EXHIBIT 10.34
PORTIONS OF THIS EXHIBIT WERE OMITTED AND FILED SEPARATELY WITH THE SECURITIES
AND EXCHANGE COMMISSION PURSUANT TO AN APPLICATION FOR CONFIDENTIAL TREATMENT
FILED WITH THE COMMISSION PURSUANT TO RULE 24b-2 UNDER THE SECURITIES EXCHANGE
ACT OF 1934. SUCH PORTIONS ARE MARKED BY ASTERISKS.
COMMERCIAL MANUFACTURING AGREEMENT
THIS COMMERCIAL MANUFACTURING AGREEMENT (the "Agreement") is entered into on
this May 22, 2001 (the "Effective Date"), by and between ViroPharma Incorporated
("ViroPharma"), a Delaware corporation having a place of business at 000
Xxxxxxxxx Xxxxxxxxx, Xxxxx, Xxxxxxxxxxxx 00000, and Produits Chimiques
Auxilliaires et de Synthese, SELOC France Division ("PCAS") having a place of
business at 23, rue Bossuet-Z.I. de la Xxxxx xxx Xxxxx, 00000 Xxxxxxxxx, Xxxxxx.
ViroPharma and PCAS may each be referred to herein individually as a "Party" and
collectively as the "Parties".
WHEREAS, ViroPharma has developed a new pharmaceutical active ingredient,
pleconaril and would like to obtain commercial supplies of Pleconaril;
PCAS has worked for ViroPharma, under previous agreements, to develop the
manufacturing process of Pleconaril, and has already supplied ViroPharma with
initial commercial quantities of Pleconaril, and has the ability and desire to
go on supplying ViroPharma with commercial quantities of pleconaril; and
InterChem Corporation, ("InterChem"), a corporation having an address at 000,
Xxxxx 00 Xxxxx, Xxxxxxx, XX, 00000-0000, has been appointed by PCAS as its
distributor for Pleconaril and other products in the USA and Canada.
NOW THEREFORE, in consideration of the mutual promises and covenants set forth
below and other good and valuable consideration, the receipt and sufficiency of
which is hereby acknowledged, the Parties agree as follows:
1. DEFINITIONS. The following terms shall, unless the context otherwise
requires, have the respective meanings set out below, and grammatical
variations of such terms shall have corresponding meanings:
1.1 "AFFILIATE" means a corporation, partnership, entity, person, firm,
company, or joint venture, whether de jure or de facto, that controls,
is controlled by or is under the common control with the referenced
Party. For the purposes of this definition the word "control"
(including, with correlative meaning, the terms "controlled by" or "is
under the common control with") means (a) ownership directly or
indirectly of at least fifty percent (50%) of the voting stock of the
applicable entity, or such lesser percentage that is the maximum
allowed to be owned by a foreign corporation in a particular
jurisdiction, or (b) the actual ability to control the management and
operations of the applicable entity.
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May 22, 2001 ViroPharma-PCAS Agreement Page 1
1.2 "API" means Pleconaril manufactured at the Manufacturing Site in
accordance with the Specifications.
1.3 "API COMPONENTS" means Raw Material, Starting Material, and Packaging
Material that comply with the Specifications and that are necessary
for the manufacture and packaging of API pursuant to this Agreement.
1.4 "CERTIFICATE OF ANALYSIS AND CONFORMANCE" means a certificate for a
batch of bulk API in a form to be mutually agreed to by the Parties,
as may be amended from time to time with the agreement of the Parties.
1.5 "cGMP" means the current good manufacturing practices for drug
substances as set forth in the U.S. Food, Drug, and Cosmetic Act and
applicable regulations promulgated thereunder, as amended from time to
time.
1.6 "CONFIDENTIAL INFORMATION" means:
1.6.1 all secret, confidential or proprietary information or data,
whether provided in written, oral, graphic, video, computer or
other form, provided by ViroPharma to PCAS pursuant to this
Agreement or any previous agreement between the Parties, or
generated by either Party pursuant to this Agreement or any
previous Agreement between the Parties, including, but not
limited to, ViroPharma Know-How, information relating to
ViroPharma's existing or proposed research, development
efforts, business, products, the terms of this Agreement and
any other materials that have not been made available by
ViroPharma to the general public. Failure to xxxx any of the
Confidential Information as confidential or proprietary shall
not affect its status as Confidential Information under the
terms of this Agreement.
1.6.2 Notwithstanding the foregoing Section 1.6.1, Confidential
Information shall not include any information or materials
that: (i) at the time of disclosure by ViroPharma to PCAS is
in, or after disclosure by ViroPharma to PCAS becomes part of
the public domain, through no improper act on the part of PCAS
or on the part of any of its respective employees or
contractors; (ii) was in PCAS' possession at the time that such
information was first disclosed by ViroPharma, as shown by
written evidence, and was not acquired, directly or indirectly,
from ViroPharma; (iii) PCAS receives from a third party,
provided that such Information was not obtained by such third
party, directly or indirectly, from ViroPharma; or (iv) is
required to be disclosed by law, provided that ViroPharma is
given reasonable advance notice of such requirement to divulge
and an opportunity to obtain a protective order.
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May 22, 2001 ViroPharma-PCAS Agreement Page 2
1.6.3 all secret, confidential or proprietary information or data,
whether provided in written, oral, graphic, video, computer or
other form, provided by PCAS to ViroPharma pursuant to this
Agreement or any previous agreement between the Parties, or
generated by either Party pursuant to this Agreement or any
previous Agreement between the Parties, including, but not
limited to, PCAS know-how, information relating to PCAS'
existing or proposed research, development efforts, business,
products, the terms of this Agreement and any other materials
that have not been made available by PCAS to the general
public. Failure to xxxx any of the Confidential Information as
confidential or proprietary shall not affect its status as
Confidential Information under the terms of this Agreement.
1.6.4 Notwithstanding the foregoing Section 1.6.3, Confidential
Information shall not include any information or materials
that: (i) at the time of disclosure by PCAS to ViroPharma is
in, or after disclosure by PCAS to ViroPharma becomes part of
the public domain, through no improper act on the part of
ViroPharma or on the part of any of its respective employees or
contractors; (ii) was in ViroPharma's possession at the time
that such information was first disclosed by PCAS, as shown by
written evidence, and was not acquired, directly or indirectly,
from PCAS; (iii) ViroPharma receives from a third party,
provided that such Information was not obtained by such third
party, directly or indirectly, from PCAS; or (iv) is required
to be disclosed by law, provided that PCAS is given reasonable
advance notice of such requirement to divulge and an
opportunity to obtain a protective order.
1.7 "(Euro)/$ EXCHANGE RATE" means the Euro per U.S. dollar exchange rate
as published in The Wall Street Journal on the specified date, or if
no rate is reported on that date, on the next subsequent date on which
the rate is reported.
1.8 "FDA" means the United States Food and Drug Administration.
1.9 "INVENTION" means any invention, modification, discovery, improvement,
technology, trade secret, chemical or biological material, assay,
method, process, technique, documentation, scientific and technical
data, drawing or other information, whether patentable or not,
resulting from the use of the Specifications, any process information,
any Confidential Information of ViroPharma, or resulting from the
manufacture of API or Starting Material.
1.10 "MANUFACTURING SITE" means PCAS' sites at 00, xxxxx xx Xxxxxx, X-
00000, Xxxxx, Xxxxxx; xxxxx xx Xxxxxx, X-00000, Xxxxxxxx, Xxxxxx; xxx
xxx Xxxxxx Xxxxxxx, X-00000, Xxxxxxxx-Xxxxxxx Xxxxxx; and any other
site approved by ViroPharma in accordance with Section 3.7.1.
1.11 "PACKAGING MATERIAL" means any materials needed to contain, store,
package and/or ship API.
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May 22, 2001 ViroPharma-PCAS Agreement Page 3
1.12 "PLECONARIL" means the compound pleconaril with CAS No. 153168-05-9,
also known as VP 63843.
1.13 "RAW MATERIAL" means chemicals, ingredients, and other supplies
necessary for the manufacture of API, other than the Starting
Materials, that meet reasonable industry standards and the
Specifications.
1.14 "REGULATORY AUTHORITY" means any national (e.g., the United States
Food and Drug Administration), supra-national (e.g., the European
Commission, the Council of the European Union, or the European Agency
for the Evaluation of Medicinal Products), regional, state or local
regulatory agency, department, bureau, commission, council or other
governmental entity in each country of the world involved in the
granting of regulatory approval for the marketing of Pleconaril.
1.15 "SAMPLE" means 100 g of a substance, unless otherwise stated in the
Specifications.
1.16 "SPECIFICATIONS" means: (a) the product, formula, processing,
testing, storage, packaging, handling, and shipping specifications,
including, without limitation, the master batch record, that will be
supplied by ViroPharma to PCAS; (b) the quality assurance and quality
control specifications and analytical methods that will be supplied by
ViroPharma to PCAS; and (c) the requirements of cGMP, in each case as
may be amended to meet the requests or requirements of FDA or another
Regulatory Authority. The complete and comprehensive Specifications
to be supplied by ViroPharma to PCAS under Sections 1.16(a-b) shall be
substantially similar to the summary specifications set forth in
Exhibit 1.16(a-b) attached to and included in this Agreement.
1.17 "STARTING MATERIALS" means: ***********, also known as *********,
and *********** also known as *********, that meet the Specifications.
1.18 "VALIDATION BATCH" means a batch of approximately 580 kg of API, but
in no event less than 450 kg of API, produced pursuant to Section 3.8
and the Validation Protocol.
1.19 "VALIDATION CAMPAIGN" means three Validation Batches made
consecutively, with no failed attempts to make a Validation Batch
intervening.
1.20 "VALIDATION PROTOCOL" means the protocol for the production of the
Validation Campaign of API, set forth in Exhibit 1.20 attached to and
included in this Agreement, as may be amended from time to time by
written agreement of the Parties.
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May 22, 2001 ViroPharma-PCAS Agreement Page 4
1.21 "VALIDATION REPORT" means the report and related documentation
described in the Validation Protocol, regarding the manufacture and
testing of all Validation Batches and the Validation Campaign.
1.22 "VIROPHARMA KNOW-HOW" means all inventions, technology, trade
secrets, physical, chemical or biological material, assays, methods,
documentation, scientific and technical data and other information
(excluding ViroPharma Patents) that ViroPharma owns or otherwise has a
right to use as of the date of this Agreement or at any time during
the term of this Agreement.
