreement shall [...***...] the [...***...] from [...***...] and/or
XXXXXXX'x [...***...] of the respective calendar year.
7. SUPPORT REGARDING POST LICENSING ISSUES
BI PHARMA KG agrees to support XXXXXXX and its licensee(s), if
applicable, with regard to post licensing issues (e. g. possible
registration issues in the various countries) on commercially reasonable
conditions to be agreed upon, [...***...].
8. PRICE AND PAYMENT
8.1 PRODUCT PRICE
The Product Price for the Product shall be calculated according to the
scheme laid down in APPENDIX 1.
*CONFIDENTIAL TREATMENT REQUESTED
13.
14
8.2 SURCHARGE
If XXXXXXX elects not to order for purchase [...***...] of Product in a
[...***...] (i.e. [...***...] are [...***...]) as set forth in Article
3.4 above, XXXXXXX shall [...***...] according to [...***...].
In case BI PHARMA KG is not able to manufacture and supply for sale the
[...***...] of Product in a given calendar year, then XXXXXXX
[...***...] according to the [...***...].
8.3 INVOICING AND PAYMENT CONDITIONS
8.3.1 INVOICING
For Bulk Product, BI PHARMA KG will release (manufacturer release) Bulk
Product, issue a Certificate of Analysis and send an invoice to XXXXXXX.
For sterile liquid fill services as described in APPENDIX 1, BI PHARMA
KG will release (manufacturer release) Finished Product or Final
Product, issue a Certificate of Analysis and send an invoice to XXXXXXX.
8.3.2 PAYMENT
Upon receipt of an invoice from BI PHARMA KG pursuant to Article 8.3.1
above by XXXXXXX, XXXXXXX will pay within [...***...]. The Product Price
for Product delivered to XXXXXXX or according to XXXXXXX'x instructions
shall be payable by XXXXXXX within 30 (thirty) days after deliver of
Product to the respective party in DEM (Deutsche Xxxx) by wire transfer
to an account to be nominated by BI PHARMA KG.
The surcharge according to Article 8.2 above shall be payable within 30
(thirty) days after receipt of the respective invoice.
8.4 PRODUCT PRICE ADJUSTMENTS
8.4.1 The Product Price set forth in Article 8.1 above [...***...] will be
[...***...] effective at [...***...] per year for [...***...]. BI PHARMA
KG shall notify XXXXXXX of any [...***...] prior to the date such
[...***...] becomes effective.
8.4.2 In case any [...***...] (in terms of [...***...] or [...***...] for
producing Bulk Product, Final Product and/or Finished Product)
[...***...] in a given calendar year, which the requesting party must
demonstrate, the parties shall agree upon the [...***...] based on good
faith negotiations.
This amount to be [...***...] respectively to [...***...] within
[...***...] of agreement and [...***...]. Thereafter on [...***...].
8.4.3 In case that a change of the Process and/or of the Specifications
influences the basic production assumptions set forth in Appendix 1 the
Product Price shall be recalculated according to the scheme for
determining the Product Price.
8.4.4 XXXXXXX may elect whether the [...***...] according to Article 8.4.2
above is payable pursuant to a separate invoice or by [...***...] for
Bulk Product, Final Product and/or Finished Product. If XXXXXXX can
demonstrate to BI PHARMA KG that any materials used for producing Bulk
Product,
*CONFIDENTIAL TREATMENT REQUESTED
14.
15
Final Product and/or Finished Product can be [...***...]
and [...***...] and on a regular basis than BI PHARMA KG's
[...***...], then BI PHARMA KG shall accept[...***...] for
purposes of Article 8.4. Such [...***...] must be available on
a regular basis and the same quality as the materials used by BI PHARMA
KG.
8.4.5 Changes of the Process and the Specifications due to the activities
performed under the intended Process [...***...] Agreement may influence
the Product Price and the parties shall negotiate in good faith a new
Product Price.
