EXHIBIT 10.2
Portions of this document have been redacted pursuant to a
Request for Confidential Treatment. Redacted portions are
indicated with the notation "*****"
BIOPROCESSING SERVICES AGREEMENT
This bioprocessing services agreement dated this 15th day of July, 2002 (this
"Agreement") between BioMarin Pharmaceutical Inc., a Delaware corporation
("Sponsor") having its principal place of business at ▇▇▇ ▇▇▇ ▇▇▇▇▇ ▇▇▇▇ ▇▇▇▇,
▇▇▇▇▇ ▇▇▇, ▇▇▇▇▇▇, ▇▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇ and Diosynth RTP Inc., a Delaware
corporation ("Diosynth"), having its principal place of business at 6051 ▇▇▇▇▇▇
▇▇▇▇▇ ▇▇▇▇ Drive, P. O. ▇▇▇ ▇▇▇▇▇, ▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇, ▇▇ ▇▇▇▇▇-▇▇▇▇, (each
a "Party", collectively, "the Parties").
Witnesseth
WHEREAS, Sponsor desires Diosynth to perform services in accordance with the
terms of this Agreement and the Scope (as hereinafter defined) related to the
production of the material known as Neutralase (the "Product") and Diosynth
desires to perform such services.
WHEREAS, Sponsor and Diosynth executed a Letter Agreement on May 15, 2002
("Letter Agreement") that provided for certain activities relating to the joint
development of the Scope, as defined below.
NOW, THEREFORE, in consideration of the above statements and other good and
valuable consideration, the sufficiency and receipt of which are hereby
acknowledged, the Parties hereto agree as follows:
Section 1.
Scope of Work
a) A detailed scope of work document ("Scope") is attached to this
Agreement as Appendix 1. Diosynth will perform the services
("Program") for Sponsor in accordance with the Scope.
b) Sponsor acknowledges that Diosynth has consulted with Sponsor in
designing the Program design in a manner consistent with current U.S.
and E.U. regulatory guidelines. Notwithstanding the foregoing,
Diosynth does not warrant that the Program and/or the Program results
will satisfy the requirements of any regulatory agencies at the time
of submission of Program results to such agencies. Sponsor shall have
responsibility for determining regulatory strategy and for all
regulatory decisions except for those matters that Diosynth, in its
sole discretion deem contrary to regulatory requirements.
c) Diosynth's performance of the Program is based on technical
information provided by or for the Sponsor and contingent upon the
accuracy of the assumptions and other information set forth in the
Scope. This information will be translated into development and/or
manufacturing documents (development plans, batch records,
specifications, etc.). cGMP documentation will be reviewed and
approved by the Sponsor as promptly as practicable. Diosynth makes no
warranties that the execution of the Scope according to Diosynth's
procedures will result in any specific quantity or quality of Product.
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Section 2.
Program Performance
a) Diosynth shall use its best efforts to provide facilities, supplies,
and staff necessary to complete the Program, as it may be modified as
provided herein, and in accordance with the terms of this Agreement.
In the event of any conflict between the Agreement and the Scope, the
terms of this Agreement shall control.
b) Diosynth and BioMarin agree to comply with the requirements of the
mutually agreed upon Quality Agreement. Failure to comply with the
Quality Agreement by either or both Parties will be managed through
the provisions for dispute resolution specified both in the Agreement
and in the Quality Agreement.
c) Diosynth will appoint a program manager (the "Program Manager") to be
responsible for the management of the Program by Diosynth. The Program
Manager will coordinate performance of the Program with a
representative designated by Sponsor (the "Sponsor Representative"),
which representative shall have responsibility relating to performance
of the Program on behalf of Sponsor. Unless otherwise agreed in the
Scope, all communications between Diosynth and the Sponsor regarding
the conduct of the Program pursuant to the Scope shall be addressed to
or routed through the Program Manager and Sponsor Representative,
directly. Both parties may substitute their Program Manager or Sponsor
Representative, as applicable, during the course of the Program.
d) Subject to the validity of the Program Assumptions, as defined below,
vial break for the first ***** fermentation shall occur no later than
*****. In the event such vial break is delayed and fails to occur by
such time and such delay is not attributable to an invalid Program
Assumption or other act or omission of Sponsor, Sponsor's obligation
to make the payments as set forth in Section 6 related to the *****
fermentations shall be correspondingly delayed. Such delayed payment
obligation shall be the sole and exclusive remedy for and impact of
the delay described in this section 2(d).
e) Any commitment in the Letter Agreement to the payment of a reservation
fee by Sponsor or reservation of capacity by Diosynth relating to
production campaigns in excess of what is set forth in the Scope is
hereby null and void and of no further force or effect.
Section 3.
Program Materials
Sponsor will provide Diosynth with documentation and other such data, items
or information necessary to perform the Program as specified in the Scope,
(the "Sponsor Deliverables"), and funding sufficient to obtain disposable
lab supplies, disposable containers, product-contact materials or surfaces,
filters, resins, test kits, raw materials or other process consumables
necessary to perform the Program ("Process Consumables"), as well as all
documentation and such other data as may be necessary to apprise Diosynth
of the: stability of the Product, cell line, reference standard, shipping
requirements or other Sponsor Deliverables, process characteristics, proper
storage, manufacturing and safety requirements. Sponsor will also provide
Diosynth with all necessary information to effect the reliable transfer of
the process from the Sponsor or a third party, as applicable, to Diosynth.
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Section 4.
Compliance with Government Regulations
a) Diosynth will perform the Program in accordance with the best of its
understanding the then-current state of the U.S. Food and Drug
Administration's (FDA) current Good Manufacturing Practice, 21CFR,
Sections 210-211 (cGMP) and ICH Guidance for Industry, QC7A Good
Manufacturing Practices for Active Pharmaceutical Ingredients, August
2001 when applicable. Subject to paragraph b) of this Section 4,
Diosynth will also comply in all material respects with all applicable
U.S. and European government regulatory requirements concerning cGMP
applicable to the Program.
b) Should such regulatory requirements change, Diosynth will use
reasonable efforts to satisfy the new requirements. In the event that
compliance with such new regulatory requirements necessitates a change
in the Scope, Diosynth will submit to Sponsor a Change Order, as
herein after defined, in accordance with Section 7 of this Agreement.
c) Subject to section 1(c), in the event of a conflict in government
regulations, Sponsor will designate, in writing, which regulations
shall be followed by Diosynth in its performance of the Program.
Section 5.
Facility Visits
a) Sponsor reserves the right to have a person in Diosynth's facilities
during normal business hours and with prior written notice to observe
the manufacturing process provided such visits are in accordance with
the "Guidelines for Sponsor Visits" attached as Appendix 3 and
provided such access does not compromise cGMP compliance or safety in
the facility. Diosynth will assist Sponsor in scheduling such visits,
which will be in compliance with Diosynth's requirement to protect
confidentiality of other clients.
b) Diosynth reserves the right to refuse visits, audits or inspection by
third parties in the event that the third party is a competitor of
Diosynth and/or in the event that Diosynth's obligations of
confidentiality or business may be compromised by such third party
involvement.
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Section 6.
Compensation
a) The budget for the Program is set forth in Appendix 2 (the "Budget")
and payment shall be remitted to Diosynth pursuant to this Section 6.
The Budget is subject to the Assumptions as defined herein.
b) Sponsor shall be invoiced and pay *****. Diosynth shall invoice
Sponsor ***** in the amounts indicated in the payment schedule below
and Sponsor shall satisfy such invoices in accordance with this
Section 6.
c) ***** Diosynth shall invoice and Sponsor shall satisfy such invoices
in accordance with this Section 6 on the dates indicated below.
d) Sponsor has paid an initial payment of ***** under the Letter
Agreement. This amount shall be applied to the payment due upon
completion the ***** fermentation.
e) In addition to the amounts set forth in the payment schedule below,
Process Consumables purchased for the Program will be invoiced
separately as such costs are incurred by Diosynth. Sponsor agrees to
pay Diosynth's actual cost for the Process Consumables purchased for
the Program *****. Resins and ***** and additional items agreed to
by the Parties will not be subject to *****.
f) Diosynth shall purchase the following item(s) in order to execute the
Program ("Capital Equipment"):
Mutually Agreed to Freezers for Released and Quarantined API
Diosynth shall rent the following item(s) in order to execute the
Program ("Rented Equipment"):
*****
Diosynth shall invoice Sponsor and Sponsor shall pay all amounts
reasonably incurred by Diosynth relating to the procurement,
installation and validation of these items at the time that such costs
are incurred. At the time the Rented Equipment is no longer necessary
for the performance of the Program, Diosynth shall return the
equipment to its owner. At the time the Capital Equipment is no longer
necessary for
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the performance of the Program, Diosynth shall so notify Sponsor and
allow Sponsor reasonable opportunity (not to exceed thirty (30) days
from notice) to arrange, at Sponsor's sole expense, for the removal of
the Capital Equipment from Diosynth's facilities. If Sponsor makes no
such arrangements within a reasonable time after notice, title to the
Capital Equipment shall transfer to Diosynth without further
consideration.
g) Payments are due thirty (30) days from the date of the invoice. Late
payments are subject to an interest charge of one and one-half percent
(1 1/2%) per month. Any payments that are greater than ninety (90)days
past due constitute a material breach of this Agreement. Invoices will
include a summary of activities completed during the invoice period,
including; labor effort, activities completed and an indication of
billable materials purchased.
h) Diosynth has allocated resources to the Program that may be difficult
or impractical to reallocate to other programs in the event of a
delay. In recognition of this, Sponsor agrees to pay the amounts set
forth in and in accordance with the payment schedule regardless of any
delay in the Program related to invalid Assumptions or decisions made
during the course of the Program to perform process development or
other activities not expressly provided for in the Scope. In such
event, amounts due under the payment schedule shall not apply to
completion of any components of the Program that are delayed. Sponsor
and Diosynth shall negotiate a Change Order for compensation for the
delayed and/or additional activities that may be necessary.
i) Diosynth shall invoice Sponsor and Sponsor shall pay for any import
duties actually incurred by Diosynth in executing the Program *****
during the term of Program as currently reflected in the Scope.