1.23 "VIROPHARMA PATENTS" means all United States and foreign patents and
patent applications, including divisions, continuations,
continuations-in-part, additions, renewals, extensions, re-
examinations and reissues of all such patents and patent applications,
that are owned or licensed by ViroPharma.
2. TERM
The term of this Agreement will begin on the Effective Date, and unless earlier
terminated as provided in Article 13, shall continue in effect until
December 31, 2003.
3. API MANUFACTURE AND SUPPLY
3.1 Manufacture. PCAS shall manufacture API at the Manufacturing Site in
accordance with the Specifications, including, without limitation
cGMP, and with its representations, warranties and covenants under
this Agreement, for delivery to ViroPharma in accordance with
Section 4.5.
3.2 REQUIREMENTS AND MINIMUM SUPPLY.
3.2.1 PCAS agrees to supply up to ********** kg of API in calendar
year 2001, up to ********* kg of API in calendar year 2002, and
up to ********* kg of API in calendar year 2003 and subsequent
calendar years, if any, of the Agreement. In the event that
ViroPharma requires more than these amounts from PCAS, PCAS
shall use its best efforts to supply such increased
requirements.
3.2.2 ViroPharma commits to purchasing from PCAS at minimum:
a. in calendar year 2001 ********* kg of API;
b. in calendar year 2002, the lesser of (i) ********* kg of
API, or (ii) *****% of its requirements for API in such
year; and
c. in calendar year 2003, the lesser of (i) ********* kg of
API, or (ii) *****% of its requirements for API.
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May 22, 2001 ViroPharma-PCAS Agreement Page 5
Nothing in this Section 3.2.2 shall prevent ViroPharma from
purchasing more than these amounts from PCAS.
3.2.3 If PCAS is unable to fulfill its commitments under
Section 3.2.1, or ViroPharma has fulfilled its commitments
under Section 3.2.2, nothing in this Agreement shall prevent
ViroPharma from purchasing Pleconaril from a third party.
3.2.4 Nothing in this Agreement shall preclude ViroPharma from taking
whatever steps necessary to qualify alternative suppliers of
Pleconaril, including, but not limited to selling any batches
of Pleconaril reasonably required to be manufactured for
purposes of the qualification of such alternative suppliers,
and for maintaining such qualifications, e.g., validation
batches.
3.2.5 If ViroPharma exercises its right to have quantities of API
manufactured by one or more alternative suppliers, and if such
alternative suppliers require ViroPharma to supply Starting
Materials, then PCAS shall have a right of first offer to
produce a minimum of *****% of ViroPharma's requirements of
such Starting Materials, provided that PCAS is able to supply
the said quantities at a competitive price.
3.3 THIRD PARTIES. PCAS shall not manufacture Pleconaril for or sell
Pleconaril to any third parties during the term of this Agreement
without the prior written consent of ViroPharma.
3.4 DOCUMENTATION. PCAS will prepare a Certificate of Analysis and
Conformance for each batch of API confirming that such batch conforms
with the Specifications. With its shipment of such batch pursuant to
Section 4.5 and Article 5 below, PCAS shall include the Certificate of
Analysis and Conformance, identifying to which batch the certificate
relates, and, at the request of ViroPharma, or as required in the
Specifications or the Certificate of Analysis and Conformance, any raw
data or executed batch records regarding the manufacture of the batch
that ViroPharma reasonably requests.
3.5 SAMPLE RETENTION. PCAS shall retain Samples of the Starting Material,
each Raw Material identified for sample retention in the
Specifications, and the manufactured API, identifying them by batch of
manufactured API. PCAS shall retain such Samples under normal
warehouse conditions for the longer of: two years after the delivery
of the relevant batch of API to ViroPharma, or the period required by
law. PCAS shall promptly deliver such samples to ViroPharma upon
ViroPharma's request. PCAS will contact ViroPharma at least sixty
days before the planned destruction of any such Samples, at which time
ViroPharma may request that PCAS deliver such Samples to ViroPharma at
ViroPharma's cost. PCAS shall promptly notify ViroPharma in writing
of any accidental loss or destruction of such Samples.
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May 22, 2001 ViroPharma-PCAS Agreement Page 6
3.6 API COMPONENT SUPPLY. PCAS shall be solely responsible for obtaining
or manufacturing at its own costs sufficient inventories of API
Components to complete the manufacture and delivery of the batches of
API ordered pursuant to the Agreement. The foregoing sentence shall
not preclude ViroPharma from assisting in obtaining supply of API
Components on behalf of PCAS if PCAS and ViroPharma so agree. PCAS
shall be solely responsible for inspecting the API Components to
ensure that they comply with the Specifications and PCAS is solely
responsible for the return or other disposal of API Components that do
not meet the Specifications. PCAS shall supply, at ViroPharma's
request, written reports and analyses of API Components to demonstrate
conformance to applicable Specifications.
3.7 CHANGES.
3.7.1 PRIOR APPROVAL AND NOTICE. PCAS shall not change the
Manufacturing Site, the Specifications, the API Components, or
any material aspect of the manufacture of API without the prior
written consent of ViroPharma, regardless of whether any such
change requires FDA or other Regulatory Authority approval.
PCAS shall provide ViroPharma with all reasonably requested
data, documentation and assistance to effectuate such change.
PCAS shall provide ViroPharma with thirty (30) days written
notice before any planned move of the manufacturing of Starting
Materials or API between PCAS' Xxxxxxxx-Jallieu, Couterne, and
Limay sites, and may proceed with such move if ViroPharma does
not object to such written notice within fifteen (15) days.
PCAS may sub-contract the manufacturing of Starting Materials
after providing notification to and receiving written approval
from ViroPharma.
3.7.2 CHANGES REQUIRED BY REGULATORS. If FDA or another Regulatory
Authority requires ViroPharma to change the Manufacturing Site,
the Specifications, or the API Components for manufacturing
API, PCAS shall make such changes. If changes in manufacturing
made pursuant this Section 3.7.2 change the costs of
manufacturing API by more than 10%, then the Parties shall
negotiate in good faith to share the costs between them.
3.7.3 PERMISSIVE CHANGES.
a. PCAS may propose changes to the Manufacturing Site, the
Specifications, or the API Components for manufacturing API
by providing ViroPharma with a detailed written report
describing such proposed changes, for ViroPharma's review
and approval. Except as set forth in Section 6.5, PCAS
shall bear the costs of such changes.
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May 22, 2001 ViroPharma-PCAS Agreement Page 7
b. If ViroPharma requests a change in the Manufacturing Site,
the Specifications, or the API Components for manufacturing
API that is not the result of a requirement of FDA or
another Regulatory Authority, PCAS shall use its best
efforts to accommodate such request, and ViroPharma will
reimburse PCAS for the costs of such changes.
3.7.4 COMPLIANCE WITH STANDARDS. In the event that PCAS's activities
are not performed at the previously approved Manufacturing
Site, or in accordance with the previously approved
Specifications, PCAS's efforts to bring its activities into
compliance with such requirements shall not constitute a change
under this Section 3.7.
3.8 VALIDATION BATCHES AND VALIDATION CAMPAIGNS.
3.8.1 REQUIREMENTS BEFORE MANUFACTURE OF VALIDATION BATCHES. PCAS
shall not begin manufacturing any Validation Batch until both:
(a) PCAS has received the complete and comprehensive
Specifications from ViroPharma pursuant to Section 1.16,
and
(b) the Parties have agreed to the form of a Certificate of
Analysis and Conformance.
3.8.2 MANUFACTURE. PCAS shall manufacture a Validation Campaign of
API consistent with the Validation Protocol, each Validation
Batch of which will be ordered and shipped like a standard
batch, except as set forth in the Validation Protocol. PCAS
shall deliver to ViroPharma a draft Validation Report within
twenty-one (21) days after the shipment of the final Validation
Batch in a Validation Campaign. ViroPharma will provide PCAS
with comments on the draft Validation Report within fifteen
(15) days of receiving such draft. PCAS shall provide
ViroPharma with a final Validation Report within fifteen (15)
days after receiving ViroPharma's comments on the draft report.
PCAS shall make all reasonable changes to the Validation Report
requested by ViroPharma. If requested by ViroPharma, PCAS will
provide a copy of the final Validation Report in electronic
format.
3.9 TECHNOLOGY TRANSFER. At ViroPharma's request, PCAS shall assist
ViroPharma in transferring to third parties manufacturing Pleconaril
for ViroPharma all technology and know-how necessary to manufacture
Pleconaril to the Specifications and in compliance with all applicable
laws and regulations. Such transfer shall be for consulting fees of
$1000 per person per day and reasonable travel and out-of-pocket
expenses.
4. ORDERING AND SHIPMENT
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May 22, 2001 ViroPharma-PCAS Agreement Page 8
4.1 FORECASTS. On or before the fifteenth day of each calendar quarter
starting respectively in January, April, July, and October, ViroPharma
shall update the eighteen-month quarterly forecast of API needs set
forth in Exhibit 4.1 attached to and included in this Agreement,
beginning with the next calendar quarter. Notwithstanding the
foregoing, ViroPharma shall promptly update such forecast if its
anticipated requirements for the first three months of such forecast
have changed by more than twenty percent.
4.2 MINIMUM BATCH SIZE. Orders for API shall be in multiples of whole
batches.
4.3 FIRM ORDERS. On or before the fifteenth day of each month, ViroPharma
shall provide PCAS with a firm written order (a "Firm Order") for the
amount of API to be produced and delivered to ViroPharma by the end of
the ******* month following the month in which such Firm Order is
made, unless ViroPharma specifies a different later date for delivery.
The Firm Order shall include a purchase order number and specify the
amount of API to be manufactured and the location of delivery. The
amount of API ordered by ViroPharma in a Firm Order shall be binding
on ViroPharma and PCAS, and shall not be subject to reduction. PCAS
shall have the right to reject any Firm Offer for an amount in excess
of the amount of its annual agreed supply set forth in Section 3.2.1.
within fifteen (15) days of the receipt of such Firm Order.
4.4 TIME OF THE ESSENCE.
4.4.1 GENERAL. PCAS understands that time is of the essence to the
manufacture and delivery of API under this Agreement. If at any
time PCAS reasonably believes that it will be unable to satisfy
a Firm Order that was not properly rejected in accordance with
Section 4.3, in either amount or delivery time, it shall notify
ViroPharma immediately, except that PCAS may use the Safety
Stock to avoid any such shortfall or delay. After discussion
with PCAS about how to remedy any such problem, ViroPharma may
accept that amount of such Firm Order that PCAS is able to
deliver. If ViroPharma elects to accept a reduced delivery,
then, in accordance with Section 6.2, the charge for such
amount of API shall be based on the amount ordered, and not the
amount delivered.