8.4.6 The Product Price shall also be valid for any change in quantity during
the respective firm order period. However a price recalculation shall
take place if [...***...] will be [...***...] effective as agreed upon
by the parties.
8.5 CURRENCY
All payments will be made in DEM.
"Deutsche Xxxx" or "DEM" means the lawful currency for the time being of
Germany or, in case of the implementation of the European Monetary
Union, the Euro on the basis of the official conversion rate.
8.6 EURO
In the event the initial conversion to the Euro will result in a Product
Price increase of [...***...] within [...***...] after that initial
conversion, the parties will meet and negotiate in good faith a solution
to the issue of a Product Price in crease due to such conversion.
9. CONFIDENTIALITY
9.1 BI PHARMA KG
BI PHARMA KG shall not disclose XXXXXXX Confidential Information to any
person other than its employees or employees of affiliated companies of
the Boehringer Ingelheim group who have a need to know such information
in order to perform their duties in carrying out the work hereunder and
who have an obligation to maintain the confidentiality thereof under
terms at least as stringent as those provided herein.
9.2 XXXXXXX
XXXXXXX shall not disclose any BI PHARMA KG Confidential Information to
any person other than
9.2.1 its employees or consultants who are bound by similar obligations of
confidentiality and who have a need to know such information in order to
provide direction to BI PHARMA KG or evaluate the results of the work,
or XXXXXXX'x licensee(s), if applicable, solely for regulatory purposes
and only if such licensee(s) have an obligation to maintain the
confidentiality thereof under the terms at least as stringent as those
provided herein, or
9.2.2 regulatory authorities, for example, the FDA or foreign equivalent, that
require such information in order to review an IND, BLA or other
regulatory filing. BI PHARMA KG will
*CONFIDENTIAL TREATMENT REQUESTED
15.
16
be informed and must agree prior to filing of any Bl PHARMA KG
Confidential Information to regulatory authorities. In these cases where
BI PHARMA KG restricts XXXXXXX'x ability to file BI PHARMA KG
Confidential Information, BI PHARMA KG agrees to provide the
Confidential Information directly to the regulatory authorities and will
provide a letter of authorization for cross-reference to XXXXXXX.
9.2.3 persons or entities that manufacture Product for XXXXXXX after
termination of this Agreement or during this Agreement as permitted
herein and who have an obligation to maintain the confidentiality
thereof under terms at least as stringent as those provided herein.
9.3 EXCEPTIONS
The obligations of confidentiality applicable to XXXXXXX Confidential
Information and BI PHARMA KG Confidential Information shall not apply to
any information that is:
(1) known publicly or becomes known publicly through no fault of the
recipient;
(2) learned by the recipient from a third party entitled to disclose it;
(3) developed by the recipient independently of information obtained
from the disclosing party;
(4) already known to the recipient before receipt from the disclosing
party, as shown by its prior written records;
(5) required to be disclosed by law, regulation or the order of a
judicial or administrative authority; or
(6) released with the prior written consent of the disclosing party.
9.4 OTHERS
The obligations of both parties under this Article 9 shall expire ten
(10) years after expiration or termination of this Agreement.
9.5 DISCLOSURE TO THE SECURITIES AND EXCHANGE COMMISSION
In the event Securities and Exchange Commission ("SEC") rules or
regulations require XXXXXXX to disclose BI PHARMA KG's Confidential
Information, XXXXXXX shall provide to BI PHARMA KG a reasonable
opportunity to comment on such disclosures and shall thereafter promptly
inform BI PHARMA KG regarding any such disclosure.
10. LICENSE
10.1 LICENSE TO USE OF XXXXXXX CELL LINE AND INTELLECTUAL PROPERTY
XXXXXXX hereby grants BI PHARMA KG a [...***...] right and license to
use the Cell Line and XXXXXXX Confidential Information solely for the
purposes of this Agreement.
