NRP104 ACTIVE PHARMACEUTICAL INGREDIENT SUPPLY AGREEMENT by and between
Exhibit
10.17
Subject
to a request for confidential treatment, certain provisions of this agreement
have been intentionally omitted. The omitted portions subject to the
confidential treatment request are designated by three asterisks (***). A
complete version of this agreement has been separately filed with the Securities
and Exchange Commission.
NRP104
ACTIVE
PHARMACEUTICAL INGREDIENT
by
and
between
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Supplier
Name:
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Organichem
Corporation
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Address:
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00
Xxxxxxxxx Xxxxxx
Xxxxxxxxxx,
Xxx Xxxx 00000
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(“ORGANICHEM”)
and
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Sponsor
Name:
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Address:
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0000
Xxxxx Xxxxxx
Xxxxxxx,
Xxxxxxxx 00000
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(“NEW
RIVER”)
TABLE
OF
CONTENTS
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PAGE
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DEFINITIONS.
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2
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ARTICLE
2.
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MANUFACTURE.
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5
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ARTICLE
3.
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PURCHASE
ORDERS, TESTING AND SUPPLY.
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8
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ARTICLE
4.
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FORECASTS
AND FIRM ORDERS.
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12
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ARTICLE
5.
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SHIPPING
AND DELIVERY; ACCEPTANCE AND REJECTION.
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15
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ARTICLE
6.
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PRICE
FOR BULK API.
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17
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ARTICLE
7.
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PAYMENT.
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19
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ARTICLE
8.
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TERM.
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19
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ARTICLE
9.
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TERMINATION.
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19
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ARTICLE
10.
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ORGANICHEM
REPRESENTATIONS, WARRANTIES AND COVENANTS.
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23
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ARTICLE
11.
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INSPECTIONS,
RECALLS AND SEIZURES.
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26
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ARTICLE
12.
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LIABILITY
AND INSURANCE.
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28
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ARTICLE
13.
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INDEMNIFICATION.
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29
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ARTICLE
14.
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CONFIDENTIALITY
AND NON-USE.
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30
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ARTICLE
15.
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INTELLECTUAL
PROPERTY.
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31
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ARTICLE
16.
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ASSIGNMENT.
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32
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ARTICLE
17.
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CHOICE
OF LAW; JURISDICTION.
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33
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ARTICLE
18.
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FORCE
MAJEURE.
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33
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ARTICLE
19.
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SEVERABILITY.
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33
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ARTICLE
20.
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HEADINGS.
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34
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ARTICLE
21.
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USE
OF NAMES.
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34
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ARTICLE
22.
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INDEPENDENT
CONTRACTOR.
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34
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ARTICLE
23.
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WAIVER.
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34
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ARTICLE
24.
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PUBLIC
DISCLOSURE.
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35
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ARTICLE
25.
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NOTICES.
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35
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ARTICLE
26.
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ENTIRE
AGREEMENT.
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36
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[***].
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APPENDIX
B
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MUTUAL
CONFIDENTIALITY AGREEMENT.
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APPENDIX
C
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QUALITY
AGREEMENT.
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APPENDIX
D
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LIST
OF SCHEDULES.
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-i-
ACTIVE
PHARMACEUTICAL INGREDIENT
THIS
SUPPLY
AGREEMENT
(the
“Agreement”) is entered into as of May 18, 2006 (the “Effective Date”), by and
between ORGANICHEM
CORPORATION,
a
Delaware corporation, with offices at 00 Xxxxxxxxx Xxxxxx, Xxxxxxxxxx, Xxx
Xxxx
00000 (“ORGANICHEM”) and NEW
RIVER PHARMACEUTICALS INC.,
a
Virginia corporation, with corporate offices at 0000 Xxxxx Xxxxxx, Xxxxxxx,
Xxxxxxxx 00000 and its designees (“NEW RIVER”).
WHEREAS,
ORGANICHEM is a contract manufacturer of bulk active ingredients with expertise
in current Good Manufacturing Practices;
WHEREAS,
NEW RIVER is a specialty pharmaceutical company engaged in the discovery,
development and commercialization of novel pharmaceutical products, including
NRP104;
WHEREAS,
ORGANICHEM and NEW RIVER (collectively, the “parties”), desire to establish
mutually agreeable terms for the non-exclusive supply of NRP104 by ORGANICHEM
to
NEW RIVER;
WHEREAS,
ORGANICHEM and NEW RIVER intend to implement this Agreement in connection
with a
separate Quality Agreement subject to and incorporating by reference the
terms
of this Agreement; and
WHEREAS,
ORGANICHEM’s manufacturing location for NRP104 is 00 Xxxxxxxxx Xxxxxx,
Xxxxxxxxxx, Xxx Xxxx 00000;
NOW,
THEREFORE, in consideration of: (i) ORGANICHEM’s agreement to contract
manufacture and supply NRP104 to NEW RIVER for the monetary amounts set forth
in
this Agreement; (ii) the promises, covenants, agreements and other valuable
consideration hereinafter set forth, the parties hereby agree as
follows.
Page
1
of 37
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ARTICLE
1.
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DEFINITIONS.
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As
used
in this Agreement, the following words and phrases shall have the meanings
provided below:
“Act”
shall
mean the United States Food, Drug and Cosmetic Act, as amended, and rules
and
regulations promulgated thereunder;
“Affiliate”
means
any
individual or entity directly or indirectly controlling, controlled by, or
under
common control with such party. For purposes of this definition, “control” means
the direct or indirect ownership of at least fifty percent (50%) of the
outstanding voting securities of a party, or the right to control the policy
decisions of such party;
“Analytical
Method(s)”
shall
mean the following tasks necessary for analytical methods development with
respect to the API: [***]
“API”
or “Active Pharmaceutical Ingredient”
shall
mean the active pharmaceutical ingredient designated by NEW RIVER as NRP104
as
described in the Specifications;
“Applicable
Laws”
means
(a) all applicable U.S. federal, state, and local law, rules, and regulations,
including, without limitation, the United States Federal Food, Drug and Cosmetic
Act, as amended, FDA regulations, the Controlled Substances Act, as amended,
and
DEA regulations, and (b) all applicable laws, statutes, rules, codes,
regulations, orders, judgments and/or ordinances of Canada,
Japan, or any country of the European Union (including any federal, state,
provincial, or local political subdivision thereof) in which API is
marketed;
“Certificate
of Analysis” or “COA”
shall
mean the certificate attesting to the attributes for each batch of API delivered
hereunder in the form contemplated by Section 3.05 of this
Agreement;
“Certificate
of Compliance” or
“COC”
shall
mean the certificate stating the batch has been manufactured according to
the
relevant guidelines established by the FDA, including cGMP;
Page
2
of 37
“cGMP”
or “current Good Manufacturing Practices” shall
mean the current Good Manufacturing Practice regulations and guidelines as
promulgated by the United States Food and Drug Administration and the equivalent
regulatory authorities of Canada, Japan, or the European Union, including
any
federal, state, provincial, or local political subdivision thereof in which
API
is marketed.
cGMP
shall
include but not be limited to 21 CFR Part 210 and FDA Q7A Good Manufacturing
Practice Guidance for Active Pharmaceutical Ingredients;
“Critical
Materials” shall
have the meaning set forth in the Quality Agreement;
“DEA”
shall
mean the United States Drug Enforcement Administration;
“Delivery
Date” shall
mean the requested delivery date for API supplied under this Agreement, as
set
forth in the applicable accepted Purchase Order;
“Drug
Product”
shall
mean any and all pharmaceutical preparations suitable for human use which
contain API that has been manufactured by ORGANICHEM pursuant to this
Agreement;
“FDA
or Food and Drug Administration” shall
mean the United States Food and Drug Administration, or any successor entity
thereto;
“Gm”
shall
mean grams;
“Improvement
Program”
shall
have the meaning set forth in Section 6.04;
“Intellectual
Property”
includes, without limitation, rights in patents, patent applications, formulae,
trademarks, trademark applications, tradenames, Inventions, copyrights and
industrial designs, relating specifically to the Manufacture of
API;
“Invention”
means
information relating to any data, innovation, improvement, development,
discovery, computer program, device, trade secret, method, know-how, process,
technique or the like, whether or not written or otherwise fixed in any form
or
medium, regardless of the media on which it is contained and whether or not
patentable or copyrightable;
“Kg”
shall
mean kilograms;
Page
3
of 37
“Manufacture”
and “Manufacturing”
means
all steps and activities necessary to produce the API, including the
manufacturing, processing, quality control, quality assurance, testing, and
release of the API in compliance with the terms and conditions of this Agreement
and the Quality Agreement;
“Mutual
Confidentiality Agreement”
shall
mean the Non-Disclosure & Confidentiality Agreement entered into between NEW
RIVER and Albany Molecular Research, Inc. (on its own behalf and for Organichem)
with an Effective Date of March 27, 2003;
“NDA”
or “New Drug Application”
shall
mean NEW RIVER’s New Drug Application covering API and filed by NEW RIVER with
the FDA pursuant to section 505 of the Act;
“Near-Term
Forecast” shall
mean the estimated requirements of API for the first [***] [***] of a [***]
forecast provided by NEW RIVER pursuant to Section 4.01, as set forth on
such
forecast;
“Process
Transfer Plan”
shall
have the meaning set forth in Section 9.08;
“Purchase
Order”
shall
mean the NEW RIVER documentation that sets forth the [***], as more fully
described in Sections 3.01 and 4.02;
“Quality
Agreement”
shall
mean the Quality Agreement between NEW RIVER and ORGANICHEM set forth in
Appendix
C
hereof
which Appendix is incorporated in and made a part of this
Agreement;
“Raw
Materials” shall
mean the materials and ingredients required to be used by ORGANICHEM for
the
manufacture of API;
“Regulatory
Authority(ies)” shall
mean the FDA as well as other applicable U.S. and foreign
authorities;
“Services”
shall
mean the manufacturing, quality control, quality assurance and stability
testing, Analytical Methods and related services required for ORGANICHEM
to
Manufacture and supply API to NEW RIVER or its designee as contemplated in
this
Agreement;
Page
4
of 37
“Sourcing
Date”
shall
mean the date of the first delivery of API to NEW RIVER following FDA approval
of NEW RIVER’s NDA for API;
“Specifications”
shall
mean the specifications for API set forth in the Quality Agreement attached
hereto as Appendix
C;
“Term”
shall
have the meaning set forth in Article 8;
“Validation
Protocol”
shall
mean the validation of lots of API under a validation protocol prepared in
accordance with the Quality Agreement.
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ARTICLE
2.
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MANUFACTURE.
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2.01
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The
parties shall negotiate and agree to a Quality Agreement which
shall
govern all quality related matters pertaining to each party’s obligations
hereunder.
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2.02
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During
the term and pursuant to the conditions of this Agreement, ORGANICHEM
shall provide the Services in accordance with the Specifications,
cGMP,
the terms of the Quality Agreement, and all Applicable Laws, including,
but not limited to, those dealing with occupational safety and
health,
those dealing with public safety and health, those dealing with
protecting
the environment, and those dealing with disposal of wastes. During
the
term of this Agreement, ORGANICHEM shall not Manufacture and/or
supply
API, or perform any other Services with respect to API, for any
person or
entity other than NEW RIVER or its
designees.
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2.03
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ORGANICHEM
shall purchase, test and store at no cost to NEW RIVER, a stock
of Raw
Materials equivalent to a [***] supply of API based upon the most
recent
forecast provided by NEW RIVER in accordance with Article 4 hereunder.