PAYMENT SCHEDULE
*****
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Section 7.
Change Orders
a) The total budget for the Program specified in Appendix 2, the
individual budget components and the estimated durations specified in
the Scope are subject to a number of general and Program specific
assumptions as well as the accuracy, timeliness and completeness of
Sponsor's Deliverables. The assumptions relate to the Program design
and objectives, manpower requirements, timing, capital expenditure
requirements, if any, and other matters relating to the completion of
the Program as set forth in the Scope (the "Program Assumptions").
Diosynth also assumes that the Sponsor will cooperate and perform its
obligations under the Agreement and Scope in a timely manner, that no
event outside the control of Diosynth will occur, including, without
limitation, the events described in Section 18, (Force Majeure) and
that there are no changes to any applicable laws, rules or regulations
which affect the Program (the foregoing assumptions together with the
Program Assumptions, collectively, the "Assumptions"). In the event
that any of the Assumptions require modification or the Program
objectives cannot be achieved based on the Assumptions (each being a
"Modification") then the Scope may be amended as provided in paragraph
b) of this Section 7.
b) In the event a Modification is identified by the Sponsor or by
Diosynth, the identifying Party shall notify the other Party as soon
as is reasonably possible. Diosynth shall provide Sponsor with a
change order containing an estimate of the required Modifications to
the estimated Program budget and estimated duration as specified in
the Scope ("Change Order") within ten (10) business days of receiving
such notice. Sponsor shall use best efforts to respond in writing to
such Change Order within five (5) business days of receiving such
Change Order. If Sponsor does not approve such Change Order and has
not terminated the Program but wants the Program to be modified to
take into account the Modification, then Sponsor and Diosynth shall
use best efforts to agree on a Change Order that is mutually
acceptable. If practicable, Diosynth shall continue work on the
Program during any such negotiations, but shall not commence work with
respect to the Change Order unless authorized in writing. If a
Modification identified by Sponsor results in a Change Order that is
not agreeable to both parties forty-five (45) days after issuance of
the relevant Change Order and after good faith negotiations, this
Agreement shall be deemed terminated by Sponsor pursuant to Section 21
hereof.
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Section 8.
Confidential Information/Legal Proceedings
a) Diosynth will not disclose, without Sponsor's written permission, any
information pertaining to the Program unless such disclosure: (i) is
to an affiliate of Diosynth that is under a similar obligation to keep
such information confidential; (ii) is or becomes publicly available
through no fault of Diosynth; (iii) is disclosed by a third Party
entitled to disclose it; (iv) is already known to Diosynth as shown by
its prior written records; or, (v) is required by any law, rule,
regulation, order decision, decree, subpoena or other legal process to
be disclosed. If such disclosure is requested by legal process,
Diosynth will make all reasonable efforts to notify Sponsor of this
request promptly prior to any disclosure to permit Sponsor to oppose
such disclosure by appropriate legal action. Diosynth shall use
reasonable precautions to protect the confidentiality of such
information comparable to precautions taken to protect its own
proprietary information.
b) Sponsor will not disclose, without Diosynth's written permission, any
information pertaining to Diosynth's performance of the Program unless
such disclosure: (i) is to an affiliate of Sponsor that is under a
similar obligation to keep such information confidential; (ii) is or
becomes publicly available through no fault of Sponsor; (iii) is
disclosed by a third Party entitled to disclose it; (iv) is already
known to Sponsor as shown by its prior written records; or, (v) is
required by any law, rule, regulation, order decision, decree,
subpoena or other legal process to be disclosed. If such disclosure is
requested by legal process, Sponsor will make all reasonable efforts
to notify Diosynth of this request promptly prior to any disclosure to
permit Diosynth to oppose such disclosure by appropriate legal action.
Sponsor shall use reasonable precautions to protect the
confidentiality of such information comparable to precautions taken to
protect its own proprietary information.
c) If Diosynth shall be obliged to provide testimony or records regarding
any Sponsor Program in any legal or administrative proceeding, then
Sponsor shall reimburse Diosynth its out-of-pocket costs therefore
plus an hourly fee for its employees or representatives equal to the
internal fully burdened costs to Diosynth of such employee or
representative.
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Section 9.
Work Product
a) All work outputs (e.g. reports) will be prepared using Diosynth's
standard format(s) unless otherwise specified in the Scope.
b) Sponsor will be supplied with copies of reports and completed cGMP
documentation generated as a result of the Program. All such written
materials will be archived by Diosynth for a period of five (5) years
following completion of the Program unless otherwise defined by the
Program or required by applicable U.S. laws or regulations. Five years
after completion of the Program, all of the aforementioned written
materials will be sent to the Sponsor and a return fee will be
charged. The Sponsor may elect to have the materials retained in the
Diosynth archives for an additional period of time at additional cost
to Sponsor. If the Sponsor chooses to have Diosynth dispose of the
written materials, a disposal fee will be charged. Diosynth will
continue to retain such written materials as required by regulations
and as may be required by law, pertaining to such activities as well
as for archival purposes.
c) Diosynth will continue to retain Product samples as required by
regulations and as may be required by law as well as for archival
purposes.
Section 10.
Inventions and Patents
a) At Sponsor's request, Diosynth will assign to Sponsor any patentable
Product improvement invention discovered by Diosynth employees
exclusively as a result of performing the Program under this Agreement
(a "Product Invention"); provided Sponsor requests such assignment, in
writing, within one year of notification of such Product Invention;
provided, further that Diosynth shall retain all rights to any and all
inventions and know-how relating to manufacturing methods and
processes discovered in connection with the Program and any
pre-existing know-how ("Process Inventions"). If Sponsor requests and
at Sponsor's expense, Diosynth will execute any and all applications,
assignments or other instruments and give testimony which shall be
necessary to apply for and obtain Letters of Patent of the US or of
any foreign country with respect to the Product Invention and Sponsor
shall compensate Diosynth for the time devoted to such activities and
reimburse it for expenses incurred.
b) For Process Inventions, Diosynth will grant to Sponsor a royalty-free,
perpetual, world-wide, non-exclusive license under terms mutually
agreed to by the Parties solely for the field of use required for
Sponsor to commercialize the Product developed or produced under this
Agreement. If Diosynth requests and at Diosynth's expense, Sponsor
will execute any and all applications, assignments or other
instruments and give testimony which shall be necessary to apply for
and obtain Letters of Patent of the US or of any foreign country with
respect to the Process Invention and Diosynth shall compensate Sponsor
for the time devoted to such activities and reimburse it for expenses
incurred.
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c) Diosynth reserves the right to use data during the course of the
Program to support applications, assignments or other instruments
necessary to apply for and obtain Letters of Patent of the U.S. or any
foreign country with respect to Process Inventions so long as no
information which Diosynth is required to keep confidential under this
Agreement is disclosed in any such application, assignment, or other
instrument. Diosynth shall notify Sponsor 90 days in advance of intent
to file such application, assignment or other instrument.
Section 11.
Independent Contractor
Diosynth shall perform the Program as an independent contractor of Sponsor and
shall have complete and exclusive control over its facilities, equipment,
employees and agents. The provisions of this Agreement shall not be construed to
establish any form of partnership, agency or other joint venture of any kind
between Diosynth and Sponsor, nor to constitute either party as the agent,
employee or legal representative of the other. All persons furnished by either
party to accomplish the intent of this Agreement shall be considered solely as
the furnishing party's employees or agents and the furnishing party shall be
solely responsible for compliance with all laws, rules and regulations
involving, but not limited to, employment of labor, hours of labor, working
conditions, workers' compensation, payment of wages, and withholding and payment
of applicable taxes, including, but not limited to income taxes, unemployment
taxes, and social security taxes.
Section 12.