*CONFIDENTIAL TREATMENT REQUESTED
16.
17
10.2 LICENSE TO USE OF BI PHARMA KG'S INTELLECTUAL PROPERTY
BI PHARMA KG hereby grants XXXXXXX a [...***...] license, [...***...]
under this Agreement in connection with the Cell Line, the Process
and/or the Product, to use, sell, offer for sale and import Product.
Except as provided for in Article 3.1 above this license shall extend to
the Process for production of the Product after regular expiration of
this Agreement only.
10.3 NO ADDITIONAL LICENSES
Except as granted under this Agreement, no right or license, either
express or implied, under any patent or proprietary right is granted
hereunder by virtue of the disclosure of XXXXXXX Confidential
Information or BI PHARMA KG Confidential Information.
11. TERM AND TERMINATION
11.1 TERM; EXTENSION
This Agreement will come into force and effect as of the Effective Date,
and shall remain valid until [...***...] (the "Initial Term").
It will automatically extend for additional [...***...] year periods in
the absence of a written notice of termination by one of the parties to
the other.
Such written notice shall be given no later than [...***...] years prior
to the end of the Initial Term and/or any extension period.
11.2 EARLY TERMINATION
11.2.1 To the extent permitted by law, if either party shall become insolvent
or shall make assignment for the benefit of creditors, or proceedings in
voluntary bankruptcy shall be instituted on behalf of or against a party
or a receiver or trustee of all, or substantially all of the property of
a party shall be appointed, the other party shall be entitled to
terminate this Agreement by giving written notice to this effect to the
first party whereupon this Agreement shall so terminate, unless such
situation is rectified within a period of 60 (sixty) days.
11.2.2 Either party may terminate this Agreement for any material breach of
this Agreement, if such breach is not cured within 60 (sixty) days
following receipt by the party committing the breach of written notice
of the intent to terminate. Such termination shall become effective
immediately upon further notice to the defaulting party.
11.2.3 This Agreement may be terminated by XXXXXXX at any time if XXXXXXX shall
withdraw the Product from the US market. In this case XXXXXXX will pay
to BI PHARMA KG the Product Price for the firm ordered quantities (see
Article 3.3 above) of the Product. Moreover, XXXXXXX will pay to BI
PHARMA KG [...***...] as follows: for the [...***...] (which is
[...***...]) XXXXXXX will pay [...***...] (according to
[...***...])[...***...]
[...***...]
[...***...]
*CONFIDENTIAL TREATMENT REQUESTED
17.
18
These payments shall be due [...***...] after receipt by BI
PHARMA KG of the notice of premature termination from XXXXXXX and
receipt by XXXXXXX of the respective invoice from BI PHARMA KG.
11.2.4 XXXXXXX shall have the right to terminate this Agreement upon the date
when [...***...] increases to [...***...] according to APPENDIX 1.
11.3 INTRODUCTION OF THE EURO
The introduction of the Euro as the legal currency or legal tender in
Germany (see Articles 8.5 and 8.6 above) shall in no way affect the
validity of this Agreement and shall not entitle any party hereto to
terminate, or to require any amendment to, this Agreement.
11.4 EFFECT OF TERMINATION
Upon the expiration or termination of this Agreement:
11.4.1 At the request of XXXXXXX, BI PHARMA KG shall either destroy the Cell
Line as well as the material derived from its culture or deliver the
same to XXXXXXX or a party nominated by XXXXXXX [...***...] and
shall promptly return all XXXXXXX Confidential Information to XXXXXXX;
except for a single copy and/or sample of each material for
documentation purposes only. BI PHARMA KG'S responsibility to keep and
store the Cell Line and any other materials shall terminate six (6)
months after expiration or termination of this Agreement and
11.4.2 XXXXXXX shall promptly return all BI PHARMA KG Confidential Information
to BI PHARMA KG, except for a single copy and/or sample for
documentation purposes only.