4.4.2 COST. If ViroPharma accepts a reduced Firm Order after notice
from PCAS pursuant to Section 4.4.1, ***********************
incurred by ViroPharma in obtaining an equivalent amount of
Pleconaril from a third party in excess of what PCAS would have
charged for such quantity of Pleconaril (the "Excess"),
provided that ViroPharma reasonably believes that such third
party can deliver the replacement Pleconaril to ViroPharma
before PCAS would have delivered the delayed order, and except
to the extent that such Firm Order would have exceeded PCAS'
supply obligations under Sections 3.2.1 or 4.5.1., as follows:
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May 22, 2001 ViroPharma-PCAS Agreement Page 9
(a) if the Excess is ****% or less of the amount that PCAS
would have charged for the relevant quantity of
Pleconaril, PCAS shall pay all of the Excess;
(b) if the Excess is more than ****%, but less than or equal
to *****% of the amount that PCAS would have charged for
the relevant quantity of Pleconaril, then PCAS shall pay a
portion of the Excess equal to *****% of the amount that
PCAS would have charged for the relevant quantity of
Pleconaril, and the Parties shall split equally the
remainder of the Excess; and
(c) if the Excess is more than ****% of the amount that PCAS
would have charged for the relevant quantity of
Pleconaril, then PCAS shall pay a portion of the Excess
equal to *****% of the amount that PCAS would have charged
for the relevant quantity of Pleconaril, and ViroPharma
shall pay the remainder of the Excess.
4.5 SHIPMENT. PCAS shall deliver all API to ViroPharma "DDP, Exton,
Pennsylvania," or such other place within the USA as ViroPharma may
designate in its Firm Order, as the term DDP is defined in INCO Terms
1990, Pub. No. 460. Transport conditions shall comply with all
applicable laws and regulations, and with the Specifications. PCAS
shall notify ViroPharma immediately of any loss of or damage to API in
transit. If any shipment of API is lost or damaged, the Parties will
cooperate in attempting to locate such shipment, or to obtain
insurance reimbursement for such shipment, and to arrange a production
schedule for PCAS to replace the lost or damaged API. If Pleconaril
is removed from the Pharmaceutical Appendix and results in a new duty
rate classification, the prevailing price to ViroPharma will be
adjusted to fully compensate PCAS for this cost.
4.6 SAFETY STOCK. During 2002 PCAS shall build up a commercially
reasonable safety stock of API. PCAS shall refresh such safety stock
regularly on a "first-in-first-out" basis from batches of API
manufactured during the course of this Agreement.
5. ACCEPTANCE
5.1 RIGHT OF REJECTION. Without limiting ViroPharma's other rights and
remedies under this Agreement or in law or equity, ViroPharma shall
have the right to reject any API that fails to meet the
Specifications, or that otherwise fails to comply with PCAS' warranty
under Section 11.2 of this Agreement ("Non-Conforming API").
5.2 PROCEDURES FOR REJECTION.
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May 22, 2001 ViroPharma-PCAS Agreement Page 10
5.2.1 Within thirty (30) days of receipt of any API, ViroPharma or
its designee shall inspect such API and give PCAS written
notice of: (i) any Non-Conforming API, or (ii) any shortages in
the amount of API delivered (together, a "Deficiency Notice").
The Deficiency Notice shall identify the rejected API by lot
number and describe the basis for rejection.
5.2.2 Within fifteen days of receiving a Deficiency Notice, PCAS
shall notify ViroPharma in writing as to whether it agrees with
the rejection. If ViroPharma and PCAS fail to agree on the
validity of such rejection within ten days after PCAS' notice,
the Parties shall agree on an independent laboratory or
consultant (the "Lab"), whose decision shall be binding, to
test the rejected API. If such testing reveals that the API in
fact was Non-Conforming API, PCAS shall pay the costs, fees and
expenses that the Lab incurred in testing the API in question.
If such testing reveals that the API in fact was not Non-
Conforming Product, ViroPharma shall pay the costs, fees and
expenses that the Lab incurred in testing the API in question.
5.3 RESPONSIBILITY FOR NON-CONFORMING API AND SHORTAGES.
5.3.1 PCAS shall be responsible for replacing at its sole cost any
Non-Conforming API properly rejected in accordance with Section
5.2 within a reasonable time not to exceed sixty (60) days from
the date that the Parties agree that the API is Non-Conforming,
or that a Lab confirms that the API is Non-Conforming.
5.3.2 In the event of any shortage of API in excess of ****% of the
total amount ordered, where each batch is expected to contain
**** kg, at ViroPharma's sole discretion, either:
(a) PCAS shall at its sole expense prepare sufficient
additional API to remedy the shortage, or
(b) The amount due for the full amount of API requested shall
be prorated to reflect the shortfall, and this reduced
amount shall be full payment for the amount of API
actually delivered. For purposes of Sections 3.2.2 and
6.2, ViroPharma shall be deemed to have ordered and
purchased the full amount ordered.
5.4 DISPOSAL OF NON-CONFORMING PRODUCT. At PCAS' request, direction, and
sole cost, ViroPharma shall either return to PCAS, or destroy any Non-
Conforming API. PCAS shall reimburse ViroPharma within thirty days of
receiving any invoice for the costs of destroying or returning any
Non-Conforming API.
5.5 INVESTIGATION. PCAS will cooperate with ViroPharma at PCAS's cost in
investigating the cause of any production of Non-Conforming API.
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May 22, 2001 ViroPharma-PCAS Agreement Page 11
6. PRICE AND PAYMENT.
6.1 GENERAL TERMS.
6.1.1 INVOICES AND PAYMENTS. PCAS shall include an invoice with each
batch of API delivered to ViroPharma. All invoices that are not
reasonably disputed by ViroPharma in accordance with Article 5
or otherwise shall be payable within forty-five (45) days after
ViroPharma's receipt. The fees and charges due hereunder shall
be payable in U.S. dollars. All payments due from ViroPharma
hereunder shall be paid to PCAS by a bank transfer sent to
PCAS's bank or by a check payable to the Designee on behalf of
PCAS. Notwithstanding the foregoing, PCAS may designate
InterChem, or another third party, in writing (the "Designee")
to assist PCAS in shipping API to ViroPharma. In such case, all
sums due hereunder from ViroPharma shall be paid to Designee on
behalf of PCAS, and upon such payment, ViroPharma shall have no
further obligation in respect of such payment to PCAS. The use
of Designee by PCAS and the receipt by ViroPharma of any API
delivered to it by Designee, shall in no way diminish any
rights that ViroPharma may have against PCAS, and shall not act
as a waiver or estoppel of any claim that ViroPharma may have
at any time against PCAS arising from or relating to this
Agreement. The Parties acknowledge that the use of Designee is
for the convenience of PCAS.
6.1.2 INVOICE RATE AND CORRECTIONS. The amount invoiced for any batch
of API delivered to ViroPharma shall be at the per kilo rate
set forth in Section 6.2 for the full amount of API projected
to be ordered in the calendar year in which the order is made.
If at the end of a calendar year, because of the amount of API
ordered in such calendar year ViroPharma was entitled to a
lower rate per kilo than was actually invoiced, PCAS shall
refund ViroPharma the difference within sixty days of the end
of such calendar year. If at the end of a calendar year PCAS
was entitled to a higher rate per kilo than was actually
invoiced, PCAS may invoice ViroPharma for the difference, which
invoice shall be payable in accordance with Section 6.1.1
above.
6.1.3 DEDUCTION FOR PRIOR PAYMENTS FOR STARTING MATERIALS. ViroPharma
shall be credited for any amounts paid under the agreement
between ViroPharma and PCAS dated February 8, 2001, for
"Materials" as that term is defined in such agreement. Any
invoices under Section 6.1 shall be offset by the amount of
such credit until the full amount of the credit has been
reached.
6.2 PRICE FOR API. Pricing for API delivered shall be based on the total
amount of API ordered by ViroPharma in a calendar year as follows. If
the amount of API
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May 22, 2001 ViroPharma-PCAS Agreement Page 12
delivered is lower than the amount of API ordered, ViroPharma
shall be charged for each kg delivered at the rate for the total
amount ordered:
6.2.1 CALENDAR YEAR 2001. In calendar year 2001:
a. If the total amount of API ordered by ViroPharma is less
than ****** kg, then ViroPharma shall pay $****** for each
kg;
b. If the total amount of API ordered by ViroPharma is ******
kg or more, but less than ****** kg, then ViroPharma shall
pay $****** for each kg;
c. If the total amount of API ordered by ViroPharma is ******
kg or more, but less than or equal to ****** kg, then
ViroPharma shall pay $****** for each kg; and
Notwithstanding the foregoing, if PCAS is unable to manufacture
any amount of API ordered by ViroPharma in calendar year 2001
up to ****** kg in accordance with Article 4, then such amount
of API shall be manufactured and delivered as soon as possible,
and shall be priced as if the order were placed in calendar
year 2002, in accordance with Section 6.2.2, below.
6.2.2 CALENDAR YEAR 2002. In calendar years 2002 and 2003:
a. If the total amount of API ordered by ViroPharma is less
than ****** kg, then ViroPharma shall pay $****** for each
kg;
b. If the total amount of API ordered by ViroPharma is
****** kg or more, but less than ****** kg, then ViroPharma
shall pay $****** for each kg;
c. If the total amount of API ordered by ViroPharma is
****** kg or more, but less than ****** kg, then ViroPharma
shall pay $****** for each kg;
d. If the total amount of API ordered by ViroPharma is
****** kg or more, but less than ****** kg, then ViroPharma
shall pay $****** for each kg;
e. If the total amount of API ordered by ViroPharma is
****** kg or more, but less than ****** kg, then ViroPharma
shall pay $****** for each kg; and
f. If the total amount of API ordered by ViroPharma is ******
kg or more, then ViroPharma shall pay $****** for each kg.
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May 22, 2001 ViroPharma-PCAS Agreement Page 13
6.3 CHARGE FOR VALIDATION CAMPAIGN.
6.3.1 Notwithstanding anything to the contrary in Section 6.2.1
above, ViroPharma shall pay PCAS $****** for each kg of API
delivered by PCAS to ViroPharma as part of a Validation
Campaign. Each such kg of API manufactured as part of a
Validation Campaign shall be included in the amounts ordered in
that calendar year for purposes of determining the price per kg
for the rest of the orders made in that calendar year.