Insurance
Diosynth shall secure and maintain in full force and effect throughout the
performance of the Program policies of insurance for (a) workmen's compensation,
(b) general liability, (c) automobile liability, and (d) professional liability
having policy limits, deductibles and other terms appropriate to the conduct of
Diosynth's business in Diosynth's sole and exclusive judgment.
Section 13.
Shipping
Diosynth shall package for shipment and ship Product, samples or other materials
at Sponsor's expense and in accordance with Sponsor's full written and
reasonable instructions with Sponsor bearing all packaging, shipping and
insurance charges. Freight terms shall be Ex Works according to INCO terms 2000.
Delivery of Product, samples or other materials by Diosynth shall be deemed to
have taken place upon delivery to carrier at Diosynth's facility and risk of
loss shall transfer to Sponsor on transfer to carrier at Diosynth's facilities.
Diosynth shall retain representative samples of Product for record keeping,
testing and regulatory purposes.
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Section 14.
Default
a) If Diosynth is in default of its material obligations under this
Agreement, then Sponsor shall promptly notify Diosynth in writing of
any such default. Diosynth shall have a period of forty-five (45) days
from the date of receipt of such notice within which to cure such
default; provided that if such default renders the Program invalid,
then Diosynth, shall, at its option, either: (i) repeat the Program at
its cost within a time period mutually agreed to by it and Sponsor;
or, (ii) refund the contract price paid by Sponsor. If Diosynth shall
fail to cure such default within the specified cure period or commence
the repetition of any portion(s) of the Program constituting the basis
for the default, as the case may be, then this Agreement shall, at
Sponsor's option, immediately terminate. In the event of such
termination, Sponsor's sole monetary remedy shall be, in the case
where such default has not rendered the Program invalid, a reduction
in the total contract price for the Program in an amount equal to the
difference between: (i) the total contract price for the Program; and,
(ii) the value of the work properly performed, and, in the case where
such default does render the Program invalid, a refund of the contract
price; provided however that except as provided in paragraph c) of
this Section 14, under no circumstance shall Diosynth be liable to
Sponsor in an amount that, in aggregate exceeds, the total contract
price paid for the Program. In the event of a termination due to a
breach of this Agreement by Diosynth, Diosynth shall deliver such
documentation and records relating to the Program as Sponsor may
reasonably request.
b) If Sponsor is in default of its material obligations under this
Agreement, Diosynth shall promptly notify Sponsor in writing of any
such default. Sponsor shall have a period of forty-five (45) days from
the date of receipt of such notice within which to cure such default;
provided that if Sponsor fails to cure such breach within the
specified cure period, this Agreement shall, at Diosynth's option,
immediately terminate.
c) Not withstanding anything herein to the contrary, UNDER NO
CIRCUMSTANCES SHALL EITHER PARTY BE ENTITLED TO INCIDENTAL, INDIRECT,
CONSEQUENTIAL OR SPECIAL DAMAGES ARISING IN CONNECTION WITH THE
DEFAULT OR BREACH OF ANY OBLIGATION OF THE OTHER PARTY UNDER THIS
AGREEMENT, THE SCOPE OR ANY DOCUMENTS OR APPENDICES RELATED THERETO.
EXCEPT FOR EACH PARTY'S INDEMNIFICATION OBLIGATIONS FOR THIRD-PARTY
CLAIMS SET FORTH IN SECTION 16, OR ITS GROSS NEGLIGENCE OR WILLFUL
MISCONDUCT, EACH PARTY'S MAXIMUM LIABILITY FOR DAMAGES IN CONNECTION
WITH A CLAIM UNDER THIS AGREEMENT, REGARDLESS OF THE CAUSE OF ACTION,
WILL NOT EXCEED THE FEES PAID AND DUE HEREUNDER.
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d) EXCEPT AS EXPRESSLY STATED HEREIN, NEITHER PARTY PROVIDES TO THE OTHER
PARTY HERETO ANY WARRANTIES, EXPRESS OR IMPLIED, WITH RESPECT TO THE
MATERIALS AND SERVICES PROVIDED HEREUNDER, AND ALL SUCH MATERIALS AND
WARRANTIES, EXPRESS OR IMPLIED, INCLUDING WITHOUT LIMITATION ANY
IMPLIED WARRANTIES OR MERCHANTABILITY OR FITNESS FOR A PARTICULAR
PURPOSE.
Section 15.
Dispute Resolution
a) In the event any dispute shall arise between the Sponsor and Diosynth
with respect to any of the terms and conditions of this Agreement or
the Program; then senior executives of the Sponsor and Diosynth shall
meet as promptly as practicable after notice of such dispute to
resolve in good faith such dispute.
b) If the Sponsor and Diosynth are unable to satisfactorily resolve the
dispute, then such dispute shall be referred to mediation in
accordance with the American Arbitration Association. If mediation
fails to resolve the dispute, then such dispute shall be finally
settled by an arbitrator in accordance with this Section 15. The
arbitration will be held in or around Wake County, North Carolina, and
except as noted below, shall be conducted in accordance with the rules
of the American Arbitration Association by two arbitrators appointed,
one by each Party. If the arbitrators appointed cannot agree on the
resolution of the dispute within sixty (60) days after the dispute is
submitted to them, they shall thereupon appoint a third arbitrator,
and if they fail to agree upon a third arbitrator within thirty (30)
days after a deadlock is declared by either arbitrator, a third
arbitrator will be appointed by the American Arbitration Association
upon the request of either arbitrator. The arbitrators shall have no
authority to award consequential, punitive or exemplary damages or to
vary from or ignore the terms of this Agreement and shall be bound by
controlling law. Finally, the Parties may seek judicial intervention
for emergency relief, such as restraining orders and injunctions and
other equitable remedies where appropriate.
Any decision by the third arbitrator and either one of the other
arbitrators shall be binding upon the Parties and may be entered as
final judgment in any court having jurisdiction. The cost of any
arbitration proceeding shall be borne by the Parties as the
arbitrators shall determine if the Parties have not otherwise agreed.
The arbitrators shall render their final decision in writing to the
Parties.
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Section 16.
Indemnification
a) Diosynth shall indemnify Sponsor and its affiliates and their
respective officers, directors and employees from any loss, cost,
damage or expense (a "Loss") from any lawsuit, action, claim, demand,
assessment or proceeding (a "Claim") for (i) personal injury to
Program participants or personal injury to any employee of Sponsor or
property damage arising or occurring during the conduct of the Program
as a result of Diosynth's negligence, gross negligence or intentional
misconduct or inaction or (ii) the negligence, gross negligence or
intentional misconduct or inaction of Diosynth in the performance of
its obligations under this Agreement or Scope related to the Program;
provided that if such Loss or Claim arises in whole or in part from
Sponsor's negligence, gross negligence or intentional misconduct or
inaction, then the amount of the Loss that Diosynth shall indemnify
Sponsor for pursuant to this Section 16 shall be reduced by an amount
in proportion to the percentage of Sponsor's responsibilities for such
Loss determined by a court of competent jurisdiction in a final and
non-appealable decision or in a binding settlement between the
Parties.
b) Sponsor shall indemnify Diosynth and its affiliates and their
respective officers, directors, employees and agents (the "Diosynth
Group") from any Claim or Loss arising from or related to: (i)
personal injury to a participant in the Program or personal injury to
any employee of the Diosynth Group directly or indirectly caused by
the Sponsor Deliverables, Process Consumables, Materials, Product,
intermediates or the Program; (ii) Diosynth's proper performance of or
involvement with the raw material, the Product or the Program or its
obligations under this Agreement or the Scope related thereto; (iii)
the Agreement, the Program or any aspect thereof set forth in the
Scope or the Program violates any applicable law, rule, regulation or
ordinance; (iv) the harmful or otherwise unsafe effect of the raw
materials or Product, including, without limitation, a Claim based
upon Sponsor or any other person's use, consumption, sale,
distribution or marketing of any substance, including the raw
material, Materials or the Product; (v) the negligence, gross
negligence or intentional misconduct or inaction of Sponsor in the
performance of its obligations under this Agreement or Scope related
to the Program; (vi) the infringement or alleged infringement of the
Scope or the Program or the Product on the intellectual property
rights of a third party; or, (vii) the Sponsor's violation,
non-compliance or non-performance of any of the terms of this
Agreement; provided that if such Loss or Claim (other than a Loss or
Claim described in clause (iv) hereof) arises in whole or in part from
Diosynth's negligence, gross negligence or intentional misconduct or
inaction, then the amount of such Loss that Sponsor shall indemnify
the Diosynth Group for pursuant to this Section 16 shall be reduced by
an amount in proportion to the percentage of Diosynth's
responsibilities for such Loss as determined by a court of competent
jurisdiction in a final and non-appealable decision or in a binding
settlement between the Parties. Sponsor shall not indemnify the
Diosynth Group from any Loss from any claim described in clause (iv)
hereof arising solely from the willful misconduct or inaction of
Diosynth.