The respective rights of BI PHARMA KG and XXXXXXX to indemnification as
set forth in Article 6 hereof and Articles 4.1 and 5.5 shall survive
termination of this Agreement with respect to any claims that relate to
or derive from the Project, or any acts or failures to act, of either BI
PHARMA KG or XXXXXXX in connection with the Project that occur prior to
termination. Article 9 shall survive termination of this Agreement as
laid down herein.
12. MISCELLANEOUS
12.1 FORCE MAJEURE.
Neither party shall be in breach of this Agreement if there is any
failure of performance under this Agreement occasioned by any act of
God, fire, act of government or state, war, civil commotion,
insurrection, embargo, prevention from or hindrance in obtaining energy
or other utilities, labor disputes of whatever nature or any other
reason beyond the control of either party. In the event the Force
Majeure lasts 1 (one) year, the other party may terminate this
Agreement.
12.2 PUBLICITY.
Except as required by law, no press release or other form of publicity
regarding the work performed hereunder or this Agreement shall be
permitted by either party to be published unless both parties have
indicated their consent to the form of the release in writing.
*CONFIDENTIAL TREATMENT REQUESTED
18.
19
12.3 NOTICES.
Any notice required or permitted to be given hereunder by either party
shall be in writing and shall be (i) delivered personally, (ii) sent by
registered mail, return receipt requested, postage prepaid or (iii)
delivered by facsimile with immediate telephonic confirmation of
receipt, to the addresses or facsimile numbers set forth below:
If to BI PHARMA KG: Boehringer Ingelheim Pharma KG
Xxxxxxxxxxxx Xxxxxxx 00
88397 Biberach an der Riss
Federal Republic of Germany
Attention: Xx. Xxxxxxx Xxxxxx
(cc: Xx. Xxxxxxxx Xxx)
Fax: ++49 73 51/54-4862
Phone: ++49 73 51/54-5134
If to XXXXXXX: Xxxxxxx Pharmaceutical Inc.
000 Xxxxxxxxxx Xxxxxx, Xxxxx 000
Xxxx Xxxx, Xxxxxxxxxx 00000-0000
U.S.A.,
Attention: Vice President, Manufacturing
(cc: Chief Financial Officer
Fax: 000-000-000-0000
Phone: 000-000-000-0000
Each notice shall be deemed given (i) on the date it is received if it
is delivered personally, (ii) one (1) day after the date it is
postmarked if it is sent by certified United States mail, return receipt
requested, postage prepaid or (iii) on the date it is received if it is
sent by facsimile with immediate telephonic confirmation of receipt.
12.4 APPLICABLE LAW/JURISDICTION
This Agreement shall be governed by and construed in accordance with the
laws of the place of domicile of the party sued and the courts of the
place of domicile of the party sued shall have exclusive jurisdiction
over all legal matters and proceedings hereunder.
12.5 COMPLIANCE WITH LAWS
BI PHARMA KG shall perform the work hereunder in conformance with GMP,
as applicable, and all German and/or European Economic Community (EEC)
laws, ordinances and governmental rules or regulations pertaining
thereto.
12.6 INDEPENDENT CONTRACTORS
Each of the parties hereto is an independent contractor and nothing
herein contained shall be deemed to constitute the relationship of
partners, joint venture, nor of principal and agent between the parties
hereto. Neither party shall hold itself out to third persons as
purporting to act on behalf of, or serving as the agent of, the other
party.
12.7 WAIVER
No waiver of any term, provision or condition of this Agreement whether
by conduct or otherwise in any one or more instances shall be deemed to
be or construed as a further or
19.
20
continuing waiver of any such term, provision or condition or of any
other term, provision or condition of this Agreement.
12.8 SEVERABILITY
If any provision of this Agreement is held to be invalid or
unenforceable by a court of competent jurisdiction all other provisions
shall continue in full force and effect.