ORGANICHEM shall use and rotate the Raw Material in accordance
with its
own inventory management policies. Such policies shall be made
available
to NEW RIVER upon prior written request. ORGANICHEM shall be responsible
for obtaining, at its own expense, sufficient quantities of Raw
Materials
for the Manufacture of API to meet [***] [***] of the most recent
Near-Term Forecast. On NEW RIVER’S written request, ORGANICHEM shall
notify NEW RIVER of its inventory of Raw Materials and its arrangements
for further supply. The parties acknowledge that certain of the
Raw
Materials may not be immediately available from approved vendors
and/or
may require government approval prior to their purchase. The parties
agree
to reasonably cooperate to minimize the impact such lead times
or
government approvals may have upon ORGANICHEM’s production schedule and,
provided that ORGANICHEM
has acted in good faith to meet its obligations hereunder, failure
to
comply strictly with the provisions of this Section 2.03 for reasons
beyond its direct control shall not constitute a breach of this
Agreement.
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Page
5
of 37
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2.04
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ORGANICHEM
agrees to Manufacture reasonable quantities of analytical reference
standards as needed for testing of the API and the Drug Product
and to
supply them at cost to NEW RIVER for its use or the use by third
party
suppliers to NEW RIVER or its designee. ORGANICHEM agrees, upon
NEW
RIVER’s written request,
to
furnish written procedures for the preparation of the mutually
agreed list
of analytical reference standards to NEW
RIVER.
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2.05
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ORGANICHEM
shall be responsible for all process and equipment validation and
shall
take all reasonable steps necessary to pass government inspection
by the
applicable Regulatory Authority. ORGANICHEM shall be responsible
for
system suitability confirmation and confirmation of API Analytical
Methods
as required in this Agreement.
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2.06
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In
accordance with cGMP, ORGANICHEM shall take all steps necessary
to ensure
that any API that may be produced by it pursuant to this Agreement
shall
be free of cross-contamination from any other manufacturing or
similar
activities and be responsible for validated cleaning and changeover
procedures prior to Manufacturing any API for NEW
RIVER.
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2.07
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ORGANICHEM
agrees to Manufacture API for NEW RIVER only at ORGANICHEM’s facilities
located at 00 Xxxxxxxxx Xxxxxx, Xxxxxxxxxx, Xxx Xxxx 00000. ORGANICHEM
shall not Manufacture the API at a different location without first
obtaining the prior written consent of NEW RIVER, which consent
shall not
be unreasonably delayed or withheld. The cost of any such change
in
location shall be borne solely by
ORGANICHEM.
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Page
6
of 37
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2.08
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ORGANICHEM
will use commercially reasonable efforts to obtain all necessary
regulatory permissions, permits, and licenses to Manufacture API
based on
the applicable DEA schedule and [***] of the highest annual volume
of API
set forth in the Tiered Commercial Quote attached hereto as Appendix
A
provided that NEW RIVER has furnished to ORGANICHEM all reasonably
necessary
supporting documentation to permit ORGANICHEM to obtain such regulatory
permission, permits, and licenses.
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2.09
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ORGANICHEM
shall reasonably assist NEW RIVER in preparing and updating any
required
regulatory submissions and all other documents required by the
Regulatory
Authorities from NEW RIVER for approval of the API under the terms
sent
forth in an applicable Statement of Work, which will be mutually
agreed
upon in writing by NEW RIVER and ORGANICHEM and, upon such mutual
agreement, deemed incorporated into this
Agreement.
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2.10
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ORGANICHEM
shall not change the Manufacturing process, the Specifications
or the
Analytical Methods without the prior written consent of NEW RIVER,
which
shall not be unreasonably delayed or withheld. ORGANICHEM shall
provide
NEW RIVER with a detailed written report of all proposed changes
to the
Manufacturing process, the Specifications, or the Analytical Methods
prior
to NEW RIVER’s consideration of such request, as covered in the Quality
Agreement.
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2.11
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Each
party agrees to promptly forward to the other party copies of any
written
communication received by such party from a Regulatory Authority
that may
be reasonably expected to affect the Manufacture of API as contemplated
herein, and shall confer with each other with respect to the best
means to
comply with any new or modified
requirements.
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2.12
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If
NEW RIVER is required by the Regulatory Authorities to change the
Specifications, the Critical Materials, sources of Cirtical Materials
or
Analytical Methods with respect to API, ORGANICHEM shall use [***]
efforts
to accommodate such request, and NEW RIVER and ORGANICHEM shall
use [***]
efforts to agree upon a revised fee for the Services if necessary
in
respect of such required change.
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Page
7
of 37
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2.13
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If
NEW RIVER requests in writing a change in the Manufacturing process,
the
Specifications, the Critical Materials, source of Critical Materials
or
Analytical Methods with respect to the API that is not the result
of a
Regulatory Authority requirement, ORGANICHEM shall use [***] efforts
to
accommodate such request, and NEW RIVER shall reimburse ORGANICHEM
for any
reasonable additional costs associated with such
change.
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2.14
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If
ORGANICHEM requests in writing a change in the Manufacturing process,
the
Specifications, the Critical Materials, source of Critical Materials
or
Analytical Method with respect to API that is not the result of
a
Regulatory Authority requirement, NEW RIVER shall use [***] efforts
to
accommodate such request, provided that any such change shall be
at
ORGANICHEM’s sole expense, unless otherwise agreed upon in writing by the
Parties.
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2.15
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Unless
otherwise agreed to in writing by the Parties, NEW RIVER shall
have the
sole responsibility for filing all documents with the FDA and taking
any
other actions that may be required for the receipt of FDA Approval
for the
commercial Manufacture of API. ORGANICHEM shall assist NEW RIVER,
to the
extent consistent with ORGANICHEM’s obligations under this Agreement, to
obtain FDA Approval for the commercial Manufacture of API as quickly
as
reasonably possible.
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ARTICLE
3.
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PURCHASE
ORDERS, TESTING AND SUPPLY.
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3.01
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NEW
RIVER shall submit Purchase Orders to ORGANICHEM for all API and
related
Services requested under this Agreement, which requests may be
made by NEW
RIVER from time to time at NEW RIVER’s discretion. Each such Purchase
Order shall set forth in reasonable detail the quantities of API
that are
desired by NEW RIVER, any additional Services that may be desired
by NEW
RIVER, and the desired date of delivery for such API and related
Services.
NEW RIVER shall not be bound by any obligation that has not been
reduced
to writing and executed by NEW RIVER. When executed by both parties,
such
Purchase Order shall become exhibits to and incorporated into,
this
Agreement. In the event of any difference between the terms and
conditions
contained in any such Purchase Order and those contained herein,
the terms
and conditions of this Agreement shall
prevail.
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Page
8
of 37
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3.02
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The
API ordered for any month may be [***] and ORGANICHEM shall use
[***]
efforts to [***], except that any Purchase Order submitted by NEW
RIVER
shall [***] and ORGANICHEM shall
[***]
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3.03
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Raw
Materials and API supplied hereunder shall conform to the Specifications
(as set forth in the Quality Agreement) and such conformance shall
be
verified in accordance with procedures set forth in the Quality
Agreement
and this Article 3. To the extent that any provision relating to
safety or
quality control documents or procedures that is
set forth in the Specifications or the Quality Agreement conflicts
with
any provision in this Article 3, the provision in the Specification
or
Quality Agreement (as the case may be) shall govern and supersede
the
conflicting provision(s) in this Article
3.
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3.04
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ORGANICHEM
agrees that once the validation of the Manufacturing process has
been
completed, it will prepare, [***], all analytical reference standards
required for its use during the preparation, release testing of
Raw
Materials, intermediates or finished API. ORGANICHEM will continue
to
provide for its purposes reasonable quantities of such analytical
reference standards throughout the
Term.
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3.05
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ORGANICHEM's
laboratory personnel shall obtain a representative sample from
each batch
of API produced by ORGANICHEM. In testing API, ORGANICHEM shall
assay and
analyze such samples in accordance with the agreed upon Analytical
Methods, and the Specifications set forth in the Quality Agreement,
and
shall promptly prepare a CoA / CoC in a format agreed to in writing
by the
parties. Such CoA / CoC shall identify the batch of API to which
it
relates. ORGANICHEM shall provide NEW RIVER with a copy of the
CoA / CoC
containing the address of the Manufacture for each batch upon delivery
of
such batch in the format required by NEW
RIVER.
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3.06
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If
ORGANICHEM’s analysis or assay indicates that such batch does not meet
Specifications, ORGANICHEM shall promptly advise NEW RIVER of its
noncompliance. ORGANICHEM shall reasonably cooperate with NEW RIVER
to
determine the cause of the failure of the API to meet Specifications.
ORGANICHEM shall not ship any API hereunder which, as indicated
by a
sample assay or analysis as set forth above, does not conform to
Specifications without the prior written consent of NEW
RIVER.
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Page
9
of 37
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3.07
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ORGANICHEM
shall not rework any batch of API without NEW RIVER’s prior written
consent, which consent shall not be unreasonably withheld. All
non-specification (out-of-Specification) API not capable of being
reworked
or reprocessed to meet Specification shall be disposed of by ORGANICHEM.
In the event that API does not meet Specifications due to ORGANICHEM’s
[***] [***], then ORGANICHEM shall be [***]. In the event that
such
noncompliance with the Specifications is for any reason other than
ORGANICHEM’s [***], the parties shall [***] cooperate to determine
[***]
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3.08
|
ORGANICHEM
shall package, label and otherwise prepare for bulk shipment API
as
outlined in the Quality Agreement, in accordance with the instructions
for
shipping and packaging included in the applicable Purchase Order,
applicable transport regulations and guidelines, and as approved
by NEW
RIVER or its designee.
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3.09
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Each
shipment of API hereunder will be shipped to a facility of NEW
RIVER or
its designee, as designated on a Purchase Order governing such
shipment or
by subsequent written instruction given by NEW RIVER. ORGANICHEM
will
include the current Material Safety Data Sheet (“MSDS”), Certificate of
Analysis and Certificate of Compliance, as required with each shipment,
for API.
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3.10
|
In
the event that, with respect to the [***] period covered by a particular
Near-Term Forecast, the quantity of API needed by NEW RIVER shall
exceed
the amount forecast by NEW RIVER in such Near-Term Forecast, ORGANICHEM
shall use [***] efforts to [***] and NEW RIVER shall reasonably
cooperate
with ORGANICHEM to [***]
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3.11
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In
the event that ORGANICHEM is unable to provide Services in accordance
with
the terms of this Agreement, or the Quality Agreement, and such
inability
subsists or is likely to subsist on a rolling [***] cumulative
basis
(“Failure Period”), the parties agree to work together in good faith
during the Failure Period to resolve the event causing ORGANICHEM’s
failure to provide the Services and to procure the continued Services
from
ORGANICHEM as soon as reasonably practicable following resolution
of the
event causing the Failure Period.
For the avoidance of doubt, failure of ORGANICHEM to use
commercially reasonable efforts to obtain sufficient quota for
Manufacture
of API and/or [***] such that ORGANICHEM is unable to meet its
obligations
under Section 4.06, or
the occurrence of any Quarterly Shortfall or Yearly Shortfall (as
defined
in Section 4.06), shall deemed to be a failure of ORGANICHEM to
provide
the Services that has continued beyond the applicable Failure Period
set
forth in Section 3.12, in response to which NEW RIVER may elect
the remedy
set forth in Section 3.12.