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c) Upon receipt of notice of any Claim which may give rise to a right of
indemnity from the other Party hereto, the Party seeking
indemnification (the "Indemnified Party") shall give written notice
thereof to the other Party, (the "Indemnifying Party") with a Claim
for indemnity ("Indemnity Claim"). Such Claim for indemnity shall
indicate the nature of the Claim and the basis therefore. Promptly
after a claim is made for which the Indemnified Party seeks indemnity,
the Indemnified Party shall permit the Indemnifying Party, at its
option and expense, to assume the complete defense of such Claim,
provided that (i) the Indemnified Party will have the right to
participate in the defense of any such Claim at its own cost and
expense, (ii) the Indemnifying Party will conduct the defense of any
such Claim with due regard for the business interests and potential
related liabilities of the Indemnified Party and (iii) the
Indemnifying Party will, prior to making any settlement, consult with
the Indemnified Party as to the terms of such settlement. The
Indemnified Party shall have the right, at its election, to release
and hold harmless the Indemnifying Party from its obligations
hereunder with respect to such Claim and assume the complete defense
of the same in return for payment by the Indemnifying Party to the
Indemnified Party of the amount of the Indemnifying Party's settlement
offer. The Indemnifying Party will not, in defense of any such Claim,
except with the consent of the Indemnified Party, consent to the entry
of any judgment or enter into any settlement which does not include an
unconditional term thereof, the giving by the claimant or plaintiff to
the Indemnified Party of a release from all liability in respect
thereof. After notice to the Indemnified Party of the Indemnifying
Party's election to assume the defense of such Claim, the Indemnifying
Party shall be liable to the Indemnified Party for such legal or other
expenses subsequently incurred by the Indemnified Party in connection
with the defense thereof at the request of the Indemnifying Party. As
to those Claims with respect to which the Indemnifying Party does not
elect to assume control of the defense, the Indemnified Party will
afford the Indemnifying Party an opportunity to participate in such
defense at the Indemnifying Party's own cost and expense, and will not
settle or otherwise dispose of any of the same without the consent of
the Indemnifying Party.
Section 17.
Representation and Warranty/Limitation of Warranty
Sponsor hereby represents and warrants to Diosynth that it has legal title
and/or a valid license to the cell line, raw material, expression systems,
process patents and the Product and that Diosynth's performance of the Program
will not violate or infringe on the patents, trademarks, tradenames,
servicemarks or copyrights of any other party.
Section 18.
Force Majeure
Either Party shall be excused from performing its respective obligations under
this Agreement if its performance is delayed or prevented by any event beyond
such Party's reasonable control, including, but not limited to, acts of God,
fire, explosion, weather, disease, war, insurrection, civil strife, riots,
government action, or power failure, provided that such performance shall be
excused only to the extent of and during such disability. Any time specified for
completion of performance in the Scope falling due during or subsequent to the
occurrence of any or such events shall be automatically extended for a period of
time to recover from such disability. Diosynth will promptly notify Sponsor if,
by reason of any of the events referred to herein, Diosynth is unable to meet
any such time for performance specified in the Scope. If any part of the Program
is invalid as a result of such disability, Diosynth will, upon written request
from Sponsor, but at Sponsor's sole cost and expense, repeat that part of the
Program affected by the disability.
13
Section 19.
Allocation of Resources
If delays in the agreed commencement or performance of the Program occur because
of the Sponsor's request or inability to supply Diosynth with agreed Sponsor
Deliverables or any information required to begin or perform the Program within
thirty (30) days of such agreed time, Diosynth may reallocate resources being
held for performance of the Program without incurring liability to Sponsor. Such
reallocation of shall not be the exclusive impact of a Sponsor delay.
Section 20.
Use of Names
Neither Party shall use the name of the other Party or the names of the
employees of the other Party in any advertising or sales promotional material or
in any publication without prior written permission of such Party.
Section 21.
Termination or Failure to Order by Sponsor
a) Sponsor may at any time terminate this Agreement prior to completion
of the Program by giving forty-five (45) days written notice to
Diosynth. In such event or any other event outside of Diosynth's
control that causes the Program to be ceased or significantly delayed,
Diosynth shall use commercially reasonable efforts to reduce cost to
Sponsor associated with the termination, and Sponsor shall pay
Diosynth upon receipt of Diosynth's invoice all of its costs incurred
or irrevocably obligated, plus, as liquidated damages and not as a
penalty, a cancellation fee in immediately available funds equal to
the uninvoiced portion of the total budget as set forth in Appendix 2
as of the effective date of the termination and including all
then-current Change Orders and amendments associated with the
Agreement, reduced by those amounts described in the second sentence
of this paragraph a).
b) The termination of this Agreement for any reason shall not relieve
either Party of its obligation to the other for obligations in respect
of: (i) confidentiality of information; (ii) consents for advertising
purposes and publications; (iii) indemnification; (iv) inventions and
patents; and, (v) compensation for services performed.
14
Section 22.
Assignment
This Agreement shall not be assigned in whole or in part by either Party without
the prior written consent of the other, which consent shall not be unreasonably
withheld or delayed. Any attempt to assign this Agreement without such consent
shall be void and of no effect. The terms of this Agreement shall inure to the
benefit of successors and assigns.
Section 23.
Notice
All notices to be given as required in this Agreement shall be in writing and
shall be delivered personally, sent by telecopies, or mailed either by a
reputable overnight carrier or first class mail, postage prepaid to the parties
at the addresses set forth above or such other addresses as the Parties may
designate in writing. Such notice shall be effective on the date sent, if
delivered personally or sent by telecopier, the date after delivery if sent by
overnight carrier and on the date received if mailed first class.
Section 24.
Choice of Law
This Agreement shall be construed and enforced in accordance with the laws of
the State of North Carolina except for its rules regarding conflict of laws.
Section 25.
Waiver/Severability
No waiver of any provision of this Agreement, whether by conduct or otherwise,
in any one or more instances shall be deemed to be or be construed as a further
or continuing waiver of any such provision, or of any other provision or
condition of this Agreement. If any provisions hereof shall be determined to be
invalid or unenforceable, the validity and effect of the other provisions of
this Agreement shall not be affected thereby.
Section 26.
Nonsolicitation
So long as this Agreement is in effect, and for twelve (12) months following
termination of the Agreement, for any reason, neither Sponsor nor Diosynth nor
any of their employees or agents shall, directly or indirectly, solicit, hire,
or attempt to solicit or hire, any employees of the other, unless otherwise
approved by the other Party.
15
Section 27.
Entire Agreement; Modification/Counterparts
a) This instrument including the attached Appendices sets forth the
entire Agreement between the Parties hereto with respect to the
performance of the Program by Diosynth for Sponsor and as such,
supersedes all prior and contemporaneous negotiations, agreements,
representations, understandings, and commitments with respect thereto
and shall take precedence over all terms, conditions and provisions on
any purchase order form or form of order acknowledgment or other
document purporting to address the same subject matter. This Agreement
shall not be waived, released, discharged, changed or modified in any
manner except by an instrument signed by the duly authorized officers
of each of the Parties hereto, which instrument shall make specific
reference to this Agreement and shall express the plan or intention to
modify same. This Agreement may be executed in one or more
counterparts each of which shall be deemed an original but all of
which together shall constitute one and the same instrument.
b) This Agreement becomes effective and binding on both Parties on and as
of the last date that the Parties hereto have executed this Agreement.
Should terms contained herein be at variance with the terms and
conditions specified in Sponsor's written acceptance, then the terms
and conditions contained herein take precedence.
[Sponsor] Diosynth RTP Inc.
By: /s/ ▇▇▇▇ ▇▇▇▇▇▇ By: /s/ R. Salsmans
------------------- --------------------------
Name: ▇▇▇▇ ▇▇▇▇▇▇ Name: ▇. ▇▇▇▇▇▇▇
------------------- --------------------------
Title: Sr. Vice President Title: President & CEO
------------------- --------------------------
Date: July 15, 2002 Date: July 16, 2002
------------------- --------------------------
By: /s/ ▇▇▇▇ ▇▇▇▇ By: /s/ ▇▇▇▇▇▇▇ ▇. ▇▇▇▇▇, Ph.D.
------------------- --------------------------
Name: ▇▇▇▇ ▇▇▇▇ Name: ▇▇▇▇▇▇▇ ▇. ▇▇▇▇▇, Ph.D.
------------------- --------------------------
Title: V.P., Manufacturing Title: Sr. V.P., Commercial Dev.