The parties hereby agree to attempt to substitute for any invalid or
unenforceable provision a valid or enforceable provision which achieves
to the greatest extent possible the economic, legal and commercial
objectives of the invalid or unenforceable provision.
12.9 ENTIRETY
This Agreement, including any exhibits and appendices attached hereto
and referenced herein, constitutes the full understanding of the parties
and a complete and exclusive statement of the terms of their agreement,
and no terms, conditions, understandings or agreements purporting to
modify or vary the terms thereof shall be binding unless they are
hereafter made in writing and signed by both parties.
12.10 ASSIGNMENT
This Agreement shall be binding upon the successors and assigns of the
parties and the name of a party appearing herein shall be deemed to
include the names of its successors and assigns provided always that
nothing herein shall permit any assignment by either party, except as BI
PHARMA KG may assign this Agreement to an affiliated company taking over
the operative biotech business of BI PHARMA KG and XXXXXXX may assign in
the case of a merger or acquisition or transfer of its assets related to
this Agreement.
20.
21
IN WITNESS WHEREOF, the parties hereto have caused this Agreement to be executed
by their duly authorized representatives on the day and year first above
written.
XXXXXXX PHARMACEUTICAL, INC. BOEHRINGER INGELHEIM PHARMA KG
PPA. PPA.
/s/ XXXXXXX X. XXXXXX /s/ XX. XXXXXXX XXXXXX /s/ XXXX. XXXX XXXXXX
---------------------------- ---------------------------- -------------------------------
Vice President and CFO Xx. Xxxxxxx Xxxxxx Xxxx. Xxxx Xxxxxx
(Head of Biopharmaceutical (Head of Industrial
Manufacture) Biopharmaceuticals world-wide)
Appendix 1: Product Price and Basic Production Assumptions
Appendix 2 a: Firm Orders (preapproval phase)
Appendix 2 b: Rolling Forecast (post approval phase)
Appendix 3: Specifications for Product
Appendix 4: Manufacturing Project Managers and Manufacturing Project Team
Members
Appendix 5: Manufacturing Forecast
Appendix 6: Certificate of Compliance
Appendix 7: Compliance Policy of BI PHARMA KG for Biopharmaceutical Contract
Manufacturing for the U.S.
21.
22
Boehringer Ingelheim
APPENDIX 7
COMPLIANCE POLICY OF BI PHARMA KG FOR
BIOPHARMACEUTICAL CONTRACT MANUFACTURING FOR THE US
Goal:
To define BI policy for establishing compliance oversight for contract
manufacturing of products were the third party is the owner of a product for
marketing in the United States of America.
Several measures are offered by BI to a third party in order to establish
compliance oversight of the license holder over its product manufactured at BI:
1.0 CONTRACT
The basic GMP Compliance aspects are laid down in a written contract
between the parties (license holder and BI).
2.0 AUDITS
The license holder has the right to conduct annual audits at the
facilities of BI to inspect GMP-status of the facility with respect to
its product. BI is committed to resolve relevant GMP- deficiencies
observed by the license holder or is consultants.
3.0 DOCUMENT CONTROL/APPROVAL
3.1 Master Batch Records
The license holder has to approve the master batch records for
commercial production of its product. All changes of the batch
records which impact regulatory filings identified by BI QA
require written approval of the license holder prior to revision
of the batch records and implementation of the changes.
3.2 Testing Records
The license holder has to approve the product specific testing
records for manufacturer release testing of its product. All
changes of the records which impact regulatory filings identified
by BI QA require written approval of the license holder prior to
revision of the document.
3.3 Process and Method Validation
The license holder has to approve the validation for process and
method validation.
22.
23
Appendix 6
Boehringer Ingelheim
CERTIFICATE OF COMPLIANCE
Page 1 of 1
PRODUCT:
Lot No.:
MANUFACTURING DATE:
EXPIRATION DATE:
It is hereby certified that all manufacturing documents including batch
manufacturing records and in-process control sheets have been inspected and
found to be in compliance with current specifications and that the analyses
carried out in our control laboratory have revealed the results of the attached
analytical certificates and are in compliance with current specifications.