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Page
10 of 37
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3.12
|
In
the event that parties are unable to resolve the event leading
to
ORGANICHEM’s failure to provide the Services, and such failure continues
beyond the Failure Period, then the
[***], subject to possible reinstatement as provided in the final
sentence
of this Section 3.12. If ORGANICHEM is unable to resume providing
the
Services within the Failure Period, then
ORGANICHEM shall: [***] For the avoidance of doubt, NEW RIVER shall
not
have any right to [***] Subject to NEW RIVER’s termination rights set
forth in Section 4.06, NEW RIVER’s
[***]
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ARTICLE
4.
|
FORECASTS
AND FIRM ORDERS.
|
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4.01
|
Within
[***] after the Effective Date of this Agreement, NEW RIVER will
provide
ORGANICHEM with a written, non-binding forecast showing NEW RIVER’s
estimated requirements for API, by month, covering a [***] period.
Following FDA approval of the first Drug Product, NEW RIVER will
issue on
the fifteenth (15th)
day of every calendar [***] a non-binding forecast update for the
next
[***] period commencing on the first day of the immediately following
quarter.
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4.02
|
Firm
orders for API shall be placed by NEW RIVER in writing (each such
writing,
a “Purchase Order”) on the [***] day of each [***] month and at a [***]
prior to desired delivery date.
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4.03
|
Provided
Purchase Orders are consistent with the most recent Near Term Forecast
(i.e., the quantity of API ordered by NEW RIVER for the [***] period
covered by a particular Near-Term Forecast does not exceed the
amount
forecast by NEW RIVER in such Near-Term Forecast, by more than
[***] as
permitted in Section 3.02) ,
ORGANICHEM agrees to accept Purchase Orders from NEW RIVER and
ship an
amount of API identified in the applicable Purchase Order, up to
the [***]
Notwithstanding the foregoing, ORGANICHEM will use [***] efforts
to meet
NEW RIVER’s demand for API in amounts [***], and shall provide, upon NEW
RIVER’s written request, written confirmation to NEW RIVER that ORGANICHEM
has sufficient Manufacturing capacity to satisfy the most recent
Near-Term
Forecast. Within [***] after receipt of NEW RIVER’s Purchase Order,
ORGANICHEM shall confirm receipt of the Purchase Order and confirm
the
delivery date of such quantity of API as set forth in the applicable
Purchase Order.
|
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|
4.04
|
NEW
RIVER may cancel any Purchase Order by providing ORGANICHEM not
less than
[***] written notice. In the event that NEW RIVER cancels any order
for
API, NEW RIVER [***] For clarity, in the event NEW RIVER cancels
a
Purchase Order with less than [***], ORGANICHEM may, at its sole
discretion, require that [***]
|
|
4.05
|
The
parties recognize that the manufacture of API involves the use
of a
substance that is regulated by the DEA. For the purposes of fulfilling
its
obligations to obtain approval to manufacture such controlled substance,
NEW RIVER shall, no later than April 1st
of
each calendar year of the Term, provide to ORGANICHEM a written
estimate
of its expected purchases of API from ORGANICHEM during the following
calendar year. NEW RIVER shall also promptly notify in writing
any
significant change in such forecast following the April 1st
forecast. The parties agree that ORGANICHEM’s inability to produce API
resulting from a failure of NEW RIVER to accurately project NEW
RIVER’s
requirements for API or failure of DEA to grant such quota or other
permissions as may be required by ORGANICHEM to fulfill its obligations
hereunder, provided that ORGANICHEM has otherwise made all reasonable
efforts to request such permissions in a timely manner, may qualify
as a
force majeure event pursuant to Article
18.
|
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|
4.06
|
If
[***] of API that is ordered and scheduled for delivery in any
one
calendar quarter
pursuant to applicable accepted Purchase Orders, as established
by the
applicable Delivery Date,
is
not delivered in that calendar quarter
in
accordance with the mutually agreed upon delivery dates
(a
“Quarterly Shortfall”)
then NEW RIVER, in addition to any other rights available to it
under this
Agreement, may terminate this Agreement on [***] written notice.
Similarly, if [***] of API that is ordered and scheduled for delivery
in
any one calendar year pursuant to applicable accepted Purchase
Orders, as
established by the applicable Delivery Date, is not delivered in
that
calendar year in
accordance with the mutually agreed upon delievery dates (a
“Yearly Shortfall”),
then NEW RIVER, in addition to any other rights available to it
under this
Agreement, may terminate this Agreement on [***]
written notice. Termination under this Section 4.06 shall be subject
to
the provisions of Article 9.
|
|
4.07
|
[***]
|
|
ARTICLE
5.
|
SHIPPING
AND DELIVERY; ACCEPTANCE AND REJECTION.
|
|
5.01
|
Unless
otherwise agreed upon by the parties in writing, NEW RIVER will
provide
requested shipping and delivery dates at the time firm orders are
placed.
API Manufactured by ORGANICHEM shall be shipped to NEW RIVER FCA
(Incoterms, 2000) Rensselaer, New York via NEW RIVER’s designated
carrier.
|
|
5.02
|
A
xxxx of lading will be furnished to NEW RIVER with respect to each
shipment. At the time of shipment, ORGANICHEM represents and warrants
that
API will be free and clear of any liens or encumbrances placed
thereon.
|
|
5.03
|
ORGANICHEM
agrees to ship products hereunder in a timely manner so as to comply
with
the scheduled Delivery Dates as set forth in the relevant Purchase
Orders.
|
|
5.04
|
NEW
RIVER shall notify ORGANICHEM in writing of any loss or damage
of API
within the following time limits:
|
|
(a)
|
Notification
by NEW RIVER to ORGANICHEM of partial loss, damage, defects or
non-delivery of any separate part of a consignment shall be made
promptly
by NEW RIVER after delivery to NEW RIVER, and if loss, damage,
defects or
partial non-delivery are not evident to NEW RIVER at the time of
delivery,
such notification by NEW RIVER to ORGANICHEM shall be made no later
than
[***] after delivery to NEW RIVER or its designee. If a defect
is not
apparent upon acceptance, NEW RIVER may notify ORGANICHEM up to
[***] from
receipt of that lot of API.
|
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|
(b)
|
Notification
by NEW RIVER to ORGANICHEM of an entire non-delivery to NEW RIVER
of a
whole consignment shall be made within [***] from the date NEW
RIVER
should have received notice of dispatch of such consignment, or
within
such longer period as may be agreed upon in writing between the
parties.
|
|
(c)
|
In
the event of such partial or full loss of such consignment, the
parties
will cooperate to insure that notification and follow-up with the
involved
ground and air carriers and customs or other warehouses is made
in order
to determine if such missing delivery can be located. NEW RIVER
may assist
ORGANICHEM in tracing such shipment and NEW RIVER [***] For such
a
consignment which has been accepted by such carrier but is not
recovered
or which is damaged or defective,
[***]
|
|
5.05
|
NEW
RIVER or its designee may test each batch of API and may reject
any batch
delivery which does not conform with the Specifications or with
applicable
documentation and process requirements as set forth in the Quality
Agreement. In testing API, NEW RIVER or its designee shall use
the agreed
upon Analytical Methods, and the Specifications set forth in the
Quality
Agreement. NEW RIVER or its designee shall analyze the API (for
purposes
of determining whether the same meets Specifications) [***] from
the date
of receipt of the affected API and NEW RIVER shall report any adverse
findings, except latent or hidden defects to ORGANICHEM within[***]
from
such date of receipt. Any such notice of rejection shall be in
writing and
shall indicate the reasons for such rejection. If no such notice
of
rejection is received, NEW RIVER shall be deemed to have accepted
such
delivery of API within [***] of delivery of the
batch.
|
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|
5.06
|
After
notice of rejection is given, NEW RIVER shall cooperate with ORGANICHEM
in
determining whether rejection is necessary or justified. ORGANICHEM
will
evaluate process issues and other reasons for such non-compliance.
ORGANICHEM shall respond to NEW RIVER’s written notice of rejection within
[***] of receipt, and shall advise NEW RIVER whether it accepts
or
challenges the basis for the notice of rejection. In the event
that the
compliance of the API lot cannot be resolved through the mutual
agreement
of the respective Quality Assurance groups in accordance with the
Quality
Agreement, then the parties will submit an agreed sample of the
API lot to
an independent qualified laboratory, mutually agreed upon by NEW
RIVER and
ORGANICHEM, for analysis and a determination whether, at the time
of
Manufacture, it complied with the Specifications. Both parties
shall be
bound by the results of such independent review, [***] Whether
or not
ORGANICHEM accepts NEW RIVER’s basis for rejection, promptly on receipt of
a notice of rejection of a full batch of API, ORGANICHEM shall
use [***]
efforts at NEW RIVER’s request to [***] Any rejected
API not replaced within ninety (90) days shall be deemed to have
[***] for
the purpose of evaluating ORGANICHEM’s performance under this Agreement
(including without limitation the evaluation contemplated by Sections
3.11
and 4.06). [***]
of
such batch of API from any of ORGANICHEM’s required safety stock of
API
or
Critical Materials may have the effect of reducing the level of
such
inventories below
those required hereunder. If such [***] is necessary, NEW RIVER
will
provide ORGANICHEM with [***] (but no more than [***]) in which
to
replenish such inventories. If the third-party tester rules that
the batch
meets Specifications, NEW RIVER
[***]
|
|
5.07
|
NEW
RIVER may not destroy any batch of API that is subject to disagreement
under Section 5.06 until it receives written notification from
ORGANICHEM
that ORGANICHEM does not dispute that the batch fails to meet
Specifications and that ORGANICHEM does not request return of the
API.
Upon authorization from ORGANICHEM to do so, NEW RIVER shall destroy
the
API received in the rejected delivery promptly at [***] ORGANICHEM
with
certification of such destruction. NEW RIVER shall, upon receipt
of
ORGANICHEM’s request for return, promptly return said API to ORGANICHEM,
[***]
|
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|
ARTICLE
6.
|
PRICE
FOR BULK API.
|
|
6.01
|
The
price for the supply of API and related Services performed hereunder
shall
be identified as a cost per Kg delivered to NEW RIVER based on
the
[***]
|
|
6.02
|
As
part of the cost of the bulk API, ORGANICHEM will provide and maintain
bulk stability testing for API and provide NEW RIVER with the related
data.
|
|
6.03
|
Beginning
[***] after the Sourcing Date, the price of API from ORGANICHEM
may be
[***] in ORGANICHEM’s direct costs to Manufacture the API, including
increases and decreases in the price of (a) Critical Materials,
and/or (b)
labor; provided, however, that no change in the price of API shall
be
effective until mutually agreed by the parties in a written amendment
to
this Agreement. NEW RIVER shall have the right, upon prior written
notice
to ORGANICHEM, to cause an independent accounting firm to audit
ORGANICHEM’s records relevant to any changes in the direct costs to
Manufacture the API for the purpose of verifying such changes.
[***] Any
increase in the price of API that is attributable to any factor
other than
the costs of Raw Materials (such as labor or other costs or fees
that are
not directly related to a rise in the cost of a starting material)
shall
be [***] if any, the percentage change in prices in the [***]
|
|
6.04
|
ORGANICHEM
agrees to use commercially reasonable efforts to identify, target
and
implement all potential areas of cost reduction relating to the
performance of its obligations under this Agreement
including:
|
|
(a)
|
a
reduction in all costs and expenses associated with the Manufacture
of the
API including the cost of Raw Materials, Manufacturing overhead,
labor,
operating costs and the delivery of the
Product;
|
|
(b)
|
improvements
in the yield of API; and
|
|
(c)
|
reduction
of waste associated with the Manufacture of
API
|
(collectively
the “Improvement Program”).