6.3.2 ViroPharma shall pay PCAS $********* for the Validation Report.
6.4 EXCHANGE RATES. The exchange rate to be used for Orders shall be as
of the date of the Order, and shall be midway between 1.189 and the
(Euro)/$ Exchange Rate on the Effective Date as set forth on Exhibit
6.4 attached to and included in this Agreement, except that if the
exchange rate on such date differs from the average of 1.189 and the
(Euro)/$ Exchange Rate on the Effective Date by less than +/- 10% in
calendar year 2001, and +/- 7% in subsequent calendar years, there
will be no price adjustment. If the variance is greater than these
amounts, the price adjustment will be equal to 50% of the total
variance, or, stated algebraically, the amount in dollars charged for
the API in accordance with Section 6.2, shall be multiplied by the
following factor:
1 + (((1.189 + X) / 2)-Y) x 0.5
--------------------
(1.189 + X)/2
where X is the (Euro)/$ Exchange Rate on the Effective Date and Y is
the (Euro)/$ Exchange Rate on the date of the Order for API.
6.5 SHARING OF EFFICIENCIES. If pursuant to Section 3.7.3, the parties
agree to implement any change for the purpose of obtaining cost
reductions for manufacturing API, the parties shall share equally in
the cost of such implementation, other than the cost of any regulatory
filings, and in the cost reduction effected by such change.
7. AUDITS.
Upon reasonable advance notice, ViroPharma, Sanofi-Synthelabo, or the authorized
representative of either company shall have the right at all reasonable times to
enter the facilities of PCAS to inspect all activities performed pursuant to
this Agreement and related documents and materials, including, without
limitation, the manufacturing facilities and warehouses of PCAS, API Components,
API, batch records, and SOPs. PCAS shall make all documents and records
available for review and copying. PCAS shall adopt reasonable suggestions of
ViroPharma or its authorized representative to correct any deficiencies
identified in any site visit or audit. Provided that no significant adverse
findings are made during any audit in a calendar year, and there are no
indications of non-compliance with PCAS' representations and warranties
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May 22, 2001 ViroPharma-PCAS Agreement Page 14
in Section 11.2, including, without limitation, any adverse findings during an
inspection by FDA or any other Regulatory Authority, the maximum audit days per
year shall be five (5) with not more than three (3) representatives at a time.
8. REGULATORY COMPLIANCE.
8.1 General. PCAS shall perform all activities under this Agreement in
compliance with all applicable laws and regulations, and with any
applicable professional standards.
8.2 RECORDKEEPING. PCAS shall maintain all records required by all
applicable laws and regulations, and by any applicable professional
standards. Without in any way limiting the foregoing, PCAS shall keep
records of the manufacturing, testing and shipping of API adequate to
assist in resolving product complaints, conducting failure
investigations, and performing recalls, field alerts, product
withdrawals, field corrections or other similar actions.
8.3 PERMITS AND AUTHORIZATIONS. PCAS shall obtain and maintain all
necessary manufacturing licenses and approvals for the manufacturing
facilities required to perform the activities under this Agreement.
8.4 INQUIRIES FROM REGULATORY AUTHORITIES. PCAS shall promptly notify
ViroPharma in writing if FDA or any foreign equivalent makes inquiries
to PCAS regarding its activities under this Agreement.
8.5 INSPECTIONS BY REGULATORY AUTHORITIES. PCAS shall promptly notify
ViroPharma if FDA or any foreign equivalent inspects PCAS regarding
activities under this Agreement. PCAS shall provide ViroPharma with a
written report of any such inspection, noting with specificity any
record or document reviewed by the regulatory inspector. When a copy
of a document or record is supplied to the inspector on request, that
fact will be noted in the report. PCAS shall keep copies of each of
these records or documents in a separate inspection file and, on
ViroPharma's request, will provide ViroPharma with copies of any or
all of these records or documents.
8.6 COMMUNICATIONS WITH REGULATORY AUTHORITIES. PCAS shall promptly
provide ViroPharma with a copy of all correspondence between PCAS and
FDA or any foreign equivalent regarding activities under this
Agreement, including, without limitation, any Form 483s, or similar
notices or observations. PCAS shall provide ViroPharma with a copy of
any proposed response or correspondence to such regulatory authority
that relates directly to activities under this Agreement for
ViroPharma's approval at least five business days before the
submission of such response or correspondence.
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May 22, 2001 ViroPharma-PCAS Agreement Page 15
8.7 NOTICE OF ACCIDENTS. PCAS shall promptly notify ViroPharma of all
accidents related to the manufacture of API, including, without
limitation, those involving injury to persons, damage to property, or
environmental release of chemicals.
8.8. RECALLS. PCAS shall immediately notify ViroPharma of any information
in its possession relating to any batches of API that may require a
recall, field alert, product withdrawal, field correction or other
similar action whether based on design defect, manufacturing defect or
otherwise. The decision to initiate a recall, field alert, product
withdrawal, field correction or other similar action, if any, shall be
made and implemented by ViroPharma. PCAS shall cooperate as
reasonably necessary in planning and implementing any such action.
PCAS shall bear the costs of any such action resulting from or arising
out of any of the causes set forth in Section 12.1.1(a-c) up to
(Euro) 45 million.
9. OWNERSHIP OF INVENTIONS.
Any and all Inventions by PCAS shall be the sole and exclusive property of
ViroPharma. PCAS hereby irrevocable assigns and transfers to ViroPharma, and to
the extent that an executory assignment is not enforceable, PCAS hereby agrees
to assign and transfer to ViroPharma, in writing, from time to time, upon
request, any and all right, title and interest that PCAS may have or may later
acquire in the Inventions under copyright, patent, and trade secret law in
perpetuity or for the longest period otherwise permitted by law, without the
necessity of further consideration. Within thirty (30) calendar days of making
any Invention, PCAS shall notify ViroPharma, in writing, of the event and shall
assist ViroPharma in protecting ViroPharma's proprietary rights to said
Invention. ViroPharma shall grant a royalty-free license to PCAS for use of
such Invention; provided, however, that without the prior written approval of
ViroPharma, PCAS shall not use such Invention in connection with a product
intended to treat or prevent the effect of viral infections in man.
10. CONFIDENTIALITY.
10.1 During the term of this Agreement and for a period of five years
thereafter, PCAS shall maintain in confidence and shall use only for
purposes of this Agreement all Confidential Information disclosed by
ViroPharma under the Agreement, except as may be otherwise provided
herein. Notwithstanding the foregoing, PCAS may disclose ViroPharma's
Confidential Information to those of its directors, officers,
employees, agents and consultants that have a need to know such
Confidential Information in order to achieve the purposes of this
Agreement (a "Recipient"), provided that such Recipient is bound by
an obligation to hold in confidence and not make use of such
Confidential Information for any purpose other than those permitted
by this Agreement. PCAS will promptly notify ViroPharma upon
discovery of any unauthorized use or disclosure of the Confidential
Information. Any breach of this obligation of confidentiality by a
Recipient or any other director, officer, employee, agent or
consultant of PCAS shall be deemed a breech by PCAS. PCAS agrees that
ViroPharma shall remain the owner of the
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May 22, 2001 ViroPharma-PCAS Agreement Page 16
Confidential Information, and all patent, copyright, trade secret,
trademark and other intellectual property rights therein.
10.2 During the term of this Agreement and for a period of five years
thereafter, ViroPharma shall maintain in confidence and shall use
only for purposes of this Agreement all Confidential Information
disclosed by PCAS under the Agreement, except as may be otherwise
provided herein. Notwithstanding the foregoing, ViroPharma may
disclose PCAS' Confidential Information to those of its directors,
officers, employees, agents and consultants that have a need to know
such Confidential Information in order to achieve the purposes of
this Agreement (a "Recipient"), provided that such Recipient is bound
by an obligation to hold in confidence and not make use of such
Confidential Information for any purpose other than those permitted
by this Agreement. ViroPharma will promptly notify PCAS upon
discovery of any unauthorized use or disclosure of the Confidential
Information. Any breach of this obligation of confidentiality by a
Recipient or any other director, officer, employee, agent or
consultant of ViroPharma shall be deemed a breech by ViroPharma.
ViroPharma agrees that PCAS shall remain the owner of the
Confidential Information, and all patent, copyright, trade secret,
trademark and other intellectual property rights therein.
Notwithstanding the foregoing, this Section 10.2, shall not prevent
or restrict ViroPharma in any way from using or disclosing ViroPharma
Confidential information, from exercising its rights in and to the
Inventions, or from performing any activity contemplated under this
Agreement, including, without limitation: complying with applicable
laws and regulations; submitting filings to Regulatory Authorities;
responding to requests or questions from Regulatory Authorities;
protecting or expanding its intellectual property rights; marketing
or selling Pleconaril; and discussing, negotiating, or entering into
collaborative agreements regarding Pleconaril.
11. REPRESENTATIONS AND WARRANTIES.
11.1 Representations and Warranties of the Parties. Each of ViroPharma
and PCAS represents, warrants and covenants to the other Party that:
11.1.1 It is duly organized and validly existing and in good
standing under the laws of its organization or formation, and
has full corporate power and authority to enter into this
Agreement and to carry out the provisions hereof.
11.1.2 It is duly authorized to execute and deliver this Agreement
and to perform its obligations hereunder.
11.1.3 This Agreement is a legal and valid obligation binding upon
it and enforceable in accordance with its terms, except to
the extent limited by applicable bankruptcy and creditor's
rights laws. The execution, delivery and performance of this
Agreement by it does not conflict with any agreement,
instrument or understanding, oral or written, to which it is
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May 22, 2001 ViroPharma-PCAS Agreement Page 17
a party or by which it may be bound, nor violate any material
law or regulation of any court, governmental body or
administrative or other agency having jurisdiction over it.
11.1.4 It has obtained all necessary consents, approvals and
authorizations of all governmental authorities and other
entities and persons required to be obtained by it in
connection with entry into this Agreement.
11.1.5 No agreement between it and a third party in existence as of
the Effective Date would prevent it from performing its
obligations under this Agreement or granting to the other
Party the rights granted hereunder, and it shall not enter
into any such third party agreement that would prevent it
from performing its obligations under this Agreement or
granting to the other Party the rights granted hereunder.
11.1.6 It shall at all times comply with all applicable material
laws and regulations relating to its activities under this
Agreement.