------------------- --------------------------
Date: July 15, 2002 Date: July 16, 2002
------------------- --------------------------
16
APPENDIX ONE
(SCOPE OF WORK)
Portions of this document have been redacted pursuant to a Request for
Confidential Treatment. Redacted portions are indicated with the notation
"*****"
--------------------------------------------------------------------------------
Scope for Process Transfer, Scale-up and Manufacturing
of Neutralase Drug Substance
PREPARED FOR: BioMarin Pharmaceuticals, Inc.,
▇▇▇ ▇▇▇ ▇▇▇▇▇ ▇▇▇▇ ▇▇▇▇., ▇▇▇▇▇ ▇▇▇
▇▇▇▇▇▇, ▇▇ ▇▇▇▇▇
PREPARED BY: Diosynth RTP, Inc. (Diosynth)
▇▇▇▇ ▇▇▇▇▇▇ ▇▇▇▇▇ ▇▇▇▇ ▇▇▇▇▇
▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇, ▇▇ ▇▇▇▇▇
DATE SUBMITTED: 07-11-2002
1
Table of Contents
1.0 EXECUTIVE SUMMARY..................................................... 3
1.1 Scope Overview...................................................... 3
1.2 Manufacturing Strategy.............................................. 3
1.3 Timeline............................................................ 3
2.0 PROGRAM DEFINITIONS................................................... 4
3.0 ABBREVIATIONS......................................................... 5
4.0 PROGRAM OBJECTIVES.................................................... 6
5.0 PROGRAM ASSUMPTIONS................................................... 7
6.0 DELIVERABLES FROM SPONSOR TO DIOSYNTH................................. 9
7.0 PROGRAM MANAGEMENT....................................................10
8.0 TECHNOLOGY TRANSFER & SCALE-UP........................................11
8.1 Fermentation Process Transfer and Scale up to *****................11
8.2 Downstream Purification Process Transfer and Scale up to *****......11
8.3 Analytical Methods Transfer.........................................12
9.0 MANUFACTURING PRE-PRODUCTION..........................................14
10.0 cGMP MANUFACTURING....................................................16
11.0 QUALITY ASSURANCE AND QUALITY CONTROL.................................17
12.0 REGULATORY SUPPORT....................................................18
2
1.0 EXECUTIVE SUMMARY
1.1 Scope Overview
BioMarin Pharmaceutical, Inc. (Sponsor) has contracted with Diosynth RTP Inc.
(Diosynth) to perform tasks related to process transfer, scale-up and cGMP
manufacturing of NeutralaseTM (Product). Sponsor has completed Phase II clinical
trials and initiated Phase III trials with Neutralase manufactured by a third
party. Key to the objectives and assumptions made in this Scope are the
significant process modifications being made and/or evaluated by Sponsor *****
prior to Diosynth's performance of this Scope as well as the requirement for
scale-up of the process by Diosynth following these modifications. In addition,
Sponsor has clearly stated its desire to assume responsibility for all process
development activities and outcomes and wishes to contract with Diosynth only
for execution of process scale-up and subsequent manufacturing runs*****,
Diosynth is responsible only for the execution of the defined activities and not
for the results thereof.
NeutralaseTM is an injectable Heparinase I intended for use in reversing
anti-coagulation induced by heparin and other heparin-like anti-coagulants.
***** This Scope assumes that the recombinant line will be used for the
manufacture of bulk Product. *****
The short lead time requested by Sponsor for Product delivery in addition to the
availability of capacity in the manufacturing schedule at Diosynth have resulted
in Diosynth's development of a dual site manufacturing strategy (described in
detail below) that is designed to be in manufacture for Product within Sponsor's
desired timeframe. This dual site strategy provides for fermentation and initial
recovery at Diosynth RTP's site with completion of downstream processing at
Diosynth B.V.'s Oss Site. By transferring the downstream process to the Oss
facility for the current campaign, the cost of technology transfer for a
subsequent scale up for future commercial supply can be reduced for the Sponsor.
1.2 Manufacturing Strategy
Sponsor will transfer the existing ***** Product manufacturing process to
Diosynth. Diosynth will scale-up and run the process ***** and subsequently
scale-up to ***** under process direction from Sponsor. Diosynth will perform
fermentation, recovery and partial purification processes at its manufacturing
site in North Carolina (RTP). The product of these activities will be shipped to
the Diosynth facility in Oss, the Netherlands, for completion of downstream
processing and bulk fill. Limited in process and limited lot release testing
will be performed at the respective sites of manufacture to assess cGMP
compliance, with Sponsor performing the final testing and lot release.
Diosynth's strategy for process transfer, scale up and manufacturing includes:
o Review of the existing process development and manufacturing documentation.
o Perform two fermentation runs ***** followed by two purification runs
intended to demonstrate the Sponsor's process at an intermediate scale to
support stepwise scale-up of the process.
o Draft technology transfer and engineering documentation, obtain and release
raw materials and develop control programs for bioreactor operation,
according to Sponsor's direction.
o Perform two manufacturing runs ***** according to cGMP.
1.3 Timeline
The activities listed in this Scope are anticipated to take ***** to complete.
Appendix 1 provides a ▇▇▇▇▇ chart for the timeline of anticipated activities and
duration based on the Program Assumptions listed in section 5.0.
3
2.0 PROGRAM DEFINITIONS
The definitions listed below are terms used in this Scope.
Sponsor: BioMarin Pharmaceuticals, Inc., ▇▇▇ ▇▇▇ ▇▇▇▇▇ ▇▇▇▇
▇▇▇▇., ▇▇▇▇▇▇, ▇▇ ▇▇▇▇▇
Diosynth: Diosynth RTP Inc. with place of business at Research
Triangle Park, NC 27709, U.S. and Diosynth B.V. with
place of business at ▇▇ ▇▇▇ ▇▇, ▇▇▇▇ ▇▇ ▇▇▇,
▇▇▇ ▇▇▇▇▇▇▇▇▇▇▇.
Active Pharmaceutical Any substance or mixture of substances intended to be
Ingedient (API) (or used in the manufacture of a drug (medicinal) product
Drug Substance) and that, when used in the production of a drug,
becomes an active ingredient of the drug product. Such
substances are intended to furnish pharmacological
activity or other direct effect in the diagnosis,
cure, mitigation, treatment, or prevention of disease
or to affect the structure and function of the body.
cGMP: Current Good Manufacturing Practice as described in:
Guidance for Industry Q7A Good Manufacturing Practice
Guidance for Active Pharmaceutical Ingredients, and 21
Code of Federal Regulations, Parts 210 and 211, and EC
Guidance for Pharmaceutical Manufactures and
Distributors.
Change Order: An order for a contractual change to the scope of the
Program. For example a Change Order can be generated
for: Program Assumptions requiring modification, the
Program Objectives cannot be achieved based on the
Program Assumptions or the Sponsor wishes to add or
delete activities to or from the Program.
Drug Product: The dosage form in the final immediate packaging
intended for clinical use.
Process Consumables: Media, resins, raw materials, filters, membranes,
disposable analytical test kits, disposable bags and
other items consumed and pre-approved subcontracted
analytical testing performed during the production and
testing of Drug Substance. Custom resins and other
extraordinary supplies, are not included in this
definition.
Product: Heparinase I *****
Program: The services to be performed by Diosynth.
Program Assumptions: Assumptions relating to the Program design,
objectives, process assumptions, manpower
requirements, timing, capital expenditure
requirements, if any, and other matters relating to
the completion of the Program as set forth in the
Scope.
Scope: A component of the Agreement that specifies the
Program design, information desired, estimated
duration of the Program and all other matters
pertinent to the completion of the Program. The Scope
is prepared through discussions with the Sponsor and
Diosynth and mutually approved before being included
in the Agreement.
SPI *****, the process intermediate resulting after the
*****, and which will be shipped from Diosynth RTP to
Diosynth B.V. for final purification.
Sponsor Deliverables: Materials or information coming from the Sponsor or
one of its agents that are required for the execution
of the Program. The Sponsor Deliverables will include
delivery dates in order to support the Program
Assumptions.
4
3.0 ABBREVIATIONS
API Active Pharmaceutical Ingredient
C of A Certificate of Analysis
CMC Chemistry, Manufacturing and Controls
DSP Downstream Processing
FDA Food and Drug Administration
FOB Freight on Board
HSE Health Safety and Environment
ICH International Committee on Harmonization
IPC In Process Control
LIMS Laboratory Information Management System
MCB Master Cell Bank
NDA New Drug Application
PBS Production Beheers (Management) System
QA Quality Assurance
QC Quality Control
SOP Standard Operating Procedure
SPI *****
STM Standard Test Method
USP United States Pharmacopoeia
WCB Working Cell Bank
5
4.0 PROGRAM OBJECTIVES
The overall objective of the Program is to transfer and scale-up the Sponsor's
existing ***** process ***** and subsequently ***** for Product manufacturing.
Sponsor has requested that Diosynth perform the following activities to support
their requirements:
1. Transfer in all process documentation related to the Manufacture of the
Product, as defined in section 6.0 (Deliverables from Sponsor to
Diosynth) in this scope.
2. Visit Sponsor operations to view process and train on analytical
techniques for the Product.
3. Establish an operational plan to support stepwise process scale-up from
***** and from *****.
4. Generate process transfer and draft documentation to support *****
manufacturing campaign.
5. Perform the processing and IPC testing for ***** runs to support
stepwise scale-up of the process, including packaging and shipping
***** purified process intermediate from Diosynth RTP to Diosynth B.V.
for subsequent purification.