Not
less
than [***] and upon [***], NEW RIVER and ORGANICHEM agree to discuss objectives
for the Improvement Program, and to exchange relevant information in their
possession relating to the Manufacture of API, including details of the cost
of
Raw Materials, the cost of the various stages of the Manufacture of API,
and
targets for cost reductions in order to pursue and implement the Improvement
Program. The Parties shall use best efforts to achieve such objectives
identified for the relevant year.
Page
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|
6.05
|
The
parties shall allocate the benefits of cost reductions and improved
efficiencies achieved as the result of the Improvement Program
equally
between NEW RIVER and ORGANICHEM.
|
|
ARTICLE
7.
|
PAYMENT.
|
Payment
shall be made by NEW RIVER to ORGANICHEM [***] following the date of NEW
RIVER’s
receipt of an invoice for API from ORGANICHEM. Each such invoice shall, to
the
extent applicable, identify NEW RIVER’s Purchase Order number, product names and
quantities delivered to NEW RIVER, unit price, Services provided, and the
total
amount to be remitted by NEW RIVER.
|
ARTICLE
8.
|
TERM.
|
This
Agreement enters into effect on the Effective Date and shall remain in full
force and effect for five (5) years from the Sourcing Date (the “Term”).
Thereafter, it shall be extended on an annual basis from year to year, unless
terminated by either party by giving no less than twelve (12) months prior
written notice to the other party or terminated as provided for under the
terms
of Article 9.
|
ARTICLE
9.
|
TERMINATION.
|
|
9.01
|
Either
party may terminate this Agreement as
follows:
|
|
(a)
|
If
the other party is unable to pay its debts as they come due, becomes
bankrupt or insolvent or enters into liquidation whether compulsory
or
voluntary, or convenes a meeting of its creditors, or has a receiver
appointed for all or part of its assets, or takes or suffers any
similar
action in consequence of a debt, or ceases for any reason to carry
on
business,
either
party may terminate this Agreement by
giving the other party [***] prior written notice;
or
|
Page
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|
(b)
|
If
the other party commits a
material breach of this
Agreement,
including, without limitation, ORGANICHEM’s breach of its obligations
under Section 4.06,
and
if
such
material
breach is not cured within [***] in the case of a breach not reasonably
curable within [***], provided that the allegedly breaching party
has made
commercially reasonable efforts to cure such breach as quickly
as
possible) after written notice thereof to the party in breach,
such notice to include a description of the nature of the breach,
then
the non-breaching party may terminate this Agreement immediately
on
written notice to the breaching party following such sixty [***] cure
period
(as applicable),
provided that
the material breach continues to exist following such cure
period.
|
|
9.02
|
NEW
RIVER may terminate this Agreement
on
not less than [***] prior written notice to
ORGANICHEM only
in the event that NEW RIVER fails to obtain approval by the FDA
of its NDA
for API and it publicly abandons its efforts to obtain such approval
or,
in the event that the FDA revokes such approval and NEW RIVER publicly
discloses that it shall not seek reinstatement of such
NDA.
|
|
9.03
|
If,
following the [***]
of
the Effective
Date,
NEW RIVER is able to obtain API of equivalent quality and comparable
quantities from any third party manufacturer at [***], NEW RIVER
shall
notify ORGANICHEM in writing and, if
requested by ORGANICHEM, produce reasonable written evidence of
[***].
ORGANICHEM shall have [***] from the date of notice to [***] but
if
ORGANICHEM does not or cannot do so for any reason within such
[***] NEW
RIVER shall be entitled, in its absolute discretion to
either:
|
|
(a)
|
reduce
its [***]
under the terms of this Agreement from [***] of its [***] of its
[***];
or
|
|
(b)
|
terminate
this Agreement by giving [***]
written notice to ORGANICHEM.
|
Any
such
termination shall be subject to the provisions of Section 9.05
and
other
applicable provisions hereunder.
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|
9.04
|
Upon
termination, expiration or cancellation of this Agreement for any
reason,
ORGANICHEM shall cease any ongoing production and take reasonable
measures
to limit further expenses associated with such ongoing production.
Upon
termination,
expiration or cancellation of this Agreement for any reason by
NEW
RIVER
(other than pursuant to Section 9.01(b)),
[***]
|
|
9.05
|
Upon
termination, expiration or cancellation of this Agreement for any
reason,
any undelivered API and API intermediate produced by
ORGANICHEM
shall be held by ORGANICHEM [***], and ORGANICHEM shall cooperate
with NEW
RIVER in the return, resale, disposal, or delivery to NEW RIVER,
[***] of
such materials as requested by NEW RIVER.
Such obligation shall only apply to undelivered API or API intermediate
to
[***] API or API intermediate pursuant to Section 9.04 or, if the
applicable terms of Section 9.04 do not apply, has [***] for
API
at
the [***] for API or
for API intermediates
at
a [***]
After such [***],
if so requested by NEW RIVER, ORGANICHEM shall store such API and/or
API
intermediates for no longer than [***] to be negotiated by the
parties in
good faith. After the end of such [***] (or earlier at NEW RIVER’s
election), NEW RIVER shall either accept delivery of such API or
API
intermediates or provide ORGANICHEM with instructions for the disposal
of
such materials. Any such shipments or disposal
[***]
|
|
9.06
|
Termination,
expiration, or cancellation of this Agreement through any means
and for
any reason shall not relieve the parties of any obligation accruing
prior
thereto, including but not limited, to the confidentiality and
proprietary
ownership provisions herein and the [***], and shall be without
prejudice
to the rights and remedies of either party with respect to the
antecedent
breach of any of the provisions of this
Agreement.
|
|
9.07
|
Upon
termination,
expiration or cancellation of this Agreement for any reason, ORGANICHEM
shall promptly return to NEW RIVER any and all materials, technical
information, trade secrets and know-how relating to or including
any
modification to the synthesis of API provided by NEW RIVER to ORGANICHEM
hereunder, if requested in writing by NEW RIVER.
[***]
|
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|
9.08
|
Following
termination, expiration or cancellation of this Agreement for any
reason
other than NEW RIVER’s insolvency, bankruptcy, or liquidation, should NEW
RIVER desire to Manufacture API at a non-ORGANICHEM facility, ORGANICHEM
shall (a) grant NEW RIVER or its designee, a [***] under any ORGANICHEM
Intellectual Property necessary for the Manufacture of API and
performance
of the Services (for the avoidance of doubt, such Intellectual
Property
shall specifically exclude ORGANICHEM’s process for the [***]);
and (b) assist NEW RIVER in transferring Manufacturing of the API
by
providing support for the transfer of the Manufacturing process
to NEW
RIVER or an organization named by NEW RIVER, pursuant to a plan
to be
negotiated in good faith and agreed upon by the parties (the “Process
Transfer Plan”). Such Process Transfer Plan shall include [***] and shall
also include without limitation all documentation relating to process
development, Manufacturing procedures, and product-specific procedures
referenced in such Manufacturing procedures, test records and technical
documents including testing and characterization of API, and any
regulatory documents prepared by ORGANICHEM to support the Manufacture
of
API. ORGANICHEM shall provide NEW RIVER or its designee, at NEW
RIVER’s or
its designee’s expense, with reasonable assistance and co-operation in the
transfer of any know how or technology required for the Manufacture
or
validation of the Services by such third party in a timely manner.
Except
in the event of termination of this Agreement pursuant to Section
9.01,
[***] for Manufacturing transfer activities such as [***]ipping,
and
[***].
|
|
9.09
|
Termination,
expiration or cancellation of this Agreement for any reason shall
not
affect the obligations and responsibilities of the parties pursuant
to
Articles 10, 12, 13, 14 and 17, all of which survive any termination,
along with any additional terms in this Agreement necessary to
give effect
to such provisions (including without limitation any perpetual
licenses
contained herein).
|
|
ARTICLE
10.
|
ORGANICHEM
REPRESENTATIONS, WARRANTIES AND COVENANTS.
|
ORGANICHEM
makes the following assurances, representations, warranties and covenants
that
at all times during the Term and any extension of this
Agreement:
Page
20 of 37
|
10.01
|
ORGANICHEM
(a) is duly organized, validly existing and in good standing under
the
laws of the state in which it is organized; (b) has the power and
authority and the legal right to own and operate its property and
assets,
to lease the property and assets it operates under lease, and to
carry on
its business as it is now being conducted; and (c) is in compliance
with
all requirements of Applicable Laws with respect to each facility
and site
to be used in the Manufacture or storage of API, except to the
extent that
any noncompliance would not materially adversely affect ORGANICHEM’s
ability to perform its obligations in compliance with Applicable
Laws and
the terms set forth under the
Agreement.
|
|
10.02
|
ORGANICHEM
(a) has the power and authority and the legal right to enter into
the
Agreement and to perform its obligations hereunder and thereunder,
(b) has
the necessary facilities, equipment, know-how, procedures and personnel
at
its manufacturing site to Manufacture the API in compliance with
this
Agreement and the Quality Agreement and in sufficient quantities
to
satisfy its Manufacturing obligations contemplated under this Agreement,
(c) shall not alter or otherwise effect any changes requiring FDA
approval
to any Manufacturing, processing or other component of API, including
without limitation, the installation of new or upgraded equipment
used in
the Manufacture or processing of API, from that utilized on the
Effective
Date, except in accordance with this Agreement the Quality Agreement,
and
Applicable Laws, and (d) has taken all necessary action on the
part of its
officers and directors necessary to authorize the execution and
delivery
of the Agreement and the performance of its obligations hereunder
and
thereunder. The Agreement has been duly executed and delivered
on behalf
of such party, and constitutes a legal, valid, binding obligation,
enforceable against such party in accordance with its
terms.
|
|
10.03
|
All
necessary licenses, permits, consents, approvals and authorizations
of all
governmental authorities and other persons required to be obtained
by
ORGANICHEM in connection with the Agreement have been
obtained.
|
|
10.04
|
The
execution and delivery of the Agreement and the performance of
ORGANICHEM’s obligations hereunder and thereunder (a) do not conflict with
or violate any requirement of Applicable Laws or regulations or
any
material contractual obligation of ORGANICHEM and (b) do not materially
conflict with, or constitute a material default or require any
consent
under, any material contractual obligation of ORGANICHEM. ORGANICHEM
shall
not in any event enter into any agreement or arrangement with any
other
party that would prevent or in any way interfere with ORGANICHEM’s
obligations pursuant to this
Agreement.
|
Page
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|
10.05
|
The
Intellectual Property utilized by ORGANICHEM in connection with
the
provision of ORGANICHEM’s obligations under this Agreement (i) may be
lawfully used as set forth in this Agreement and the Quality Agreement,
and (ii) such use does not knowingly infringe any third party
rights.
|
|
10.06
|
ORGANICHEM
shall convey good title in any API delivered to NEW RIVER or its
designee
under this Agreement, and that all such API will be delivered to
NEW RIVER
or its designee free from any security interest, lien, or other
encumbrance.
|
|
10.07
|
ORGANICHEM
shall not in the performance of its obligations under this Agreement
use
the services of any person debarred or suspended under 21 U.S.C.
§335a(a)
or (b). The parties represent that they do not currently have,
and
covenants that they will not hire, as an officer or an employee
any person
who has been convicted of a felony under the laws of the United
States for
conduct relating to the regulation of any drug product under the
Federal
Food, Drug, and Cosmetic Act.
|
|
10.08
|
ORGANICHEM
is cognizant of current Good Manufacturing Practices as defined
herein,
that ORGANICHEM shall meet the requirements as provided for in
the FDA Q7A
Good Manufacturing Practice Guidance for Active Pharmaceutical
Ingredients
and the provisions of the Quality Agreement, and ORGANICHEM warrants
that
API delivered hereunder will (i) be Manufactured by ORGANICHEM
in
compliance with cGMP and other Applicable Laws, (ii) be Manufactured
in
compliance with the agreed-upon Manufacturing procedures described
in the
Quality Agreement and (iii) conform to the applicable Specifications
set
forth in the Quality Agreement hereto at the time of delivery.