11.2 PCAS REPRESENTATIONS AND WARRANTIES. In addition to representations,
warranties and covenants made elsewhere in this Agreement, PCAS
represents, warrants and covenants that:
11.2.1 As of the date of shipment or delivery to ViroPharma of any
API manufactured by PCAS, such API shall conform in all
material respects to the Specifications, and all applicable
laws and regulations, and shall be free from material defects
in materials and workmanship.
11.2.2 As of the date of shipment or delivery to ViroPharma of any
API manufactured by PCAS, such API will not be adulterated or
misbranded within the meaning of the U.S. Food, Drug, and
Cosmetic Act, and will not be an article which may not, under
the provisions of Sections 404, 505, or 512 of the U.S. Food,
Drug, and Cosmetic Act, be introduced into U.S. interstate
commerce.
11.2.3 PCAS will not use in its performance of its obligations under
this Agreement any person, corporation or other entity
debarred or suspended under the provisions of the Generic
Drug Enforcement Act of 1992, including without limitation,
21 U.S.C. Section 335a.
11.2.4 PCAS does not currently have, and covenants that it will not
hire, as an officer or an employee any person who has been
convicted of a felony under the laws of the U.S. for conduct
relating to the regulation of any drug product under the U.S.
Food, Drug, and Cosmetic Act.
11.2.5 PCAS has the right to assign Inventions to ViroPharma, such
Inventions will not infringe the rights of any third parties,
and PCAS has obtained an enforceable written agreement from
each person providing services under this Agreement
transferring all right title and interest in any Invention
either directly, or through PCAS, to ViroPharma.
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May 22, 2001 ViroPharma-PCAS Agreement Page 18
11.3 VIROPHARMA REPRESENTATIONS AND WARRANTIES. In addition to
representations, warranties and covenants made elsewhere in this
Agreement, ViroPharma represents, warrants and covenants that:
11.3.1 ViroPharma owns or otherwise has the right to disclose the
Specifications to PCAS.
11.3.2 PCAS may use the ViroPharma Know How for the purposes of
manufacturing the API pursuant hereto and that to the best of
ViroPharma's knowledge, such use shall not result in PCAS
infringing or misappropriating any third party right thereto.
11.3.3 ViroPharma has identified potential suppliers of Starting
Materials at the following prices:
(a) ********: $****** /kg; and
(b) ********: $****** /kg.
12. LIABILITY.
12.1 Indemnifications.
12.1.1 PCAS Indemnification of ViroPharma. PCAS will indemnify,
defend and hold harmless ViroPharma and its employees,
officers, directors and agents (each, a "ViroPharma
Indemnified Party") from and against any and all liability,
loss, damage, expense (including reasonable attorneys' fees
and expenses) and cost (collectively, a "Liability") that the
ViroPharma Indemnified Party may be required to pay to one or
more third parties resulting from or arising out of:
(a) any PCAS representation or warranty set forth herein
being untrue in any material respect when made;
(b) any claim of any nature, including any products
liability claim, directly arising from the failure of
API to have been manufactured, processed, prepared,
packed, or held in accordance with the Specifications,
applicable laws and regulations, or PCAS'
representations or warranties hereunder; and/or
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May 22, 2001 ViroPharma-PCAS Agreement Page 19
(c) any negligent act or omission or willful misconduct on
the part of PCAS, its employees, officers, directors or
agents.
except in each case, to the extent caused by the negligence
or willful misconduct of ViroPharma or any ViroPharma
Indemnified Party.
12.1.2 VIROPHARMA INDEMNIFICATION OF PCAS. ViroPharma will
indemnify, defend and hold harmless PCAS and its employees,
officers, directors and agents (each, a "PCAS Indemnified
Party") from and against any and all liability, loss, damage,
expense (including reasonable attorneys' fees and expenses)
and cost (collectively, a "Liability") that the PCAS
Indemnified Party may be required to pay to one or more third
parties resulting from or arising out of:
(a) any ViroPharma representation or warranty set forth
herein being untrue in any material respect when made;
(b) the testing, consumption, promotion, sale or advertising
of API, except to the extent arising from the failure of
API to have been manufactured, processed, prepared,
packed, or held in accordance with the Specifications,
applicable laws and regulations, or PCAS'
representations or warranties hereunder; and/or
(c) any negligent act or omission or willful misconduct on
the part of ViroPharma, its employees, officers,
directors or agents.
except in each case, to the extent caused by the negligence
or willful misconduct of PCAS or any PCAS Indemnified Party.
12.2 Procedures for Indemnification. If a Party seeks indemnification
under Section 12.1, it shall inform the other Party (the
"Indemnifying Party") of a claim as soon as reasonably practicable
after it receives notice of the claim, shall permit the Indemnifying
Party to assume direction and control of the defense of the claim
(including the right to settle the claim solely for monetary
consideration), and, at the Indemnifying Party's expense, shall
cooperate as reasonably requested in the defense of the claim. The
Indemnified Party shall have the right to retain its own counsel,
subject to the approval of any such outside counsel by the
Indemnifying Party, with the fees and expenses to be paid by the
Indemnifying Party if representation of such Party by the counsel
retained by Indemnifying Party would be inappropriate due to actual
or potential differing interests between such indemnitee and any
other party represented by such counsel in such proceedings. The
Indemnifying Party may not settle such action or claim, or otherwise
consent to an adverse judgment in such action or claim, without the
express written consent of the Indemnified Party if such settlement
or adverse judgment
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May 22, 2001 ViroPharma-PCAS Agreement Page 20
diminishes the rights or interests of, or imposes any obligation on,
the Indemnified Party.
12.3 INSURANCE. Each Party hereby agrees to maintain, during the term of
this Agreement, insurance with reputable and sound independent
insurers at commercially reasonable levels of coverage in relation to
the type, scope and size of business it conducts and to all its
obligations herein contained and shall give the other Party an
opportunity from time to time to review the insurance policies so
that the other Party may satisfy itself that such insurance policies
are valid, that the premiums are being paid regularly and that the
policies are kept in full force and effect.
13. TERMINATION.
13.1 TERMINATION FOR DIVERGENCE FROM VIROPHARMA QA/QC REQUIREMENTS.
13.1.1 NOTICE OF COMPLIANCE. Before ViroPharma submits the first
Firm Order pursuant to Section 4.3, for a Validation Batch
pursuant to Section 3.8, ViroPharma shall provide PCAS with
written notice of ViroPharma's determination that the
quality assurance, quality control, and GMP compliance
functions and standards of PCAS are substantially in
compliance with FDA's requirements.
13.1.2 TERMINATION. If ViroPharma does not provide notice of
compliance to PCAS pursuant to Section 13.1.1 by June 29,
2001, because ViroPharma concludes that the quality
assurance, quality control, and GMP compliance functions and
standards of PCAS are not substantially in compliance with
FDA's requirements, then on June 29, 2001, ViroPharma may
provide PCAS with written notice of termination under this
Section 13.1.2 by facsimile, which termination shall be
effective on July 6, 2001, or as set forth in Section
13.1.3.
13.1.3 DISPUTE RESOLUTION. If ViroPharma provides notice of
termination to PCAS pursuant to Section 13.1.2, and PCAS
disagrees with ViroPharma's conclusion that the quality
assurance, quality control, and GMP compliance functions and
standards of PCAS are not substantially in compliance with
FDA's requirements, then PCAS shall notify ViroPharma by
July 6, 2001 of its disagreement. By July 13, 2001, the
Parties shall agree on an expert in QA/QC and GMP compliance
to arbitrate the dispute. If the Parties cannot agree on an
expert, then by July 18, 2001, each Party shall select one
expert, both of which experts together shall by July 20,
2001, select another expert who shall be treated as the
expert agreed to by the Parties. Within three (3) weeks of
being selected, the expert agreed to by the Parties shall
perform an audit of PCAS, and determine whether the quality
assurance, quality control, and GMP
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May 22, 2001 ViroPharma-PCAS Agreement Page 21
compliance functions and standards of PCAS are or are not
substantially in compliance with FDA's requirements. If the
expert agrees with ViroPharma's assessment, then PCAS shall
bear all the costs of such determination under this Section
13.1.3, and the Agreement shall be terminated effective upon
such decision of the expert. If the expert agrees with PCAS,
then ViroPharma shall bear all the costs of such
determination under this Section 13.1.3, and the Agreement
shall not be terminated.
13.2 TERMINATION FOR MATERIAL BREACH. A non-defaulting Party shall have
the right to terminate this Agreement after written notice to the
other that the other is in material breach of this Agreement (the
"Defaulting Party"), unless the Defaulting Party cures the breach
before the expiration of sixty days after such written notice.
13.3 TERMINATION FOR INSOLVENCY. Either Party may terminate this Agreement
if, at any time, the other Party shall file in any court or agency
pursuant to any statute or regulation of any state or country, a
petition in bankruptcy or insolvency or for reorganization or for an
arrangement or for the appointment of a receiver or trustee of the
Party or of its assets, or if the other Party proposes a written
agreement of composition or extension of its debts, or if the other
Party shall be served with an involuntary petition against it, filed
in any insolvency proceeding, and such petition shall not be
dismissed within sixty days after the filing thereof, or if the other
Party shall propose or be a party to any dissolution or liquidation,
or if the other Party shall make an assignment for the benefit of
creditors.
13.4 TERMINATION FOR DEBARMENT. ViroPharma may terminate this Agreement
effective immediately upon notice if at any time during the term of
this Agreement PCAS becomes debarred or receives notice of action or
threat of action with respect to its debarment. PCAS shall notify
ViroPharma immediately if at any time during the term of this
Agreement PCAS becomes debarred, or receives notice of action or
threat of action with respect to its debarment.
13.5 TERMINATION FOR DELAY IN REGULATORY APPROVAL. At any time before
June1, 2001 ViroPharma may terminate this Agreement upon fifteen days
advance written notice if ViroPharma reasonably believes that
regulatory approval of pleconaril is likely to be delayed
significantly beyond current projections. ViroPharma shall pay PCAS
$630,000 within thirty days of exercising its right of termination
under this Section 13.5.
13.6 TERMINATION FOR ADVERSE REGULATORY ACTION. ViroPharma may terminate
this Agreement upon sixty days advance written notice if the FDA or
any other Regulatory Authority directly or indirectly prohibits or
prevents the manufacture or sale of Pleconaril or any finished dosage
form containing Pleconaril.
13.7 TERMINATION UPON PURCHASE OF ************** TONS OF API. If at any
time before December 31, 2003, the total amount of API that
ViroPharma has purchased from PCAS under this Agreement exceeds
********** kg, ViroPharma may terminate this Agreement upon three (3)
months advance written notice.