6. Evaluate the performance of the ***** runs.
7. Adjust process documentation following the ***** activities to account
for experience and current process knowledge prior to the ***** runs.
8. Procure, test and disposition Process Consumables, to support process
transfer, scale-up and cGMP manufacturing at *****.
9. Perform two cGMP production runs ***** according to operational
parameters established with Sponsor during the ***** operations.
10. Perform all activities in accordance with the Quality Agreement.
11. Assemble data and CMC documentation for work performed at Diosynth.
6
5.0 PROGRAM ASSUMPTIONS
The Program Assumptions listed below provide the framework on which the Scope is
based. If the Program Assumptions change or prove to be invalid, the Program
activities, price and duration are subject to revision. In addition, in such
case Sponsor shall pay to Diosynth the amounts set forth in the Agreement as if
the Program Assumptions were valid and the activities described in the Scope
have been performed as intended in the approximate time frame set forth herein.
Such payment will not be credited towards Scope activities performed at a later
date if the change or invalidity of any Program Assumption results in a delay.
1. The existing manufacturing process will transfer and perform *****
without additional process development, as represented by the Sponsor.
No process development activities are necessary.
2. Diosynth personnel will be able to observe the ***** process that will
be transferred to Diosynth at Sponsor's facility.
3. Current Diosynth raw material item numbers will be used where possible
to support manufacturing activities. Sponsor will provide detailed full
testing requirements for all critical raw materials. Raw Material
testing and release requirements will be in accordance with a ▇▇▇▇ of
Material associated testing requirements to be provided as a Sponsor
Deliverable described in section 6.0. Testing for raw material will be
according to compendial (USP and EP) methods.
4. Fermentation productivity range will be approximately ***** and
subsequently redefined after ***** manufacturing. If productivity is
outside of this range, Sponsor will provide Diosynth with instruction
on how to proceed with further processing operations.
5. Two ***** runs will be performed. Under the Quality Agreement, the
Product will be analyzed against pre-defined specifications. Sponsor
agrees to pay Diosynth the amounts set forth in the Agreement,
irrespective of the disposition of the lots.
6. Sponsor will deliver a robust scaleable feed control strategy for the
fermentation process transfer and scale up on or before the effective
date of the Agreement.
7. Sponsor is responsible for characterization of product or
process-related impurities.
8. The action/alert levels and/or specifications for bulk API, process
intermediates and manufacturing process will be communicated to
Diosynth within 30 days of the effective date of the Agreement.
9. Diosynth will perform analytical testing only as specified in this
Scope and in accordance with the Quality Agreement.
10. Diosynth will prepare all documentation, including SOPs, batch records,
item specifications, etc., required to execute the Program in
accordance with the Quality Agreement.
11. Sponsor will procure and ship all chromatography resins to Diosynth.
Sponsor will perform any applicable functional testing requirements
prior to shipment of chromatography resins to Diosynth. Diosynth will
only perform identity testing on resins.
12. Sponsor will provide to Diosynth data and specifications that
demonstrate that SPI can be packaged and shipped from Diosynth RTP to
Diosynth B.V. without adversely affecting its properties. The shipment
of SPI will be in accordance with Sponsor specifications and FOB terms.
13. Diosynth B.V. will ship bulk Drug Substance to Sponsor or a third party
vendor for fill/finish. Diosynth will perform bioburden, LAL and
identity testing, and prepare the bulk Drug Substance for shipment
according to Sponsor's instructions.
14. All analytical methods required to be performed by Diosynth have been
fully developed and appropriately qualified by Sponsor for API and
process intermediates produced from recombinant cell line prior to
transfer within 30 days of the effective date of the Agreement. No
assay development is necessary.
7
15. Purchase and/ or rental of capital equipment will be approved by and
billed to the Sponsor. No dedicated equipment will be required for this
campaign. Should dedicated equipment be required, the requisite
activities and budget will require revision.
16. Sponsor will generate and provide all required stability data for SPI
(up to 90 day stability) and API.
17. All assays will be qualified by Sponsor before transfer of the
manufacturing process to Diosynth begins. All assays will be
transferred and qualified by Diosynth prior to the start of *****
manufacturing.
18. Sponsor will provide all deliverables set forth in Section 6.0 on or
before the effective date of the Agreement.
8
6.0 DELIVERABLES FROM SPONSOR TO DIOSYNTH
Sponsor will provide the following items on or before the date specified, if no
date is specified, the delivery date is within 30 days of the effective date of
the Agreement. Any delay in providing these items/information will result in
delays to the Program timeline and additional cost to Sponsor.
1. Vials from the Master Cell Bank (MCB) or Working Cell Bank (WCB) and
cell line test results: The cell bank must be certified to have passed
testing for *****. Results from a certified laboratory must be provided
by Sponsor and approved prior to receipt of vials at Diosynth.
2. Product reference standard and associated C of A (Effective Date of
Agreement).
3. All necessary documentation related to the production of the Product,
including the following:
A. Development reports for ***** process with new cell line
B. Process documentation and reports from previous large scale
manufacturing campaign
C. Assay transfer protocols in format as agreed with Diosynth
D. Standard Operating Procedures for all analytical methods
E. Development and Qualification/Validation reports for all
analytical methods to be transferred to Diosynth as performed
at Sponsor
F. Copies of production batch records for Sponsor's ***** process
G. Development reports for all phases of the Sponsor's process
development
H. Procedures for shipping of bulk API and SPI
I. Specifications for API formulation
J. Specifications for the modified manufacturing process
4. Process Consumables ▇▇▇▇ of Materials, and associated requirements, to
describe raw material quantities, specifications and applicable testing
methods and specifications.
5. Item Specifications for raw materials, SPI and Drug Substance.
6. Cleaning Validation reports.
7. SPI and Drug Substance stability reports.
8. Column and filter use reports.
9
7.0 PROGRAM MANAGEMENT
7.1.1 Objective:
Provide overall management of the Program according to the Scope of Work and
contractual terms.
7.1.2 Activities:
Diosynth will provide a Program Manager and Program team with representation
from both Diosynth sites to execute the activities described in this Scope. The
selected personnel will represent activities to be completed at respective
Diosynth RTP and Diosynth B.V. sites.
7.1.2.1 The Diosynth Program Managers will:
o Serve as the primary contact for the Program and manage communications with
Sponsor and all internal Diosynth Program Team members.
o Proactively work with Sponsor to determine what additional manufacturing
activities may be required to support future clinical plans and/or
regulatory submissions.
o Manage Program activities defined in the Scope.
o Manage Program performance against financial objectives and ensure
pre-approval of all Change Orders by the Sponsor.
o Proactively work with Sponsor to identify any issues affecting completion
of the scope as defined. Confer with Sponsor to determine and agree upon a
suitable course of action.
7.1.2.2 Joint Steering Committee will:
o Consist of senior management from Diosynth RTP, Diosynth B.V. and Sponsor.
The membership will be determined jointly between Diosynth and Sponsor upon
contract agreement.
o Meet as needed to evaluate Project progress and provide guidance for
activities moving forward. The Diosynth Program Managers will provide the
committee with regular updates on progress, and/or significant issues as
they arise.
o Provide feedback upon review of manufacturing results. The steering
committee will act on information in an expeditious manner.
10
8.0 TECHNOLOGY TRANSFER & SCALE-UP
Objective:
Diosynth's objective for the technology transfer is to enable an efficient
scale-up of the Sponsor's ***** process to *****. This will be accomplished by
transferring all pertinent process documentation from the Sponsor and through
close ongoing communication with the Sponsor's process development personnel.
8.1 Fermentation Process Transfer and Scale up to *****
8.1.1 Activities:
1. Develop a plan to scale-up Sponsor's ***** fermentation process to the
*****, with the intent of subsequent scaling to the *****.
2. Perform a single ***** fermentation based on the process documentation
provided by the Sponsor. Operating ranges identified by Sponsor at the
***** will be used. This run will be completed in Diosynth's Small
Scale manufacturing area using draft batch records based on Sponsor's
direction.
3. Perform IPC testing to support the production run as defined in the
Quality Agreement.
4. Evaluate the performance of the fermentation process and review
critical process issues with Sponsor.
5. Perform a second ***** fermentation based on Sponsor process
documentation and experience from the first ***** fermentation run.
6. Evaluate fermentation performance in accordance with previously
established criteria. Establish fermentation process performance
criteria for further process scale up to the *****.
7. In conjunction with the Joint Steering Committee and Program team,
adjust process manufacturing instructions for scale-up to the *****.
8.2 Downstream Purification Process Transfer and Scale up to *****
8.2.1 Recovery and ***** Transfer Activities Performed at Diosynth RTP:
1. Develop a plan to scale-up Sponsor's ***** recovery and ***** to the
*****, with the intent of subsequent scaling to *****.
2. Perform Product recovery and ***** operations on material produced in
one ***** fermentation based on the process documentation provided by
the Sponsor. Operating ranges will be based on data from Sponsor's
***** runs. This scale run will be completed in Diosynth's *****
manufacturing area using draft batch records.