NEW RIVER’s
remedies and ORGANICHEM’s liability with respect to this warranty are set
forth below. This warranty is the only warranty made by ORGANICHEM
with
respect to API delivered hereunder, and may only be modified or
amended by
a written instrument signed by a duly authorized officer of ORGANICHEM
and
accepted by NEW RIVER. THE EXPRESS WARRANTY IN THIS SECTION 10.08
IS IN
LIEU OF ALL OTHER WARRANTIES, EXPRESS OR IMPLIED, INCLUDING, WITHOUT
LIMITATION, THE WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A
PARTICULAR
PURPOSE.
|
Page
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|
10.09
|
Any
lot of API delivered to NEW RIVER by ORGANICHEM which does not
conform to
Specifications and is rejected by NEW RIVER [***] of delivery,
does not
conform to Specifications as a result of latent or hidden defects,
or is
otherwise not in compliance with the warranty made in this Section
10.09,
will, with ORGANICHEM’s [***] efforts, be [***] or, if ORGANICHEM has
acknowledged in writing that it is unable to produce conforming
API, [***]
The remedy of [***] is available only if such nonconformance was
not
caused by NEW RIVER’s misuse, unauthorized modifications, neglect,
improper testing or improper storage, including without limitation
storage
at inappropriate temperatures, transportation, use beyond any dating
provided, by accident, fire or other hazard or other circumstances
beyond
the reasonable control of ORGANICHEM. THE EXPRESS OBLIGATIONS STATED
IN
THIS SECTION 10.09 AND ARTICLE 13 ARE IN LIEU OF ALL OTHER LIABILITIES
OR
OBLIGATIONS OF ORGANICHEM FOR DAMAGES, INCLUDING BUT NOT LIMITED
TO LOSS,
DAMAGE OR BODILY OR PERSONAL INJURY, DIRECT OR CONSEQUENTIAL, ARISING
OUT
OF OR IN CONNECTION WITH THE DELIVERY, USE OR PERFORMANCE OF ORGANICHEM’S
PRODUCTS.
|
|
10.10
|
All
assurances, representations, warranties and covenants contained
in this
Article 10 shall survive termination of this
Agreement.
|
|
ARTICLE
11.
|
INSPECTIONS,
RECALLS AND SEIZURES.
|
|
11.01
|
The
parties shall comply with the Quality Agreement with respect to
government
and regulatory inspections. At NEW RIVER’s request and expense, ORGANICHEM
further agrees to use its best efforts to assist NEW RIVER or its
designee
in obtaining FDA approval of its NDA with respect to API, as well
as
approvals from any other government or agency which may be required
for
the marketing of API in any other country. Notwithstanding the
foregoing,
NEW RIVER shall not be obligated to [***] ORGANICHEM specifically
agrees
to cooperate with any inspection by the FDA or other regulatory
agency,
including but not limited to any inspection prior to approval of
NEW
RIVER’s NDA. ORGANICHEM shall permit a NEW RIVER representative to review
any response it intends to make to the FDA only as it relates specifically
to API. When required NEW RIVER shall assist ORGANICHEM in filing
such
requests as necessary to obtain DEA quotas and permits for the
manufacture
of API and the appropriate starting
materials.
|
Page
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|
11.02
|
Upon
prior written request and at mutually agreeable times, ORGANICHEM
will
permit representatives of NEW RIVER or its designee to observe
such
Manufacture of API and to have access to any relevant records in
connection with such Manufacture as more fully provided in Quality
Agreement. Upon reasonable written request to ORGANICHEM, NEW RIVER
or its
designee shall have the right to have representatives visit ORGANICHEM’s
manufacturing facilities during normal business hours to review
ORGANICHEM’s manufacturing operations and assess its compliance with cGMP
and quality assurance standards and to discuss any related issues
with
ORGANICHEM’s manufacturing and management
personnel.
|
|
11.03
|
ORGANICHEM
shall notify NEW RIVER of any inspections by any governmental agency
involving the API. NEW RIVER or its designee reserves the right
to be
present at ORGANICHEM during any inspection by any governmental
agency but
does not have the right to be directly involved with the inspection
process. NEW RIVER or its designee reserves the right to review
any
findings by such governmental agency that are communicated to ORGANICHEM
and directly related to API, and ORGANICHEM shall allow NEW RIVER
to have
a reasonable period in which to comment on any response before
such
response is sent to the governmental
agency.
|
|
11.04
|
The
parties shall comply with the Quality Agreement with respect to
inspection
and audit rights. NEW RIVER may perform an annual Quality or cGMP
audit or
inspect as necessary as defined in the Quality Agreement. NEW RIVER
will
provide notification, ORGANICHEM will not refuse so long as the
request is
reasonable [***] and within normal business hours. All audited
data shall
be treated as Confidential Information of ORGANICHEM and NEW RIVER
or its
designee shall not be permitted to remove or copy data without
ORGANICHEM’s prior written consent. In accordance with the batch
documentation audit schedule outlined in the Quality Agreement
and upon
NEW RIVER’s written request, ORGANICHEM shall supply NEW RIVER or its
designee with copies of ORGANICHEM’s Manufacturing records, including its
batch records, for the purposes of assuring product quality and
compliance
with agreed-upon Manufacturing
procedures.
|
Page
24 of 37
|
11.05
|
ORGANICHEM
shall retain samples of API and isolated intermediates for each
batch of
API for a period of [***] after NEW RIVER’s acceptance of such batch. The
sample size shall be [***] to conduct quality control testing.
Upon NEW
RIVER’s reasonable written request, ORGANICHEM shall provide NEW RIVER
or
its designee with up to [***] of the retained samples. Such request
from
NEW RIVER or its designee will fully document the reason(s) why
such
quantity of retained sample would be
needed.
|
|
11.06
|
The
parties shall comply with the Quality Agreement with respect to
recall or
seizure.
|
|
ARTICLE
12.
|
LIABILITY
AND INSURANCE.
|
|
12.01
|
Other
than for a party’s breach of its obligations under Articles 10 or 14,
neither party shall be liable to the other party for any exemplary,
special, punitive, incidental or consequential damages. The foregoing
provision shall not be construed to limit a party’s indemnification
obligations under this Agreement for third party claims which may
include
consequential, punitive or other types of
damages.
|
|
12.02
|
Each
party shall secure and maintain at its own expense during the term
of this
Agreement and any extension of this Agreement, commercial general
liability insurance with
an annual aggregate limit of [***]
and products liability insurance for up to [***]
Upon written request, each party shall furnish
the other party with certificates of such commercial general liability
and
products liability insurance.
|
Page
25 of 37
|
12.03
|
The
liability provisions and insurance obligations set forth in this
Article
12 shall survive termination of this Agreement, except to the extent
such
provisions or obligations are explicitly limited to the
Term.
|
|
ARTICLE
13.
|
INDEMNIFICATION.
|
|
13.01
|
Subject
to Article 12, NEW RIVER shall indemnify, defend and hold harmless
ORGANICHEM (except to the extent ORGANICHEM is obligated to indemnify
NEW
RIVER as set forth below) against all claims, losses, damages and
liabilities, [***] (“NEW RIVER Indemnification Claims”) asserted by a
third party, to the extent arising out of or connection
with:
|
|
(a)
|
NEW
RIVER’s or its designee’s distribution, marketing, sale, and use of Drug
Product;
|
|
(b)
|
a
breach of NEW RIVER’s representations, warranties and covenants under this
Agreement; or
|
|
(c)
|
NEW
RIVER’s willful misconduct or
negligence.
|
ORGANICHEM
shall not settle any such claim without the prior written approval of NEW
RIVER.
NEW RIVER shall have the right, if NEW RIVER so wishes, to retain legal counsel
of its own choosing, conduct negotiations to settle, settle or to conduct
any
litigation arising out of, any such claim. ORGANICHEM shall provide prompt
written notice of any claim to NEW RIVER and shall cooperate in the defense
of
the claim.
|
13.02
|
Subject
to Article 12, ORGANICHEM shall indemnify, defend and hold harmless
NEW
RIVER or its designee (except to the extent NEW RIVER is obligated
to
indemnify ORGANICHEM as set forth above) against all claims, losses,
damages, and liabilities [***] (“ORGANICHEM Indemnification Claims”), to
the extent arising out of or in connection
with:
|
|
(a)
|
any
failure of API supplied by ORGANICHEM hereunder to conform to
Specifications as outlined in the Quality Agreement when it was
delivered
to NEW RIVER or its designee’s shipping
agent;
|
Page
26 of 37
|
(b)
|
any
failure of API supplied by ORGANICHEM hereunder to be Manufactured
in
accordance with Applicable Laws, including without limitation,
current
Good Manufacturing Practices;
|
|
(c)
|
a
breach of ORGANICHEM’s representations, warranties and covenants under
this Agreement; or
|
|
(d)
|
ORGANICHEM’s
willful misconduct or negligence.
|
NEW
RIVER
shall not settle any such claim without the prior written approval of
ORGANICHEM, and that ORGANICHEM shall have the right, if it so wishes, to
retain
legal counsel of its own choosing, conduct negotiations to settle, settle
or to
conduct any litigation arising out of, any such claim. NEW RIVER shall provide
prompt written notice of any such claim to ORGANICHEM and shall cooperate
in the
defense of the claim.
|
13.03
|
The
indemnification obligations set forth in this Article 13 shall
survive the
termination of this Agreement.
|
|
ARTICLE
14.
|
CONFIDENTIALITY
AND NON-USE.
|
|
14.01
|
NEW
RIVER and ORGANICHEM agree that the provisions of the Mutual
Confidentiality Agreement, which is incorporated herein by reference
and
made a part of this Agreement, shall apply to all confidential
information
disclosed by the parties under this Agreement, and that the activities
contemplated and carried out under this Agreement shall be deemed
to be
included within the purpose of the Mutual Confidentiality Agreement,
which
agreement remains in effect in accordance with its terms, provided
however,
that in the event the Mutual Confidentiality Agreement expires
or is
terminated prior to the expiration or termination of this Agreement,
the
terms of the Mutual Confidentiality Agreement shall continue to
govern the
parties’ obligations of confidentiality with respect to any confidential
or proprietary information disclosed by the parties hereunder,
for the
term of this Agreement and for [***] thereafter, as though such
agreement
remained in full force and effect. The parties agree that any confidential
or proprietary information that satisfies the requirements of Section
5(e)
or 5(f) of the Mutual Confidentiality Agreement shall, subject
to the
remainder of the Mutual Confidentiality Agreement, continue to
be
considered Confidential Information (as defined therein) for all
purposes
other than the disclosures specifically contemplated by such
sections. In
addition, in the event a party desires or is required by law to
make a
disclosure pursuant to Section 5(e) of the Mutual Confidentiality
Agreement, it shall, except where impracticable, give reasonable
advance
notice to the other party of such disclosure and use best efforts
to
secure confidential treatment of such information. A copy of the
Mutual
Confidentiality Agreement is attached hereto as Appendix
B.
|
Page
27 of 37
|
ARTICLE
15.
|
INTELLECTUAL
PROPERTY.
|
|
15.01
|
ORGANICHEM
shall promptly disclose to NEW RIVER all Inventions which ORGANICHEM
makes, conceives, learns or reduces to practice, either alone or
jointly
with others, in performing the Analytical Methods or Services under
this
Agreement.