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May 22, 2001 ViroPharma-PCAS Agreement Page 22
13.8 EFFECT OF TERMINATION.
13.8.1 GENERAL. Upon the expiration or any termination of this
Agreement: (a) all licenses under this Agreement shall be
terminated; and (b) upon the written request of ViroPharma,
PCAS shall destroy and shall not retain any copies of any
Confidential Information provided by ViroPharma hereunder,
except for one copy to be retained by legal counsel solely
for archival purposes.
13.8.2 SURVIVAL OF RIGHTS. Termination or expiration of this
Agreement shall not affect any rights to payment or other
rights that accrued before the date of termination or
expiration. The terms of the following Articles and Sections
shall survive any termination or expiration of this
Agreement: 3.5, 4.4, 5.3, 6.1.2, 8.2, 8.4-8.6, 8.8, 9, 10,
11.2-11.3, 12, and 13.8.
13.8.3 RIGHTS NOT EXCLUSIVE. All rights to terminate, and rights
upon termination, provided for either Party in this Agreement
are in addition to other remedies in law or equity which may
be available to either Party.
14. GENERAL TERMS.
14.1 ENTIRE AGREEMENT. This Agreement constitutes and contains the
complete, final and exclusive understanding and agreement of the
Parties and cancels and supersedes any and all prior negotiations,
correspondence, understandings and agreements, whether oral or
written, between the Parties respecting the subject matter hereof and
thereof.
14.2 AMENDMENT. No amendment, modification or supplement of any provision
of this Agreement shall be effective unless made in writing and
signed by a duly authorized officer of each Party.
14.3 ASSIGNMENT. Neither this Agreement nor any interest hereunder shall
be assignable by either Party without the prior written consent of
the other Party, except for an assignment by a Party to a successor
to substantially all of the business of such Party or to an Affiliate
of such Party. This Agreement shall be binding upon the successors
and permitted assigns of the Parties. Any assignment not in
accordance with this Section 14.3 shall be void.
14.4 WAIVER. No provision of the Agreement shall be waived by any act,
omission or knowledge of a Party or its agents or employees except by
an instrument in writing expressly waiving such provision and signed
by a duly authorized officer of the waiving Party.
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May 22, 2001 ViroPharma-PCAS Agreement Page 23
14.5 SEVERABILITY. If any part of this Agreement is for any reason held to
be invalid, illegal or unenforceable, the Agreement shall be
construed as if such part had never been contained in this Agreement,
and there shall be deemed substituted for such part a provision that
will most nearly carry out the intent of the Parties in this
Agreement.
14.6 GOVERNING LAW. This Agreement shall be governed by and interpreted in
accordance with the substantive laws of the Commonwealth of
Pennsylvania, U.S.A., without regard to conflict of law principles
thereof or of any other jurisdiction.
14.7 NOTICES. All notices, requests and other communications required
under this Agreement, shall be in writing and, unless otherwise
provided herein, shall be deemed to have been given:
a. when delivered by hand;
b. if communicated by facsimile, cable or similar electronic means,
at the time that receipt thereof has been confirmed by return
electronic communication or signal that the message has been
received;
c. five days after being deposited in the United States mail,
postage prepaid, certified, return receipt requested; or
d. three days after being deposited with an internationally
recognized overnight courier, return receipt requested.
Unless otherwise agreed, notices shall be addressed to the parties as
follows:
If to ViroPharma: ViroPharma Incorporated
Attn: Director of Manufacturing
000 Xxxxxxxxx Xxxxxxxxx
Xxxxx, XX 00000
X.X.X.
Fax: (000) 000-0000
With a copy to: ViroPharma Incorporated
Attn: General Counsel
000 Xxxxxxxxx Xxxxxxxxx
Xxxxx, XX 00000
X.X.X.
Fax: (000) 000-0000
If to PCAS: PCAS
Attn: Directeur General
Xxxxx Xxxxxxx 000
00000 Xxxxxxxxxx Xxxxx
Xxxxxx
Fax: 00 (0)0 00 00 00 19
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May 22, 2001 ViroPharma-PCAS Agreement Page 24
Either party may change the facsimile number, name or address to
which notices should be sent by a notice given to the other party in
the manner set forth above.
14.8 LANGUAGE. All documents, records or notices required under this
Agreement shall be kept or made in English, or shall be translated
into English at ViroPharma's request and at the expense of PCAS,
except for current working procedures such as batch records, working
instructions and SOP's.
14.9 FORCE MAJEUR. Neither Party shall be liable to the other for delay or
failure in the performance of the obligations on its part contained
in this Agreement if and to the extent that such failure or delay is
due to circumstances beyond its control which it could not have
avoided by the exercise of reasonable diligence. It shall notify the
other Party in writing promptly should such circumstances arise (the
"Force Majeure Notice"), giving an indication of the likely extent
and duration thereof, and shall use all commercially reasonable
efforts to resume performance of its obligations as soon as
practicable. In the event that such Party has been unable to perform
its obligations under the Agreement within sixty days of the Force
Majeure Notice, the other Party shall have the right to terminate
this Agreement without penalty.
14.10 RELATIONSHIP OF THE PARTIES. Both Parties are independent contractors
under this Agreement. Nothing in this Agreement creates an
employment, agency, joint venture or partnership relationship between
the Parties hereto or any of their agents or employees, or any other
legal arrangement that would impose liability upon one Party for the
act or failure to act of the other Party.
14.11 COUNTERPARTS. This Agreement may be executed in any number of
counterparts, each of which need not contain the signature of more
than one Party but all such counterparts taken together shall
constitute one and the same agreement.
14.12 REPRESENTATION BY LEGAL COUNSEL. Each Party hereto represents that it
has been represented by legal counsel in connection with this
Agreement and acknowledges that it has participated in the drafting
hereof. In interpreting and applying the terms and provisions of this
Agreement, the Parties agree that no presumption shall exist or be
implied against the Party that drafted such terms and provisions.
IN WITNESS WHEREOF, the Parties hereto have duly executed this Agreement as of
the date first above written.
VIROPHARMA INCORPORATED PCAS
--------------------------------------------------------------------------------
May 22, 2001 ViroPharma-PCAS Agreement Page 25
By: /s/ Xxxxxx xx Xxxxx By: /s/ A. Galigne /s/ X.X. Xxxx
-------------------------- ------------------------------
Xxxxxx xx Xxxxx Name: A. Galigne X.X. Xxxx
President & CEO ----------------------------
Its: Director, Pharma Synthesis
-----------------------------
--------------------------------------------------------------------------------
May 22, 2001 ViroPharma-PCAS Agreement Page 26
EXHIBIT 1.16(A-B)
SUMMARY SPECIFICATIONS
NDA Commercial Specification for Pleconaril Drug Substance (Unmicronized)
=============================================================================
Tests Method Number Acceptance Criteria
-----------------------------------------------------------------------------
DESCRIPTION ********* **********
-----------------------------------------------------------------------------
Identification ********* **********
-----------------------------------------------------------------------------
Assay (HPLC) ********* **********
-----------------------------------------------------------------------------
Chromatographic Impurity ********* **********
(HPLC)
-----------------------------------------------------------------------------
Residue on Ignition ********* **********
-----------------------------------------------------------------------------
Heavy Metals ********* **********
-----------------------------------------------------------------------------
Polymorphic Form (DSC)/1/ ********* **********
-----------------------------------------------------------------------------
Melting Range ********* **********
(DSC)
=============================================================================
/1/ : Carried out by a contract laboratory under the responsibility of
ViroPharma
Appendix: In-House Tests for ******* Drug Substance (Unmicronized)
=============================================================================
Tests Methods Internal Guidelines
-----------------------------------------------------------------------------
Water ********* **********
(Xxxx Xxxxxxx)
-----------------------------------------------------------------------------
************* ********* **********
=============================================================================
1 : Carried out by a contract laboratory under the responsibility of
ViroPharma
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 1.16(b) Page 1
NDA Commercial Specification for ***********
==============================================================================
Tests Method Number Acceptance Criteria
------------------------------------------------------------------------------
Description ********* **********
------------------------------------------------------------------------------
Identification (IR) ********* **********
------------------------------------------------------------------------------
Water (Xxxx Xxxxxxx) ********* **********
------------------------------------------------------------------------------
Chromatographic Impurity (HPLC) ********* **********
==============================================================================
NDA Commercial Specification for *******
==============================================================================
TESTS Method Number Acceptance Criteria
------------------------------------------------------------------------------
DESCRIPTION ********* **********
------------------------------------------------------------------------------
IDENTIFICATION (IR) ********* **********
------------------------------------------------------------------------------
WATER (XXXX XXXXXXX) ********* **********
------------------------------------------------------------------------------
CHROMATOGRAPHIC IMPURITY ********* **********
(HPLC)
==============================================================================
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 1.16(b) Page 2
NDA Commercial Specification for ********
===============================================================================
TESTS METHOD NUMBER ACCEPTANCE CRITERIA
-------------------------------------------------------------------------------
DESCRIPTION ********* **********
-------------------------------------------------------------------------------
IDENTIFICATION (IR) ********* **********
-------------------------------------------------------------------------------
CHROMATOGRAPHIC IMPURITY ********* **********
(GC)
===============================================================================
APPENDIX: IN-HOUSE TEST FOR ********
===============================================================================
TESTS METHODS INTERNAL GUIDELINES
-------------------------------------------------------------------------------
CHROMATOGRAPHIC IMPURITY ********* **********
(GC)
===============================================================================
NDA Commercial Specification for ********
===============================================================================
Tests Method Number Acceptance Criteria
-------------------------------------------------------------------------------
DESCRIPTION ********* **********
-------------------------------------------------------------------------------
IDENTIFICATION (IR) ********* **********
-------------------------------------------------------------------------------
CHROMATOGRAPHIC IMPURITY ********* **********
(GC)
-------------------------------------------------------------------------------
ASSAY (HPLC) ********* **********
-------------------------------------------------------------------------------
WATER (XXXX XXXXXXX) ******* **********
===============================================================================
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 1.16(b) Page 3
EXHIBIT 1.20
VALIDATION PROTOCOL
Protocol number Process Validation Protocol-PLECONARIL-DATE
VALIDATION PROTOCOL AND VALIDATION PLAN
-----------------------------------------------------------------------------
| Production: PLECONARIL |
|----------------------------------------------------------------------------|
| Validation type: Prospective validation |
|----------------------------------------------------------------------------|
| Initial references: Validation report VALPLE1/ 08/10/99, see |
| also chapters 3 and 9 of the present |
| protocol. |
|----------------------------------------------------------------------------|
| Applicable SOP's: Validation of New Productions |
| Quality manual sections 4.4, 4.9 and 4.10 |
-----------------------------------------------------------------------------
Approved by:
--------------------------------------------------------- --------------
Xxxxxx Xxxxxx, Quality Manager, Seloc Date
--------------------------------------------------------- --------------
Xxxx Xxxxx Xxxxxxxxx, R&D Manager, Seloc Date
--------------------------------------------------------- --------------
Xxxxxx Xxxxxxx, Quality Control Supervisor, Seloc Date
--------------------------------------------------------- --------------
Xxxxxx Peure, Chemical Development, Seloc Date
--------------------------------------------------------- --------------
Xxxx Xxxxxxxxx, Manufacturing, ViroPharma Date
--------------------------------------------------------- --------------
Xxxxxxx Xxxxxxxxx, CMC, ViroPharma Date
--------------------------------------------------------- --------------
Xxxxxxx Xxxxxx, Chemical Development, ViroPharma Date
--------------------------------------------------------- --------------
Xxxxxxx Xxxxxx, Quality Manager, ViroPharma Date
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 1.20 Page 1
Protocol number Process Validation Protocol-PLECONARIL-DATE
TABLE OF CONTENTS
Table of Contents..............................................................2
1 Objective and Scope........................................................3
2 Responsibilities...........................................................3
2.1. Research and Development..............................................3
2.2. Production............................................................3
2.3. Quality Control.......................................................3
2.4. Quality Assurance.....................................................4
2.5. ViroPharma............................................................4
3 Type of Validation.........................................................4
4 Number of Validation Batches...............................................5
5 Quality of Materials.......................................................5
6 Process Description........................................................5
7 Process Equipment..........................................................6
8 Specifications.............................................................6
8.1. In Process Controls...................................................6
8.2. Starting Materials....................................................7
8.3. Intermediates.........................................................8
8.4. Pleconaril Drug Substance.............................................8
9 Process Parameters.........................................................9
10 Sampling Plans............................................................10
11 Validation Review and Validation Report...................................11
12 Validation Acceptance Criteria............................................12
13 Process Validation Failure................................................13
14 Validation Plan...........................................................14
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 1.20 Page 2
Protocol number Process Validation Protocol-PLECONARIL-DATE
1 OBJECTIVE AND SCOPE
The objective of this Protocol is to describe the commercial manufacturing
process for the production of pleconaril drug substance at the 600 kg
scale. It also defines the requirements for process validation and the
acceptance criteria for this process validation. The successful completion
of this Protocol will provide assurance that the commercial manufacturing
process for pleconaril will consistently produce material that meets the
Specifications for pleconaril, including polymorph form (Form III), and is,
therefore, validated.