If occurred, deviations during manufacturing and testing of the product are
documented in the batch manufacturing and testing records and have been assessed
and found to be acceptable.
The batch was manufactured in accordance with cGMP's and with the product's.
The lot is approved and released.
BOEHRINGER INGELHEIM PHARMA KG
QUALITY ASSURANCE
Signature:
------------------------
Date:
-----------------------------
(day/month/year)
23.
24
Boehringer Ingelheim
4.0 PRODUCT RELEASE
4.1 BI-Manufacturers release
Bl certifies to the license holder that manufacturing and testing
of a batch has been performed according cGMP and according the
BLA. BI certifies the analytical results of a batch. BI provides
a summary of all deviations which might have occurred during
manufacturing and testing.
4.2 Final product release
The final release of product for marketing is the responsibility
of the license holder.
5.0 FACILITY CHANGES
BI notifies the license holder of significant facility changes.
24.
25
Appendix 5
Manufacturing Forecast for Xxxxxxx B 1 Therapy
Years
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
US Demand [...***...] [...***...] [...***...] [...***...] [...***...]
European Demand [...***...] [...***...] [...***...] [...***...] [...***...]
Total Demand [...***...] [...***...] [...***...] [...***...] [...***...]
Assumes:
[...***...]
[...***...]
*CONFIDENTIAL TREATMENT REQUESTED
25.
26
Appendix 4
MASTER-PROJECT PLAN: ANT-B1
XXXXXXX PHARMACEUTICALS INC./B1 PHARMA KG
MANUFACTURING PROJECT MANAGERS AND
MANUFACTURING PROJECT TEAM MEMBERS
[...***...]
*CONFIDENTIAL TREATMENT REQUESTED
26.
27
Appendix 3.1
Product Specification Doc. Number: PSP/PCP XXXXX
ANTI-B1 ANTIBODY BULK Effective Date: DRAFT
Manufactured by BI Pharma KG Page Number: 1 of 3
PRODUCT DESCRIPTION
Purified Monoclonal Antibody Bulk directed against CD20 Antigen formulated in
[...***...]
PART NUMBER: LOT NUMBER: Storage Conditions [...***...]
MANUFACTURER: XXXXXX MANUFACTURE DATE EXPIRATION DATE [...***...]
ATTRIBUTE TEST METHOD Specification
Quality
[...***...] [...***...] [...***...]
Identity
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
Composition
[...***...] [...***...] [...***...]
Purity
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
Potency
[...***...] [...***...] [...***...]
Safety
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
*CONFIDENTIAL TREATMENT REQUESTED
27.
28
Appendix 3.1
FOR INFORMATION ONLY
ATTRIBUTE TEST METHOD SPECIFICATION
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
*CONFIDENTIAL TREATMENT REQUESTED
28.
29
Appendix 3.2
FOR INFORMATION ONLY
ATTRIBUTE TEST METHOD SPECIFICATION
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...]
[...***...] [...***...] [...***...]
POTENCY
[...***...] [...***...] [...***...]
SAFETY
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...]
[...***...]
Product Specification Doc. Number PSP/PCA
ANTI-B1 ANTIBODY FINAL BAGGED PRODUCT XXXX
for further manufacturing Effective Date: DRAFT
Manufactured by BI Pharma KG Page Number: 1 of 3
PRODUCT DESCRIPTION Purified
Monoclonal Antibody directed
against CD20 Antigen
formulated in [...***...]
PART NUMBER: LOT NUMBER: STORAGE CONDITIONS [...***...]
MANUFACTURER: XXXXXX MANUFACTURE DATE EXPIRATION DATE [...***...]
ATTRIBUTE TEST METHOD SPECIFICATION
QUALITY
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
IDENTITY
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
*CONFIDENTIAL TREATMENT REQUESTED
29.