|
|
15.02
|
Subject
to Section 15.06, ORGANICHEM agrees that all such Inventions and
Intellectual Property related thereto are the sole property of
NEW RIVER
and may be transferred by NEW RIVER to its designee. Notwithstanding
anything to the contrary set forth in the Mutual Confidentiality
Agreement, such Inventions and Intellectual Property shall be deemed
to be
the Confidential Information (as defined in the Mutual Confidentiality
Agreement) of NEW RIVER.
|
|
15.03
|
ORGANICHEM
shall be permitted to use such Inventions and Intellectual Property
related thereto exclusively and strictly for the purpose of carrying
out
its obligation to Manufacture API. In no event shall ORGANICHEM
be
permitted to use the Inventions and Intellectual Property for any
other
purpose or for any other customer of ORGANICHEM without the consent
of NEW
RIVER, which consent may be withheld for any reason and which consent
may
be [***] to be agreed upon by the
parties.
|
|
15.04
|
[***].
|
|
15.05
|
ORGANICHEM
shall cooperate with NEW RIVER, and at [***], shall execute any
instrument
or do such act or thing as may be necessary or desirable to ensure
that
any such Intellectual Property referred to in Section 15.02 above
vest in
NEW RIVER.
|
Page
28 of 37
|
15.06
|
All
Intellectual Property generated or derived by ORGANICHEM in the
course of
performing the Services which are not specific to, or dependent
upon, API
and which have application to manufacturing processes or formulation
development of drug products or drug delivery systems shall be
the
exclusive property of ORGANICHEM (the “Broader Intellectual Property
Rights”). ORGANICHEM hereby grants to NEW RIVER a non-exclusive,
perpetual, irrevocable, sublicensable, paid-up, royalty-free, transferable
license under the Broader Intellectual Property Rights to make,
have made,
use, import, offer for sale, and sell products containing API (and
any
intermediates thereof). For the avoidance of doubt, such requirement
to
license shall not apply to ORGANICHEM’s process for the
[***].
|
|
ARTICLE
16.
|
ASSIGNMENT.
|
|
16.01
|
ORGANICHEM
shall not have the right to assign any or all of its rights or
obligations
under this Agreement without NEW RIVER’s prior written consent, which
shall not be unreasonably delayed or withheld. Notwithstanding
the
foregoing, NEW RIVER’s consent shall not be required in connection with an
assignment made by ORGANICHEM to a successor in connection with
a merger,
consolidation, or a sale of all or substantially all of ORGANICHEM’s
assets to a third party; provided, however, ORGANICHEM shall provide
NEW
RIVER with written notice of such
assignment.
|
|
16.02
|
NEW
RIVER shall have the right to assign any or all of its rights or
obligations under this Agreement without the consent of ORGANICHEM;
provided, however, that NEW RIVER shall provide ORGANICHEM with
written
notice of such assignment. For clarity, this Agreement shall be
assigned
by NEW RIVER to any entity to which NEW RIVER may license Drug
Product,
without the consent of ORGANICHEM.
|
|
16.03
|
In
the event of a permitted assignment pursuant to Article 16, this
Agreement
shall be binding upon and insure to the benefit of any permitted
successors or assigns of the
parties.
|
Page
29 of 37
|
ARTICLE
17.
|
CHOICE
OF LAW; JURISDICTION.
|
The
provisions of this Agreement shall be governed by and construed in accordance
with the laws of the State of Delaware, without regard to conflict of laws
principles.
|
ARTICLE
18.
|
FORCE
MAJEURE.
|
Any
delay
in the performance of any of the duties or obligations of either party (except
the payment of money due hereunder) shall not be considered a breach of this
Agreement; provided that such delay has been caused by or is the result of
any
acts of God, acts of the public enemy, insurrections, riots, embargoes, labor
disputes, including strikes, lockouts, job actions or boycotts, fires,
explosions, floods, shortages of energy, government action including to grant
sufficient quota for Manufacture of API [***], or other unforeseen causes,
in
each case provided that such delay is beyond the reasonable control and without
the fault or negligence of the party so affected. The party so affected shall
give prompt notice to the other party of such cause, and shall take whatever
reasonable steps are necessary to relieve the effect of such cause as rapidly
as
reasonably possible. In the event that such delay is unacceptable to the
other
party or such purchase order specified that time was of the essence, the
other
party shall have the right, but not the obligation, to terminate such Purchase
Order affected by such delay without further liability to the affected party.
For
clarity, nothing in this Article 18 shall limit NEW RIVER’s right to exercise
its rights under this Agreement relating to supply failures, shortfalls,
or
disruptions (other than termination of this Agreement for breach), including
its
rights under Section 3.12 or Section 4.06.
|
ARTICLE
19.
|
SEVERABILITY.
|
In
the
event that any provision of this Agreement is judicially determined to be
void
or unenforceable, such provision shall be construed to be separable from
the
other provisions of this Agreement and the other provisions of this Agreement
shall retain full force and effect. Notwithstanding the foregoing, if a
provision is judicially determined to be void or unenforceable and that
provision is essential to the purpose of the Agreement such that separating
that
provision from the Agreement would frustrate the original purpose of the
Agreement, then there shall be no separation and the entirety of the Agreement
shall be deemed void and unenforceable.
Page
30 of 37
|
ARTICLE
20.
|
HEADINGS.
|
All
titles and captions in this Agreement are for convenience purposes only and
shall not be of any force or substance.
|
ARTICLE
21.
|
USE
OF NAMES.
|
Except
as
expressly required pursuant to the Act, neither party will without the prior
written consent of the other:
|
(a)
|
use
in advertising, publicity, promotional premiums or otherwise, any
trade
name, trademark, trade device, service xxxx, symbol, or any abbreviation,
contraction or simulation thereof owned by either party, or
|
|
(b)
|
represent,
either directly or indirectly, that any product or service of one
party is
a product or service of the other
party.
|
|
ARTICLE
22.
|
INDEPENDENT
CONTRACTOR.
|
Each
party is acting under this Agreement as an independent contractor and not
as the
agent or employee of the other party. Each party understands and agrees that
it
has no authority to assume any obligation on behalf of the other party and
that
it shall not hold out to third parties that it has any authority to act on
the
other party’s behalf except as expressly permitted herein. Each party shall be
responsible for its own expenses relating to its performance under this
Agreement and shall not incur expenses for the other party’s account unless
expressly authorized by this Agreement or subsequent written
agreements.
|
ARTICLE
23.
|
WAIVER.
|
No
waiver
or modification of any of the terms of this Agreement shall be valid unless
in
writing and signed by an authorized representative of both parties hereto.
Failure by either party to enforce any rights under this Agreement shall
not be
construed as a waiver of such rights nor shall a waiver by either party in
one
or more instances be construed as constituting a continuing waiver or as
a
waiver in other instances.
Page
31 of 37
|
ARTICLE
24.
|
PUBLIC
DISCLOSURE.
|
Neither
party shall disclose to any third party or originate any publicity, news
release
or public announcement, written or oral, whether to the public or the press,
or
otherwise, referring to the terms of this Agreement, including its existence,
the subject matter to which it relates, the performance under it or any of
its
specific terms and conditions, except by such announcements as are:
|
(a)
|
mutually
agreed upon by the parties in writing;
or
|
|
(b)
|
in
the opinion of counsel for the party making such announcement are
required
by law or regulation. If a party believes a public announcement
to be
required by law or regulation with respect to this Agreement, it
will give
the other party such notice as is reasonably practicable and an
opportunity to comment upon the
announcement.
|
|
ARTICLE
25.
|
NOTICES.
|
Unless
otherwise specified herein, all notices required or permitted to be given
under
this Agreement shall be in writing and shall be delivered either personally
or
by facsimile, and promptly confirmed, if sent by facsimile, by registered
or
certified mail or courier service. Notices may also be sent by registered
or
certified mail, return receipt requested, or by courier service. All notices
shall be to the receiving party at such party’s address set forth below, or at
such other address as may from time-to-time be furnished by similar notice
by
either party. Any notice sent by registered, certified mail or courier service
or by facsimile if promptly confirmed as aforesaid shall be deemed to have
been
given when mailed.
|
If
to ORGANICHEM:
|
|
Vice
President & General Manager
|
|
Organichem
Corporation
|
|
00
Xxxxxxxxx Xxxxxx
|
|
Xxxxxxxxxx,
XX 00000
|
|
Fax
Number (000) 000-0000
|
|
With
a copy to:
|
|
Director,
Contracts, Licensing, & Legal
Affairs
|
|
Albany
Molecular Research, Inc.
|
|
00
Xxxxxxxxx Xxxxxx
|
|
Xxxxxx,
XX 00000-0000
|
|
Fax
Number (000) 000-0000
|
Page
32 of 37
|
If
to NEW RIVER:
|
|
Xxxxx
X. Xxxxxxxx
|
|
CFO
& COO
|
|
0000
Xxxxx Xxx
|
|
Xxxxxxx,
XX 00000
|
|
Fax
Number (000) 000-0000
|
or
to
such other address as the addressee shall have last furnished in writing
to the
addresser.
|
ARTICLE
26.
|
ENTIRE
AGREEMENT.
|
|
26.01
|
This
Agreement (including, without limitation, the Appendices hereto)
constitutes the entire Agreement between the parties concerning
the supply
of API by ORGANICHEM to NEW RIVER, and supersedes all written or
oral
agreements or understandings with respect thereto; provided, however,
that
the Mutual Confidentiality Agreement shall survive the execution
of this
Agreement; shall continue to govern all matters regarding Confidential
Information; and remain in full force and effect in accordance
with its
stated terms and conditions.
|
|
26.02
|
Neither
party shall claim any amendment, modification, nor release from
any
provision hereof unless such an amendment is in writing signed
by an
authorized representative of each
party.
|
Page
33 of 37
IN
WITNESS WHEREOF, the parties hereto have caused this Agreement to be executed
by
their duly authorized representatives.
ACKNOWLEDGED,
ACCEPTED AND AGREED TO:
|
By:
|
/s/ Xxxxx X. Xxxxxxxx | |
|
Name:
|
Xxxxx X. Xxxxxxxx | |
|
(Print/Type)
|
||
|
Title:
|
Chief Financial Officer / Chief Operating Officer | |
|
Date:
|
May 18, 2006 | |
|
ACKNOWLEDGED,
ACCEPTED AND AGREED TO:
|
||
|
ORGANICHEM
CORPORATION
|
||
|
By:
|
/s/ Xxxxxx X. X'Xxxxx, PhD. | |
|
Name:
|
Xxxxxx X. X'Xxxxx, PhD. | |
|
(Print/Type)
|
||
|
Title:
|
President, Chairman and Chief Executive Officer | |
|
Date:
|
May 22, 2006 | |
Page
34 of 37
Appendix
A - [***]
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
Page
35 of 37
APPENDIX
B
- Mutual Confidentiality Agreement.
Dated
March 27, 2003
Page
36 of 37
APPENDIX
C
- Quality Agreement.