3. Perform IPC testing to support the scale-up run, as defined in the
Quality Agreement.
4. Aliquot SPI into Sponsor-selected storage containers and ship SPI in
accordance with Sponsor specifications to Diosynth B.V. for further
processing.
5. Evaluate the performance of the recovery and ***** process and review
critical process issues with Sponsor.
6. Perform a second ***** recovery and ***** based on Sponsor process
documentation and experience from the first ***** run.
7. Aliquot SPI into Sponsor-selected storage containers and ship SPI in
accordance with Sponsor specifications to Diosynth B.V. for further
processing.
11
8. Evaluate recovery and ***** performance in accordance with previously
established criteria. Establish recovery and ***** process performance
criteria for further process scale up to the *****.
9. In conjunction with the Joint Steering Committee and Program team,
adjust process manufacturing instructions for scale-up to the *****.
8.2.2 Purification Transfer Activities Performed at Diosynth B.V.
1. Develop a plan to scale-up Sponsor's ***** purification process to the
***** with the intent of subsequent scaling to *****.
2. Receive and release SPI as a process from Diosynth RTP in accordance
with the Quality Agreement.
3. Perform one final purification and bulk fill processing steps on SPI
produced at Diosynth RTP at the ***** scale. Bulk API will be
aseptically filled in Sponsor selected storage containers. Sampling for
testing (Release, Stability and/or For information Only) will be
performed based on a sampling plan that has been mutually agreed to
between Diosynth and the Sponsor.
4. Evaluate the performance of the purification process and review
critical process issues with Sponsor.
5. Perform a second ***** scale purification based on Sponsor process
documentation and experience from the first ***** run.
6. Evaluate purification performance in accordance with previously
established criteria. Establish purification process performance
criteria for further process scale up to the *****.
7. In conjunction with the Joint Steering Committee and Program team,
adjust process manufacturing instructions for scale-up to the *****.
8.2.3 Deliverables:
o Technical reports for fermentation, recovery and purification transfer
and scale-up activities for the *****.
o Non-cGMP Bulk Drug Substance from the ***** manufacturing. Product
produced at the ***** will not be suitable for clinical studies.
8.2.4 Estimated Duration:
These activities are estimated to require ***** for completion.
8.3 Analytical Methods Transfer
8.3.1 Objective:
The objective of the analytical component of the work described in this Scope is
to transfer Sponsor's IPC assays into Diosynth's analytical laboratories at RTP
and Oss. The transferred assays will be used to test process intermediates and
bulk Drug Substance and support the fermentation, recovery and purification
process transfer activities.
8.3.2 Activities Performed at Diosynth RTP and Diosynth B.V.:
The assay transfer activities for this Program will be run in parallel between
the Sponsor's analytical labs and Diosynth's analytical groups at RTP and Oss.
Sponsor will transfer the following qualified and/or validated assays for use as
IPC methods:
1. *****
2. *****
3. *****
12
4. *****
5. *****
6. *****
7. *****
8. *****
9. *****
For each of these assay methods, Sponsor and Diosynth will agree on the contents
of an assay transfer protocol. The protocol will specify the criteria used to
measure successful transfer of the assay to Diosynth. Diosynth will execute the
protocol and provide the sponsor with the resultant data and summary report to
be approved by Sponsor. If the criteria are met, the assay will have been
successfully transferred and Diosynth will be considered qualified to perform
the specified testing. When the assay has been transferred, Diosynth will
prepare the appropriate written procedures.
8.3.3 Deliverables:
o Technical report of analytical transfer activities
o Qualification Reports for each assay transferred
8.3.4 Estimated Duration:
These activities will be performed concurrently with technology transfer and are
estimated to continue for *****.
13
9.0 MANUFACTURING PRE-PRODUCTION
9.1.1 Objectives:
o Prepare and modify as necessary documentation for the cGMP
manufacturing of bulk Drug Substance.
o Procure, test and disposition Process Consumables to be used in the
cGMP manufacture at ***** according to established item specifications.
9.1.2 Activities Performed at Diosynth RTP:
9.1.2.1 Documentation for cGMP manufacturing
1. Following completion of ***** runs, perform process adjustments and
modify batch records and associated equipment and process documentation
prior to proceeding with ***** cGMP manufacturing.
2. Generate and approve appropriate engineering documentation to support
the processing activities to this Product. This includes applicable
automation control programming and documentation to support each
process unit operation. A plan will be established for confirming the
***** and operational strategy selected by the Sponsor for the *****.
3. Write and approve specifications necessary for the manufacture of bulk
Drug Substance. Existing Diosynth item specifications will be used
where applicable. Where Diosynth item specifications are not available,
Diosynth will prepare new item specifications.
4. Finalize analytical method STMs for use in testing process
intermediates and bulk Drug Substance.
5. Establish internal procedures based on Sponsor specifications for
shipping SPI from Diosynth RTP to Diosynth B.V.and of API to third
party fill/finish vendor. Shipping validation studies are not included
in this Scope.
6. Write protocols for all non-dedicated equipment and perform the
appropriate studies required for change over cleaning verification of
Diosynth ***** process equipment.
9.1.2.2 Process Consumables Testing
1. Diosynth will procure, sample, test, and disposition Process
Consumables in accordance with the raw material specifications provided
by the Sponsor. Multi-compendial and full release testing will be
completed in accordance with Diosynth procedures and as specified by
the Sponsor Deliverables in Section 6.
2. Where appropriate, sufficient quantities of Process Consumables will be
purchased to supply the entire campaign, plus a minimum backup supply
for one additional ***** run. Where possible, a single lot of Process
Consumables will be purchased to supply the entire manufacturing
campaign.
3. Diosynth will perform sampling and submission of samples for testing to
be performed by a third party vendor where necessary with prior
approval by Sponsor. Where applicable, Diosynth will use
Diosynth-qualified vendors for raw material testing.
Note: Shipping of Process Consumables and samples will be funded by Sponsor and
performed per FOB terms.
9.1.3 Activities Performed at Diosynth B.V.
9.1.3.1 Documentation for cGMP manufacturing
1. Following fermentation at *****, perform necessary process adjustments
and modify batch records and associated documentation prior to
proceeding with cGMP manufacturing.
14
2. Write and approve specifications necessary for the manufacture of bulk
Drug Substance. Existing Diosynth item specifications will be used
where applicable with Sponsor review and approval. Where Diosynth item
specifications are not available, Diosynth will prepare new item
specifications with Sponsor approval.
3. Write protocols for all non-dedicated equipment and perform the
appropriate studies required for change over cleaning verification of
Diosynth ***** process equipment.
4. Finalize analytical method STM's for use in testing process
intermediates and Drug Substance.
5. Prepare shipping specifications based on information received from
Sponsor for delivery of Product to fill/finish facility. Shipping
validation studies are not included in this Proposal.
6. Prepare the necessary logistics and process descriptions in Production
Beheers (Management) System and Health Safety and Enviornment system.
7. Prepare the necessary entries in LIMS.
8. Apply for import notification as required.
9.1.3.2 Process Consumables Testing
1. Diosynth will procure, sample, test, and disposition Process
Consumables in accordance with the raw material specifications provided
by the Sponsor. Multi-compendial and full release testing will be
completed in accordance with Diosynth procedures and as specified by
the Sponsor Deliverables in Section 6.
2. Where appropriate, sufficient quantities of Process Consumables will be
purchased to supply the entire campaign, plus a minimum backup supply
for one additional ***** run. Where possible, a single lot of a Process
Consumable will be purchased to supply the entire manufacturing
campaign.
3. Diosynth will perform sampling and submission of samples for testing to
be performed by a third party vendor where necessary with prior
approval by Sponsor. Where applicable, Diosynth will use
Diosynth-qualified vendors for raw material testing.
Note: Shipping of process consumables and samples will be funded by Sponsor and
performed per FOB terms.
Deliverables:
o Process Transfer Document and Process Flow Chart
o cGMP master documentation necessary for manufacturing
o Tested and dispositioned Process Consumables
9.1.4 Estimated Duration:
These activities are estimated to require ***** to complete.
15
10.0 cGMP MANUFACTURING
10.1.1 Objective:
Manufacture, at ***** two lots of bulk Drug Substance according to cGMP.
10.1.2 Activities Performed at Diosynth RTP:
1. Perform two cGMP fermentation manufacturing runs at the ***** . Each
run will be processed through the ***** unit operation in the large
scale manufacturing facility at Diosynth's RTP location.
2. Post ***** Product intermediate (SPI) will be packaged and shipped to
Diosynth's Oss facility for completion of the downstream processing
under Sponsor-defined conditions, in Sponsor-designated containers.
3. Perform testing as defined by the Quality Agreement.
4. Release the SPI prior to shipping, according to procedures mutually
agreed between the Sponsor and Diosynth.