2 RESPONSIBILITIES
2.1. RESEARCH AND DEVELOPMENT
The Research and Development Department will:
Establish the Summary Development Report and provide Quality
Assurance with the information necessary for the development of
the Validation Protocol.
Review and approve the Validation Protocol prior to execution.
Assist the Production Department during the manufacture of the
validation batches.
Review and approve the final Validation report.
2.2. PRODUCTION
The Production Department will:
Review and approve the Validation Protocol prior to execution.
Review and approve the Master Batch Records prior to execution.
Manufacture the validation batches in accordance with the approved
Master Batch Records and the specific instructions of this
Validation Protocol.
Remove the in-process control samples according to the sampling
plan during manufacturing for analysis.
Review the executed Batch Records for completeness and accuracy
prior to submission to the Quality Assurance Department for final
review and approval.
Review and approve the final Validation report.
2.3. QUALITY CONTROL
The Quality Control Department will:
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 1.20 Page 3
Protocol number Process Validation Protocol-PLECONARIL-DATE
Review and approve the Validation Protocol prior to execution.
Receive in-process samples for analysis.
Remove samples of intermediate or final API for release testing.
Test the in-process control samples as well as the samples for the
final product of each manufacturing step in accordance with the
validated and/or approved analytical methods.
Review the analytical results for completeness and accuracy,
prepare the analytical reports prior to submission to Quality
Assurance for final review and approval.
Review and approve the final Validation report.
2.4. QUALITY ASSURANCE
The Quality Assurance Department will:
Prepare and approve the Validation Protocol prior to execution.
Review and approve the Master Batch Records prior to execution.
Review and approve the executed Batch Records and the analytical
results for completeness, accuracy and compliance with the Master
Batch Records, analytical methods and current Good Manufacturing
Practices.
Prepare and approve the final Validation report.
2.5. VIROPHARMA
ViroPharma Incorporated as Sponsor will:
Review and approve the Validation Protocol prior to execution.
Review and approve the Master Batch Records prior to execution.
Review and approve the executed Batch Records.
Review and approve the final Validation report.
3 TYPE OF VALIDATION
The validation is a prospective validation of the three-step synthesis of
pleconaril. The validation will verify the previous validation results for
steps 1 and 2 with a 1.5 time batch size increase in these steps and to
demonstrate that control of crystallization will consistently produce
polymorphic form III of pleconaril.
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 1.20 Page 4
Protocol number Process Validation Protocol-PLECONARIL-DATE
4 NUMBER OF VALIDATION BATCHES
The validation will be carried out on all three (3) steps of the synthesis
on the new production campaign. The relevant data will be collected for all
the batches produced during that additional campaign. The campaign will
consist in 5 batches of both 1st and 2nd steps and 4 batches of the 3rd
step.
After completion of each batch, the batch record will be reviewed to
determine the effect of any modifications and/or deviations to the
procedure described in the applicable Master Batch Record (MBR) on the
validation. For a successful validation, at least three (3) consecutive
batches of each step will be produced without deviations of the critical
process parameters. In addition, the three consecutive batches of each step
must conform to the critical quality attributes.
If any step requires modifications to the process and MBR, this validation
protocol will be amended and additional batch(es) will be produced so that
the validation includes three consecutive batches by the amended process
and if a validation batch fails for reasons unrelated to process
performance (e.g., power failure or equipment or equipment breakdown), that
batch will be removed from the validation study and an additional batch
will be produced, which will be considered consecutive to the batch
preceding the batch that failed for non-process related reasons.
5 QUALITY OF MATERIALS
Only fresh, not recovered, solvents are used . All reagents, solvents and
other materials used in this validation will meet their currently approved
specifications.
6 PROCESS DESCRIPTION
STEP 1: PREPARATION OF *********** (**************)
**************
STEP 2: PREPARATION OF *********** (**************)
**************
STEP 3: PREPARATION OF *********** (**************)
**************
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 1.20 Page 5
Protocol number Process Validation Protocol-PLECONARIL-DATE
7 PROCESS EQUIPMENT
Major equipment used for the manufacture of pleconaril is specified in the
batch record. The equipment is multi-purpose, has been previously qualified
and is subject to periodic calibrations.
8 SPECIFICATIONS
The specifications for In Process Controls, Pleconaril, the two
intermediates and the starting materials are listed in the tables below:
0.0.XX PROCESS CONTROLS (IPC's)
The following are the acceptance criteria for IPC's.
=========================================================================
IPC # AND
DESCRIPTION METHOD NUMBER ACCEPTANCE CRITERIA
------------------------------------------------------------------------
203-1
Chromatographic *************** ***************
Impurity
------------------------------------------------------------------------
203-1.5
Loss on drying *************** ***************
------------------------------------------------------------------------
203-2
Chromatographic *************** ***************
Impurity
------------------------------------------------------------------------
203-3
Water (Xxxx *************** ***************
Xxxxxxx)
------------------------------------------------------------------------
203-4
Residual *************** ***************
solvents
=========================================================================
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 1.20 Page 6
Protocol number Process Validation Protocol-PLECONARIL-DATE
8.2. STARTING MATERIALS
The following are the acceptance criteria for the starting materials.
*********** (************)
=======================================================================
TESTS METHOD NUMBER ACCEPTANCE CRITERIA
-----------------------------------------------------------------------
Description *************** ***************
-----------------------------------------------------------------------
Identification (IR)
*************** ***************
-----------------------------------------------------------------------
Chromatographic
Impurity (GC) *************** ***************
-----------------------------------------------------------------------
Assay (HPLC)
*************** ***************
-----------------------------------------------------------------------
Water (Xxxx
Xxxxxxx) *************** ***************
=======================================================================
************ (**************)
=======================================================================
TESTS METHOD NUMBER ACCEPTANCE CRITERIA
-----------------------------------------------------------------------
Description *************** ***************
-----------------------------------------------------------------------
Identification (IR)
*************** ***************
-----------------------------------------------------------------------
Chromatographic
Impurity (GC) *************** ***************
=======================================================================
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 1.20 Page 7
Protocol number Process Validation Protocol-PLECONARIL-DATE
8.3. INTERMEDIATES
The following are the acceptance criteria for each intermediate.
************ (**************)
=======================================================================
TESTS METHOD NUMBER ACCEPTANCE CRITERIA
-----------------------------------------------------------------------
Description *************** ***************
-----------------------------------------------------------------------
Identification (IR)
*************** ***************
-----------------------------------------------------------------------
Water (Xxxx
Xxxxxxx) *************** ***************
-----------------------------------------------------------------------
Chromatographic
Impurity (HPLC) *************** ***************
=======================================================================
************ (**************)
=======================================================================
TESTS METHOD NUMBER ACCEPTANCE CRITERIA
-----------------------------------------------------------------------
Description *************** ***************
-----------------------------------------------------------------------
Identification (IR)
*************** ***************
-----------------------------------------------------------------------
Water (Xxxx
Xxxxxxx) *************** ***************
-----------------------------------------------------------------------
Chromatographic
Impurity (HPLC) *************** ***************
=======================================================================
8.4. PLECONARIL DRUG SUBSTANCE
The following are the acceptance criteria for pleconaril drug
substance.