Page
37 of 37
ACTIVE
PHARMACEUTICAL INGREDIENT (API) QUALITY AGREEMENT
BETWEEN
AND
ORGANICHEM
CORPORATION
1
QUALITY
AGREEMENT
CONTENTS
|
1.
|
PARTIES
|
4
|
|
|
2.
|
QUALITY
AGREEMENT
|
4
|
|
|
3.
|
ADMINISTRATIVE
INFORMATION
|
4
|
|
|
4.
|
API
|
4
|
|
|
5.
|
DURATION
OF AGREEMENT
|
4
|
|
|
6.
|
JURISDICTION
|
4
|
|
|
7.
|
CONFIDENTIALITY
|
5
|
|
|
8.
|
SECURITY
|
5
|
|
|
9.
|
SUPPLY
|
5
|
|
|
9.1
|
Premises
|
5
|
|
|
9.2
|
API
Specification and Master Production Records
|
5
|
|
|
9.3
|
GMP
Guidelines
|
6
|
|
|
9.4
|
Materials
|
6
|
|
|
9.5
|
Master
Production Record Approval
|
7
|
|
|
9.6
|
Production
|
7
|
|
|
9.7
|
Methodology
|
7
|
|
|
9.8
|
Standard
Operating Procedure
|
7
|
|
|
9.9
|
Dates
of Manufacture and Expiration
|
7
|
|
|
9.10
|
Manufacturing
and Equipment Data
|
7
|
|
|
10.
|
QUALITY
ASSURANCE
|
8
|
|
|
10.1
|
QC
of Materials
|
8
|
|
|
10.2
|
API
Testing
|
8
|
|
|
10.3
|
Release
Procedures
|
8
|
|
|
10.4
|
Documentation
|
9
|
|
|
10.5
|
Sampling
|
9
|
|
|
10.6
|
Stability
|
10
|
|
|
10.7
|
Deviations
and Investigations
|
10
|
|
|
10.8
|
Rejection
of API
|
11
|
|
|
10.9
|
Dispute
Resolution
|
11
|
|
|
10.10
|
Regulatory
Inspection
|
11
|
|
|
10.11
|
Regulatory
Actions at NEW RIVER
|
12
|
|
|
10.12
|
Regulatory
Investigations
|
12
|
|
|
10.13
|
Manufacturing
Audits
|
12
|
|
|
10.14
|
Right
to Audit
|
12
|
|
|
10.15
|
Product
Complaints, Recall
|
13
|
|
|
10.16
|
Compliance
Deficiencies
|
13
|
|
|
11.
|
CHANGE
MANAGEMENT
|
13
|
|
2
|
12
|
API
PROCESS VALIDATION
|
13
|
|
|
12.1
|
Process
|
13
|
|
|
12.2
|
Cleaning
Validation
|
14
|
|
|
12.3
|
Equipment,
Computer, Facility, and Utilities Qualification
|
14
|
|
|
12.4
|
Laboratory
Qualifications
|
14
|
|
|
13
|
PRODUCT
QUALITY REVIEW AND ANNUAL REPORTS
|
14
|
|
|
13.1
|
Product
Quality Review
|
14
|
|
|
13.2
|
Annual
Reports
|
14
|
|
|
14.
|
STORAGE
AND SHIPPING
|
14
|
|
|
14.1
|
Storage
|
14
|
|
|
14.2
|
Packing
and Labeling for Transit
|
15
|
|
|
14.3
|
Shipment
of API to NEW RIVER or Third Party
|
15
|
|
|
15.
|
CONTRACTUAL
AGREEMENT
|
16
|
|
|
APPENDIX
I
|
Quality
Assurance Responsibility Matrix
|
||
|
APPENDIX
II
|
List
of Contacts
|
||
|
APPENDIX
III
|
NRP104
Drug Substance Specifications and Approved Raw Materials Sources
|
||
|
APPENDIX
IV
|
Batch
Release Documentation
|
||
|
APPENDIX
V
|
Batch
Document Audit Schedule
|
||
|
1.
|
PARTIES
|
This
AGREEMENT is effective as of May 18, 2006, by and between NEW RIVER
PHARMACEUTICALS INC., a Virginia corporation having its principal offices
at
0000 Xxxxx Xxxxxx, Xxxxxxx, Xxxxxxxx 00000 (hereinafter referred to as “NEW
RIVER”) and ORGANICHEM CORPORATION, a Delaware corporation having its principal
offices at 00 Xxxxxxxxx Xxxxxx, Xxxxxxxxxx, Xxx Xxxx 00000 (hereinafter referred
to as “ORGANICHEM”).
|
2.
|
QUALITY
AGREEMENT
|
|
2.1
|
This
agreement defines the roles and responsibilities of ORGANICHEM
for
services or materials supplied to NEW RIVER or affiliates, for
Commercial
Distribution or Clinical Trial use to ensure compliance with applicable
current Good Manufacturing Practice (cGMP) and ICH Q7A guidelines.
This
agreement is supplemental to and shall be incorporated within and
constitute a part of the API Supply Agreement entered into between
NEW
RIVER and ORGANICHEM. The provisions of this Agreement are intended
to be
supplemental to and not in derogation from the terms of the API
Supply
Agreement and provisions contained herein shall be treated as supplemental
to the API Supply Agreement and in particular but without limitation
in
relation to the application, compliance, verification and implementation
of cGMP. Capitalized expressions used in this Agreement shall have
the
meaning ascribed thereto in the API Supply
Agreement.
|
3
|
3.
|
ADMINISTRATIVE
INFORMATION
|
A
Responsibilities Matrix covering the responsibilities of the quality assurance
functions is found in Appendix I. This matrix is intended to supplement the
document and the Quality Agreement will have jurisdiction over any discrepancies
between the two. Contact names will be provided from both sites for key
functional areas. Contact names are provided in Appendix II and may be updated
as needed upon written notice of a Party.
|
4.
|
API
|
The
API
is described in the schedule of the API Supply Agreement to which this Agreement
is appended and as outlined within the specifications attached as Appendix
III.
|
5.
|
DURATION
OF AGREEMENT
|
This
Agreement shall commence on execution thereof by both parties and subject
to the
following provisions of this clause shall expire or terminate in respect
of any
API Supply Agreement on the expiry or termination of that agreement. Any
section
of this agreement which has a predefined retention, survival or maintenance
period, for example raw data storage, product complaints and sample retention,
shall survive the termination of this contract for the period defined in
the
appropriate section. The agreement cannot be modified except with the written
approval of both parties. Specifications and Master Batch Records may be
modified with written authorization from designated representatives of both
companies.
|
6.
|
JURISDICTION
|
In
case
of a disagreement on analytical test results between parties, such disputes
will
be resolved in accordance with the terms of the API Supply Agreement. For
batches with an out-of-specification result, ORGANICHEM’s out-of-specification
SOP will be followed to determine suitability for batch release. ORGANICHEM
may
ship API to the Finished Product manufacturer when the API has been released
by
ORGANICHEM’s internal procedures.
4
|
7.
|
CONFIDENTIALITY
|
Both
parties will treat as confidential all data supplied by the other in connection
with the manufacture of the API in accordance with the API Supply
Agreement.
| 8. |
SECURITY
|
ORGANICHEM
has and will maintain controlled access to the facility through a security
card
key or similar system.
|
9.
|
SUPPLY
|
|
9.1
|
Premises
|
|
9.1.1
|
ORGANICHEM
will manufacture, package, and/or test the API at the Plant and
will not
use or transfer at a later date any of the manufacturing, packaging
or
testing operations for the API (s) to third parties or other sites
without
the prior written agreement of NEW RIVER Quality
Assurance.
|
|
9.1.2
|
ORGANICHEM
will ensure at all times that the premises and equipment comprising
the
Plant used to manufacture/supply the API comply with current regulatory
requirements, applicable cGMP’s, ICH Q7A, and are in accordance with the
documentation approved by NEW RIVER Quality
Assurance.
|
|
9.2
|
API
Specification and Master Production
Records
|
|
9.2.1
|
ORGANICHEM
will manufacture, package, and test the API in accordance with
and subject
to the terms of the API Supply Agreement against the most recent
version
of the Specifications and Master Batch Record (in process, release
and
shelf-life/regulatory) and formula of the API listed in Appendix
III. API
Specifications will be approved by the NEW RIVER QA Department
or
designee. A list of authorized signatures will be provided by NEW
RIVER.
|
|
9.2.2
|
ORGANICHEM
will evaluate and/or qualify suppliers through QA and Purchasing
evaluation which verifies compliance by the supply company with
cGMP (if
applicable) and specifications, where appropriate, an on-site audit
of the
manufacturing site may be required if mutually agreed to in the
Master
Supply Agreement. Critical Material supplies are identified as
[***].
ORGANICHEM will be limited to those qualified suppliers. Any change
from
these Critical Material suppliers will be handled through Critical
Material change control procedures, and must be first approved
by NEW
RIVER Quality Assurance or designee. ORGANICHEM will be responsible
to
qualify these Critical Material suppliers according to ORGANICHEM
SOPs.
|
5
|
9.2.2.1
|
Chemical
Component Specification
|
If
ORGANICHEM has the responsibility in the API Supply Agreement for providing
Raw
Material, ORGANICHEM will obtain (from approved ORGANICHEM suppliers as defined
in the appropriate Regulatory documentation) and test raw materials to the
full
Specification unless a supplier Certificate of Analysis (COA) is available
from
an approved supplier. Then provided ORGANICHEM has provided a reasoned
justification for the application for reduced standards for review by NEW
RIVER,
reduced testing following ORGANICHEM’S SOP may be applied. Any reference
standards for testing that are supplied by NEW RIVER or its Affiliates must
be
accompanied by a COA listing expiration date and any correction factors that
need to be applied.
If
raw
material is provided by NEW RIVER, ORGANICHEM will obtain and test raw materials
to the full specification unless a Certificate of Analysis (COA) is available,
then provided ORGANICHEM has provided a reasoned justification for the
application for reduced standards for review by NEW RIVER, reduced testing
after
approval by NEW RIVER may be applied.
At
NEW
RIVER’s request, ORGANICHEM will provide confirmation that all [***] raw
materials purchased by ORGANICHEM for the manufacture of API have a [***]
certificate of compliance from the supplier.
|
9.2.2.2
|
Label
Component Specifications
|
ORGANICHEM
will provide copies of Master labels that meet all appropriate GMP, Regulatory
and Shipping requirements applicable to the NEW RIVER API for approval by
NEW
RIVER QA. Any modifications to the Label and or Label copy will be submitted
to
NEW RIVER QA for approval prior to use.
|
9.2.2.3
|
Packaging
Component Specifications
|
ORGANICHEM
will obtain product contact packaging components (from approved ORGANICHEM
suppliers as defined in the appropriate Regulatory documentation) and test
packaging components to the full Specification unless a qualified supplier
COA
is available from a certified supplier.
|
9.3
|
GMP
Guidelines
|
Any
applicable API license or pharmacopoeia or formulatory requirements applicable
to the Manufacture of APIs shall be complied with in addition to cGMP, Q7A,
and
Specifications.
|
9.4
|
Materials
|
|
9.4.1
|
Materials
Procured by ORGANICHEM
|
6
ORGANICHEM
is responsible for ensuring that all raw materials procured for use in the
product are in full compliance with the specifications. Raw materials are
given
a retest date upon the satisfactory completion of all initial testing. Retesting
will be performed at defined time intervals to ensure the chemical and physical
stability of the raw materials unless NEW RIVER provides an official expiration
date. NEW RIVER QA or designee must approve any program that allows retesting
of
raw materials through annual on-site audit.
|
9.4.2
|
Materials
Provided by NEW RIVER
|
Raw
materials provided by NEW RIVER may require acceptance testing by ORGANICHEM
to
confirm that the product is in full compliance with the Specifications. Where
acceptance testing is to be performed by ORGANICHEM to ensure full compliance
with Specifications then ORGANICHEM shall undertake such acceptance testing
as
is agreed. Should this testing be performed by NEW RIVER it will be the
responsibility of NEW RIVER for ensuring that these raw materials are in
full
compliance with the Specifications. ORGANICHEM is responsible for ensuring
that
all materials are used correctly, have the correct identity by testing identity
on receipt, and have the relevant COA required for the Batch.