5. Collect samples of unprocessed fermentation harvest for non-host
contamination testing.
10.1.3 Activities Performed at Diosynth B.V.:
1. Perform two cGMP purification runs on SPI produced at Diosynth RTP at
the *****.
2. Perform IPC testing according to terms of the Quality Agreement.
3. Test bulk Drug Substance according to terms of the Quality Agreement.
4. Using aseptic techniques under a laminar flow hood, perform bulk fill
of the bulk Drug Substance and ship to Sponsor or Sponsor-selected
fill-finish contractor, under Sponsor-defined conditions, in
Sponsor-designated containers.
10.1.4 Deliverables:
o API dispositioned in accordance with the Quality Agreement.
o Copies of all executed batch records or master process documentation,
including results of in process testing, as described in the Quality
Agreement.
o Manufacturing campaign report. Report will be according to Diosynth
standard formats.
10.1.5 Estimated Duration:
The estimated duration of the manufacturing campaign will be *****.
16
11.0 QUALITY ASSURANCE AND QUALITY CONTROL
11.1.1 Objective:
Provide QA and QC support for cGMP manufacturing in accordance with the approved
Quality Agreement.
11.1.2 Activities:
1. Provide oversight to ensure cGMP compliance during bulk Drug Substance
manufacture.
2. Issue and maintain controlled documents such as item specifications and
batch records.
3. Perform QA review of completed production records.
4. Support internal and customer audits of documents and facility
according to Sponsor Visit Guidelines.
5. Review and approve investigations.
6. Qualify appropriate IPC and release methods in accordance with the
Quality Agreement.
7. Prepare appropriate documentation for dispositioning of SPI and API in
accordance with the Quality Agreement.
Note: Sponsor will be responsible for all assays involving the use of tissue,
cell lines or animals.
11.1.3 Deliverables:
Documentation as specified in the Quality Agreement
17
12.0 REGULATORY SUPPORT
12.1.1 Objective:
o Support Sponsor's regulatory filing, by assembling data and CMC
documentation from services performed at Diosynth.
o Ensure compliance with applicable regulations pertaining to drug and
biologics manufacturing for human use as stated in regulatory
documents. (Guidance for Industry Q7A Good Manufacturing Practice
Guidance for Active Pharmaceutical Ingredients, and 21 Code of
Federal Regulations, Parts 210 and 211 and EC Guidance for
Pharmaceutical Manufactures and Distributors.)
12.1.2 Manufacturing Documentation:
Copies of executed batch records and/or documentation as specified in the
Quality Agreement will be provided.
12.1.3 Regulatory Activities:
1. Provide manufacturing information and data to Sponsor for amendments to
the CMC section of Sponsor's IND. Data and documents will be developed
according to Sponsor determined format for IND amendment with the U.S.
Food and Drug Administration.
12.1.4 Regulatory Activities that can be provided to Sponsor based on Time and
Material Pricing
1. Respond to follow-up requests from Sponsor or FDA for additional CMC
information and documents.
2. Host client and/or regulatory compliance audits as mutually agreed.
Provide follow-up and completion of action items resulting from
compliance audits.
3. Maintain a copy of final version of CMC and related updates/changes at
Diosynth.
Note: Diosynth will only act in advisory capacity with regard to regulatory
strategy. Sponsor will be solely responsible for determining the regulatory
strategy. Diosynth is available to attend meetings with relevant regulatory
agencies, as reasonably requested, along with the Sponsor.
Note: This scope does not include regulatory support for licensure of the
Product.
12.1.5 Deliverables:
Copies of data and documents for regulatory submission support.
12.1.6 Estimated Duration:
For duration of contracted manufacturing program, which is estimated to be
*****.
18
APPENDIX TWO
(ESTIMATED BUDGETand/or payment schedule)
PROGRAM BUDGET FOR BIOMARIN'S NEUTRALASE
----------------------------------------------------------------- -----------------------------------------------------
PROGRAM ACTIVITY [ESTIMATED BUDGET]
----------------------------------------------------------------- -----------------------------------------------------
----------------------------------------------------------------- -----------------------------------------------------
I. Program Management *****
----------------------------------------------------------------- -----------------------------------------------------
----------------------------------------------------------------- -----------------------------------------------------
II. Technology Transfer *****
o Fermentation Process Transfer
o Downstream Process Transfer
o Analytical Method Transfer
o Analytical Support for Process Transfer
----------------------------------------------------------------- -----------------------------------------------------
----------------------------------------------------------------- -----------------------------------------------------
III. Scale-up/Engineering and Pre-production Activities *****
o cGMP Documentation: Batch Records, Formulation
Records, Item Specifications, STMs, etc.
o Procurement and Testing of Raw Materials/Process
Consumables (does not include purchase price for
Raw Materials/Process Consumables)
o Process Engineering:
o DCS configuration
o Utility and equipment configuration
o Process Flow Diagrams
----------------------------------------------------------------- -----------------------------------------------------
----------------------------------------------------------------- -----------------------------------------------------
IV. Manufacturing, Quality Assurance, & reduced *****
Quality Control testing by Diosynth:
o *****
o *****
o IPC testing
o Reduced QC testing of Drug Substance by Diosynth
o Quality Assurance
----------------------------------------------------------------- -----------------------------------------------------
----------------------------------------------------------------- -----------------------------------------------------
V. Regulatory Support *****
----------------------------------------------------------------- -----------------------------------------------------
----------------------------------------------------------------- -----------------------------------------------------
TOTAL BUDGET*** *****
----- ---------
----------------------------------------------------------------- -----------------------------------------------------
Note:
*Budget does not include Process Consumables which will be billed separately
35
APPENDIX THREE
(Sponsor Visit Guidelines)
[OBJECT OMITTED]
Guidelines for Sponsor Visits
1. Access to production areas:
During production runs, it may be possible to arrange Sponsor access to the
manufacturing floor, if space allows. A Diosynth escort will be assigned and
will accompany the Sponsor at all times while in controlled areas of the plant.
During this time it is critical that the visitor:
o Follows all GMP / access / gowning / safety procedures as directed by
Diosynth personnel.
o Does not touch or operate any equipment in the production area.
o Does not direct manufacturing personnel. Suggestions or recommendations
may be made to an area Manager or Director.
o Does not remove any documentation or in-process data. Requests for
documentation must be made in writing to an area Manager or Director. Any
documentation provided in this fashion will be tracked by the area
Director.
o Makes all requests for additional immediate in-process sampling, in
writing to the area Manager or Director with full justification, prior to
sampling.
o Does not enter areas where production is ongoing for another client.
o Does not take any photos inside any Diosynth facility. Diosynth can
provide digital photographs as appropriate.
Lack of adherence to these very basic guidelines will result in immediate loss
of access to production areas.
2. Audits:
Existing customers:
o Diosynth will support one (1) audit of up to two (2) days duration, during
each twelve (12) month period of an active contract, to be billed on a time
and materials basis or as specified in the contract.
o The audit may be performed by the Sponsor or by an external third party,
with third party costs being at the sole expense of the client. A maximum
of three (3) auditors / Sponsor participants will be allowed to take part
in the actual audit, due to space limitations and dedicated Diosynth
personnel availability.
o Dates for the audit must be arranged and agreed with Diosynth a minimum of
one month prior to the audit. Diosynth reserves the right to make final
approval of audit dates, based on availability of the facility and
appropriate Diosynth personnel.
36
o Confidentiality agreements must be in place with all parties participating
in the audit, prior to scheduling the audit.
o Three weeks before the audit occurs, a list of areas / topics to be covered
in the audit will need to be received by Diosynth. This will allow Diosynth
to ensure appropriate Diosynth personnel availability during the audit,
while also ensuring minimal impact to programs in production for other
clients.
o No access will be allowed into areas where production is underway for
another client.
o Any audit observations being sent to Diosynth for review or response must
be provided by the client, not directly from a third party auditor.
Diosynth will formally respond to audit findings within forty-five (45)
days.
o All audit observations are confidential, covered in the confidentiality
agreement between Diosynth and the client, and may not be shared with any
other party without express written permission. All third party auditors
must also sign confidentiality agreements with Diosynth confirming
adherence to this condition and may not share their findings beyond the
Sponsor who contracts the audit, without express written permission from
Diosynth.
o It may be possible to arrange additional audits during a given year, to be
billed to the Sponsor on a time-and-materials basis. An estimate of this
charge can be provided in advance and will be determined by the scope of
the audit and the resources required to support it.
During audits:
All non-Diosynth personnel will be escorted at all times while in controlled
areas of the plant, Process Development or Quality laboratories. During this
time it is critical that the visitor:
o Follows all GMP / access / gowning / safety procedures as directed by
Diosynth personnel
o Does not direct manufacturing personnel.
o Does not touch or operate any equipment in the production or laboratory
area.
o Does not remove any documentation.
o Does not enter areas where production is underway for other clients.
o Does not take photos within any Diosynth facility. Diosynth can provide
digital photographs as appropriate.
37