PLECONARIL DRUG SUBSTANCE (UNMICRONIZED), ************
=======================================================================
TESTS METHOD NUMBER ACCEPTANCE CRITERIA
-----------------------------------------------------------------------
Description
*************** ***************
-----------------------------------------------------------------------
Identification
*************** ***************
-----------------------------------------------------------------------
Assay (HPLC)
*************** ***************
-----------------------------------------------------------------------
Chromatographic
Impurity (HPLC)
*************** ***************
-----------------------------------------------------------------------
Residue on
Ignition
*************** ***************
-----------------------------------------------------------------------
Heavy Metals *************** ***************
-----------------------------------------------------------------------
Polymorphic
Form III (DSC)
*************** ***************
-----------------------------------------------------------------------
Melting Range
(DSC) *************** ***************
=======================================================================
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 1.20 Page 8
Protocol number Process Validation Protocol-PLECONARIL-DATE
9 PROCESS PARAMETERS - CRITICAL PROCESS PARAMETERS
The critical process parameters for the manufacture of pleconaril are
discussed in:
o Validation Plan and Validation Protocol for Pleconaril - Limay,
June 29, 1998
o Pleconaril Production Batches - Development Report, B. Peure, Seloc,
September 21, 1999
o Pleconaril Process Control - Critical Parameter Justification,
X. Xxxxxx, February 2, 2000
o Summary of Development Report, X. Xxxxxx February 12, 2001
As defined during the development of the manufacturing process for
pleconaril, the following parameters are critical to the manufacturing
process:
PROCESS STEP 1:
No critical parameters.
PROCESS STEP 2:
o The addition of ************** will be within ************** % of the
******* ratio target.
o The water content of isolated ************** (**************) will be
************** %
PROCESS STEP 3:
o Temperature prior to ***********: ******** to ******** (degree)C
o Seed amount will be ***%-*****% of target batch size and seed quality
will be ********% form III determined by DSC.
o Temperature and time for drying: ***** to *******(degree)C for Not Less
Than ***** hours
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 1.20 Page 9
Protocol number Process Validation Protocol-PLECONARIL-DATE
10 SAMPLING PLANS
Sampling of raw materials, in-process control materials, intermediates and
final product will be carried out according with current SOPs. Any specific
sampling is indicated in the batch instructions.
The proposed sampling plan for the validation batches is as follows:
PROCESS STEP 1
. IPC#203-1 Samples taken and analyzed at *********** hours to profile
completion of reaction. When IPC#203-1 results are ********%
***********, then the reaction will be cooled and no further samples
taken. The IPC results from all three validation batches will be
evaluated in conjunction with previous pilot and production batches to
confirm that the target reaction time is consistently between ********
hours.
. At least three samples are taken from each batch (first centrifuge shot,
half-way through-centrifugation and last centrifuge shot) and each
sample analyzed individually for impurities (method no. 61834.000) to
evaluate efficiency of the washing procedure and an LOD (IPC 203-1.5) to
evaluate centrifugation efficiency.
PROCESS STEP 2
. After drying, a representative sample from the first drum, middle drum
and last drum of total number of drums will be taken and each sample
analyzed individually for water content (IPC#203-3).
PROCESS STEP 3
. During and after drying and sieving, sampling and testing are carried
out according to the following plan:
Production Batch Number
---------- ----- ------
Drying time/1/ 5 6 7
---------------------------------------------------------------------------
24 h B B B
---------------------------------------------------------------------------
32 h* A A A
---------------------------------------------------------------------------
40 h* A A A
---------------------------------------------------------------------------
48 h* A A A
---------------------------------------------------------------------------
60 h* A A A
---------------------------------------------------------------------------
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 1.20 Page 10
Protocol number Process Validation Protocol-PLECONARIL-DATE
---------------------------------------------------------------------------
72 * A A A
---------------------------------------------------------------------------
After IPC passes
remove from dryer B B B
and sample
---------------------------------------------------------------------------
After sieving C C C
---------------------------------------------------------------------------
/1/ All sampling times are plus or minus 1 hour
*If necessary (IPC results exceed specs).
Sampling:
. for samples A and B, the sampling is carried out as per SOP G3-033
. for sample C (final sampling of the batch after sieving), a representative
sample from the first drum, middle drum and last drum of total number of
drums will be taken per SOP G3-032.
Testing; according to the sampling identification, the following testing is
carried out:
A: Residual solvents (method 3482)
B: Residual solvents (method 3482)
Chromatographic purity (Method-1 63843DS.003)
Polymorphic form III (DSC) (Method 63843DS.600)
C: Residual solvents (method 3482) and full release testing as per
section 8.4
11 VALIDATION REVIEW AND VALIDATION REPORT
The studies, documents and data listed in the validation plan will be
subject to periodic reviews and a final review. A validation report will be
written. The final review and the approval of the validation report will be
carried out by the functions involved for the approval of the present
protocol as defined in section 2.
The validation report will include the following, at a minimum:
Copy of the Control Sheets of the Executed Batch Records.
o Listing of all modifications and deviations from the MBR for each batch
for each step, as well as an evaluation of the impact on the validation
of each modification and deviation.
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 1.20 Page 11
Protocol number Process Validation Protocol-PLECONARIL-DATE
o Table listing steps with defined process parameters, the acceptance
criteria for each listed process parameter, the actual conditions for
those parameters for each batch and an evaluation as to whether the
actual conditions met the acceptance criteria.
o Tables with the analytical results of the testing in the quality
specifications for Intermediates and pleconaril, as well as an
evaluation as to whether each batch met the acceptance criteria.
o Evaluation to determine that each step met all acceptance criteria and
is considered validated.
o Conclusions.
The complete validation file will contain the above validation report and all
documentation collected.
12 VALIDATION ACCEPTANCE CRITERIA
The validation acceptance criteria are as follows:
o Acceptance of each executed batch record demonstrating that the process
parameters have been met within the defined ranges.
o The two starting materials, two intermediates and the final API will
meet all specification acceptance criteria as outlined in section 8.
o The following samples described under the sampling plan section will
meet the following acceptance criteria:
12.1. PROCESS STEP 1:
. IPC 203-1 Samples: IPC 203-1 results are ********% ***********.
The IPC results from all three validation batches will be
evaluated in conjunction with previous pilot and production
batches to confirm that the target reaction time is consistently
****** hours.
. Centrifuge Shots: Each sample will be analyzed for residual
solvents by LOD (IPC 203-1.5). Acceptance criteria: Any individual
LOD value across all batches will not be ************%.
12.2. PROCESS STEP 2:
. IPC 203-2 Samples: IPC 203-2 results are *********% *************.
. Samples from Dryer: Each sample will be analyzed using the most
current version of the water content method (IPC#203-3).
Acceptance criteria: Water content ********%
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 1.20 Page 12
Protocol number Process Validation Protocol-PLECONARIL-DATE
12.3. PROCESS STEP 3:
. Samples from the Dryer: The samples are analyzed according to the
plan given in section 10 - process step 3. The samples will
validate
- Purity, polymorphic form at "middle" (about 24 hours), end of
drying and after sieving
- That the IPC will determine end of drying and batch
homogeneity.
The intention of this plan is not to validate a certain drying
time.
. Samples from Drums: Each sample will be analyzed using the most
current version of methods listed in section 8.4. Acceptance
criteria: Each sample must meet all specifications acceptance
criteria listed in section 8.4. of this protocol.
. The analytical results on both samplings will be evaluated for the
incidence of drying and sieving on the polymorphysm and on the
impurities profile.
13 PROCESS VALIDATION FAILURE
If any step fails to meet the process validation criteria specified in
Section 12, an investigation will be carried out to determine the cause of
the failure. If necessary, additional developmental work may be carried
out. Based on the results of the investigation and any additional work,
this protocol will be amended to describe the additional work required to
complete the validation.
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 1.20 Page 13
Protocol number Process Validation Protocol-PLECONARIL-DATE
14 VALIDATION PLAN - Studies, Activities, Documentation and responsibilities
--------------------------------------------------------------------------------------------------------
# STUDIES / ACTIVITIES / DOCUMENTS RESPONSIB.
--------------------------------------------------------------------------------------------------------
1 Specifications and specifications change history MJ
--------------------------------------------------------------------------------------------------------
2 Review of analytical data of raw material prior to batches launches MJ
--------------------------------------------------------------------------------------------------------
3 Follow up of specific additional IPC sampling and relative additional BP
instructions to the Batch Manufacturing Instructions
--------------------------------------------------------------------------------------------------------
4 Follow up of specific cleaning validation sampling and update of cleaning BP / BD
validation matrix
--------------------------------------------------------------------------------------------------------
5 Production review of executed Batch Records and evaluation of deviations BD
prior to submission to QA and reporting on the Batch Records control forms
--------------------------------------------------------------------------------------------------------
6 Shipment of samples to be studied for polymorphysm (DSC) MJ
--------------------------------------------------------------------------------------------------------
7 Follow up analytical work for drying validation SF
--------------------------------------------------------------------------------------------------------
8 Review of the executed Batch Records and related analytical results JLH
QA Batch approval
--------------------------------------------------------------------------------------------------------
9 Analytical profiles for intermediates and final product - Chromatographic MJ / SF
profiles
Summaries for drying and cleaning validation
--------------------------------------------------------------------------------------------------------
10 Intermediate reviews and actions in case of deviations on individual BP / MJ / CB
intermediate or API batches
--------------------------------------------------------------------------------------------------------
11 Analytical data summary tables MJ
--------------------------------------------------------------------------------------------------------
12 Global review of data and documentation relative to the validation batches BP / MJ / CB /
JMS
--------------------------------------------------------------------------------------------------------
13 Preparation and approval of the final Validation Report including the Summary BP / MJ / CB /
of Validation. JMS
--------------------------------------------------------------------------------------------------------
Responsibilities (full names):
JMS Xxxx Xxxxx XXXXXXXXX R&D Manager
SF Xxxxxxxx XXXXXX Analytical Methods Engineer
XX Xxxxxx XXXXXXX Quality Control Supervisor
BD Xxxxx XXXXXXXXXXX Chemical Development Technician
XX Xxxxxx PEURE Chemical Development Engineer
JLH Xxxx Xxx HELLO Quality Assurance Supervisor
CB Xxxxxx XXXXXX Quality Manager
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 1.20 Page 14
EXHIBIT 4.1
Rolling Annual Forecast by Quarter
PCAS
Quarterly Forecasted Material Requirements
July 2001 through December 2002
Quarter 1st 2nd 3rd 4th Total
------------------------------------------------------------------------------
Calendar Year 2001
Forecast (kg) ****** ****** ****** ****** ******
Batches ****** ****** ****** ****** ******
------------------------------------------------------------------------------
Calendar Year 2002
Forecast (kg) ****** ****** ****** ****** ******
Batches ****** ****** ****** ****** ******
------------------------------------------------------------------------------
Assumes a yield and order quantity of ******* kg per batch
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 4.1 Page 1
EXHIBIT 6.4
(Euro)/$ EXCHANGE RATE - EFFECTIVE DATE
The (Euro)/$ Exchange Rate on the Effective Date is: 1.140
--------------------------------------------------------------------------------
May 22, 2001 Exhibit 6.4 Page 1