30
COMPOSITION
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
PURITY
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
Product Specification Doc. Number: PSP/PCA
ANTI-BI ANTIBODY FINAL VIALED PRODUCT xxxx
Manufactured by BI Pharma KG Effective Date: DRAFT
Page Number; 1 of 2
PRODUCT DESCRIPTION: Purified Monoclonal Antibody directed against CD20 Antigen
formulated in
[...***...]
ATTRIBUTE TEST METHOD SPECIFICATION
QUALITY
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
IDENTITY
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
COMPOSITION
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
PURITY
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
POTENCY
[...***...] [...***...] [...***...]
*CONFIDENTIAL TREATMENT REQUESTED
30.
31
SAFETY
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...]
[...***...]
*CONFIDENTIAL TREATMENT REQUESTED
31.
32
Appendix 3.3
FOR INFORMATION ONLY
ATTRIBUTE TEST METHOD SPECIFICATION
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
[...***...] [...***...] [...***...]
*CONFIDENTIAL TREATMENT REQUESTED
32.
33
Appendix 2a
FIRM ORDER PLANNING SYSTEM OF ANTI-B1 COMMERCIAL SUPPLY
PRE FDA APPROVAL
Year [......***.....]
[..........*******...........]
[...***...]
*CONFIDENTIAL TREATMENT REQUESTED
33.
34
Appendix 2b
ROLLING FORECAST PLANNING SYSTEM OF BULK PRODUCT AND
FINAL PRODUCT ANTI-B1 COMMERCIAL SUPPLY
1998 1999 2000 2001 2002
IQ IIQ IIIQ IVQ IQ IIQ IIIQ IVQ IQ IIQ IIIQ IVQ IQ IIQ IIIQ IVQ IQ IIQ IIIQ IVQ
[...***...]
*CONFIDENTIAL TREATMENT REQUESTED
34.
35
Appendix 1 Page 1 of 2
Master Project plan : ANTI B1
XXXXXXX PHARMACEUTICAL BI Pharma KG
Basic Production Assumptions and Pricing System for
Commercial Supply
BASIC PRODUCTION ASSUMPTIONS OF BULK DRUG SUBSTANCE
Scale [...***...]
Titer [...***...]
Overall Yield [...***...]
Total amount per run [...***...]
PRICE [...***...]
Quantity per year Price [...***...]
[...***...] [...***...]
[...***...] [...***...]
[...***...] [...***...]
[...***...] [...***...]
[...***...] [...***...]
STERILE LIQUID FILL [...***...]
Batch Size [...***...]
Final Dosage [...***...]
Fill Volume [...***...]
Price [...***...] [...***...]
STERILE LIQUID FILL [...***...]
Batch Size [...***...]
Final Dosage [...***...]
Fill Volume [...***...]
Price[...***...] [...***...]
FILL [...***...]
Bulk Drug Substance approximately [...***...]
Fill Volume [...***...]
Price [...***...] [...***...]
*CONFIDENTIAL TREATMENT REQUESTED
35.
36
APPENDIX 1 PAGE 2 OF 2
Master Project plan : Anti B1
XXXXXXX PHARMACEUTICAL / BI Pharma KG
Basic Production Assumptions and Pricing System for
Commercial Supply
S = SURCHARGE
The surcharge system is effective, [...***...]
If the annual placed firm order Quantity falls below [...***...], BI Pharma KG
will charge
[...***...]
Calculated as follows:
[...***...]
[...***...]
Surcharge= [...***...]
PRICE CALCULATION FINAL PRODUCT
PB= Bulk Drug price [...***...]
[...***...]
Price = [...***...]
[...***...]
Price = [...***...]
BAG OR APPROPRIATE CONTAINER FILL
[...***...]
Price = [...***...]
*CONFIDENTIAL TREATMENT REQUESTED