|
9.5
|
Master
Production Record Approval
|
ORGANICHEM
may transcribe the information into its own format and must obtain written
approval from NEW RIVER QA or designee for each document version before
manufacturing. NEW RIVER will have [***] to provide approval, unless otherwise
mutually agreed to. If NEW RIVER approval is not received within the mutually
agreed upon timeframe, then ORGANICHEM will give NEW RIVER notification that
ORGANICHEM intends to proceed with the execution of the procedure in [***]
without NEW RIVER approval.
|
9.6
|
Production
|
|
9.6.1
|
The
API will be manufactured in accordance with the manufacturing and
packaging procedures set forth in the API Monograph and Master
Production
Record.
|
|
9.7
|
Methodology
|
ORGANICHEM
will test using the approved methodology listed in the NEW RIVER QA approved
API
Monograph.
|
9.8
|
Standard
Operating Procedures
|
ORGANICHEM
is responsible for maintaining any Standard Operating Procedures (SOPs) required
to make the API in accordance with cGMPs, ICH Q7A, and as described in the
NDA
or Compendial documentation as well as any other regulatory
requirements.
|
9.9
|
Dates
of Manufacture and Retest
|
7
|
9.9.1
|
Date
of Manufacture
|
ORGANICHEM
will allocate the Date of Manufacture based on ORGANICHEM written procedures,
reviewed by NEW RIVER during annual on-site audit.
|
9.9.2
|
Retest
Date
|
NEW
RIVER
will provide the appropriate Retest Date information (for ORGANICHEM review)
based upon available stability data.
|
9.10
|
Manufacturing
Equipment and Supporting Data
|
ORGANICHEM
shall maintain all equipment used in the manufacturing, packaging, testing
and
supply of API hereunder in good operating condition and shall maintain the
Facility and such equipment in accordance with applicable current Good
Manufacturing Practices (21 CFR Parts 210 and 211), ICH Q7A, specification,
applicable laws, rules and regulations. As deemed appropriate, equipment
shall
be qualified prior to use by performing Installation Qualification, Operation
Qualification and Performance Qualification (as applicable) using protocols
in
accordance with all applicable laws, rules and regulations.
Equipment
and instruments used to produce or test the API or components thereof shall
be
calibrated, where appropriate, at suitable intervals in accordance with an
established written program.
ORGANICHEM
is responsible for safe keeping and retention of records of machine usage
(previous API produced in non-dedicated machinery), cleaning, any
maintenance/calibration performed, API batch numbers and certification,
in-process results and parameters, and test results in accordance with and
shall
perform all functions in accordance with legal and regulatory
requirements.
|
10.
|
QUALITY
ASSURANCE AND CONTROL
|
|
10.1
|
QC
of Materials
|
|
10.1.1
|
Quality
control of Materials supplied by ORGANICHEM will be undertaken
by
ORGANICHEM in accordance with all applicable SOPs and meet ICH
Q7A or
applicable requirements. All Critical Raw Materials will be evaluated
in
accordance with the approved
Monograph.
|
| 10.2 |
API
Testing
|
|
10.2.1
|
APIs
and packaging components:
|
ORGANICHEM
will ensure that all materials used are in compliance with the
Monograph.
8
|
10.2.2
|
ORGANICHEM
will perform all API testing using the Specifications, and methods
of
analysis listed in Appendix III or the latest version approved
by NEW
RIVER.
|
|
10.3
|
Release
Procedures
|
A
list of
documents issued to facilitate batch release is provided in Appendix
IV.
|
10.3.1
|
API
|
ORGANICHEM
is responsible for ensuring and certifying that the API has been made according
to applicable cGMPs and the specifications/procedures documented in the Master
Batch Record. This includes a complete and thorough review of the executed
batch
records.
|
10.3.2
|
Certificate
of Conformity/Analysis
|
ORGANICHEM’s
QA Representative will sign a Certificate of Conformity/Analysis confirming
that
the API has been manufactured, packaged, tested, in accordance with cGMP,
appropriate regulations and meets the requirements of the Master Batch Record
and Specification. A copy of this documentation will be sent to NEW RIVER
as
generated during release of the batch prior to shipment. ORGANICHEM will
issue a
Certificate of Analysis and Certificate of Conformance containing the lot
number, date of release, date of manufacture, retest date, compound name,
and
testing results. A copy of the COA and COC will be forwarded to NEW RIVER
as
generated during Batch Release prior to shipment. An additional copy of the
COA
and COC will be sent with the shipment. ORGANICHEM will send a copy of the
packing list with pertinent shipping information to NEW RIVER at the same
time
the material leaves the ORGANICHEM facility.
|
10.3.3
|
Executed
batch records will be requested by NEW RIVER QA or designee for
periodic
review independent of batch investigations conducted for batch
or testing
difficulties. The planned frequency of New River full review of
batch
records will be outlined in Appendix V. ORGANICHEM will supply
requested
documents within [***] of completion of ORGANICHEM internal batch
release.
|
|
10.3.4
|
NEW
RIVER Confirmatory Testing
|
NEW
RIVER
or its affiliates may perform confirmatory testing to validate ORGANICHEM’S
data.
|
10.4
|
Documentation
|
|
10.4.1
|
Requests
for Full Documentation
|
ORGANICHEM
agrees to supply NEW RIVER or its Affiliates with copies of any manufacturing,
packaging, testing, or stability data within [***] of request.
|
10.4.2
|
ORGANICHEM
will retain, at minimum, batch production records, quality control
testing
records, all records of shipments of the API from ORGANICHEM, all
validation data and other documentation relating to the API for
[***] or
the time periods required by applicable laws and regulations with
respect
to the API plus one year. ORGANICHEM will retain, at minimum batch
packaging documents for [***] [***] materials were last used in
the
packaging or labeling of API.
|
9
|
10.4.2.1
|
ORGANICHEM
shall supply the documentation outlined in Appendix V for the “Batch
Document Audit Schedule” as outlined for both routine and regulatory or
validation batches. Copies of the documents and records required
to
complete the NEW RIVER batch review will be made at ORGANICHEM’s expense
and supplied in a timely manner as for NEW RIVER to complete the
review
and release (where applicable) of the drug substance (API), as
quickly as
possible, but not to exceed [***] of ORGANICHEM internal batch
release.
|
|
10.4.2.2
|
ORGANICHEM
shall make such records and data available for review by NEW RIVER
at
ORGANICHEM’s facility during the annual compliance
audit.
|
|
10.4.3
|
NEW
RIVER may review the ORGANICHEM document retention policy during
annual
on-site audit. Upon termination or expiration of this Agreement
or prior
to destruction of any records, whichever occurs first, ORGANICHEM
will
upon NEW RIVER’s written request and at NEW RIVER’s expense, make copies
of such records and data for NEW
RIVER.
|
|
10.5
|
Sampling
|
|
10.5.1
|
Retain
Samples - Raw Materials
|
ORGANICHEM
will retain samples of the raw materials where possible or reasonable given
the
chemistry of the material for a time period as defined in ORGANICHEM’s
procedures. ORGANICHEM will retain samples of the active ingredient for a
minimum of five years or at least one year beyond the expiry period of the
API.
The amount of sample retained will be [***] required to carry out all of
the
tests required to determine of the material meets its specifications, with
the
exception of Sterility and Pyrogen testing, if applicable. (CFR
211.170a)
|
10.6
|
Stability
|
|
10.6.1
|
Routine
Stability Program
|
|
10.6.1.1
|
ORGANICHEM
is responsible for maintaining a routine stability testing program
for the
API, and will provide a stability report to NEW RIVER annually
or on
reasonable request intervals. Stability samples will be tested
[***] of
the target stability pull date or as indicated per the approved
stability
protocol. Completed testing data will be provided to NEW RIVER
[***] of
the request.
|
|
10.6.1.2
|
NEW
RIVER is responsible to provide or approve a stability indicating
method
to support the Routine Stability
Program.
|
|
10.6.1.3
|
The
stability program will be in compliance with any license commitments
as
notified by NEW RIVER. At a minimum one lot of each API, in each
package
type (largest to smallest, as applicable) will be placed on stability
each
year unless otherwise agreed to in writing by ORGANICHEM, NEW RIVER
and
FDA. The stability program will comply with ICH guidelines. The
stability
protocol or any changes must be approved by NEW RIVER QA or
designee.
|
10
|
10.6.2
|
Development
Stability Program
|
ORGANICHEM
will be responsible for performing any development stability required to
support
the API. If that development stability is to support projects initiated by
ORGANICHEM, then ORGANICHEM will develop, execute and write reports for the
program. Stability samples will be tested [***] of the target stability pull
date. All protocols for such work must be approved by NEW RIVER.
|
10.6.3
|
Stability
Failures
|
Any
confirmed problems or out-of-specification results which arise as a result
of or
during any of the stability programs will be communicated verbally [***]
and in
writing [***] to NEW RIVER Quality Assurance. ORGANICHEM will supply NEW
RIVER’s
Quality Assurance department with stability results [***] of receiving a
written
request.
|
10.7
|
Deviations
and Investigations
|
|
10.7.1
|
Deviations
|
Any
deviation from the process during Manufacture must be carefully explained
and
documented in the batch records, justified and approved by ORGANICHEM’s quality
management and production management, and included in the documentation
package.
|
10.7.1.1
|
Any
“planned” or “un-planned” process deviations affecting a Regulatory Filing
and/or Process Validation will be fully documented and investigated
according to ORGANICHEM procedures. Any such deviations will be
reviewed
with NEW RIVER’s QA Representative prior to batch
release.
|
NOTE:
A
deviation is defined as any anomalous event that may occur during the processing
of a Batch that is a departure from the specifications, and approved procedures
or validated processes filed in the NDA. Planned deviations are considered
those
that occur before a process step is executed and when a batch can be interrupted
to consider the ramifications of the proposed process or batch instruction
deviation.
|
10.7.2
|
Failure
Investigations
|
ORGANICHEM
is responsible for investigating any test result or in-process test which
fails
to meet Specification. Each investigation will be reviewed and approved by
ORGANICHEM’s designated Quality person. The investigation must document that any
failure has not jeopardized the safety, efficacy or quality of the API. NEW
RIVER must be notified in writing promptly but within 5 working days of the
confirmed failing test result.
11
|
10.7.3
|
ORGANICHEM
will notify NEW RIVER in writing as soon as reasonably possible
but [***]
of any batch of API rejected by
ORGANICHEM.
|
|
10.7.4
|
ORGANICHEM
will notify NEW RIVER forthwith if any problems are discovered
that may
impact API batch(s) previously shipped to NEW RIVER or its affiliates
identifying the batches in
question.
|
|
10.7.5
|
Some
deviations/failures may require that additional testing, stability,
or
validation be conducted. This work will be performed by ORGANICHEM
as
agreed by both parties.
|
|
10.8
|
Rejection
of API
|
|
10.8.1
|
Investigation
of Problems
|
NEW
RIVER
or its affiliates will notify ORGANICHEM of any problems thought to be due
to
manufacture or stability, which are found during the finish dose manufacture
of
the product. When requested by NEW RIVER, ORGANICHEM will promptly perform
investigations for these problems. Investigation reports will be forwarded
to
NEW RIVER as required.
|
10.9
|
Dispute
Resolution
|
In
the
event that a dispute arises between ORGANICHEM and NEW RIVER or its affiliates
in the analysis of the API, the resolution will proceed in stages. The first
stage requires direct communication between analysts from both parties to
determine that the methods of analysis are the same and are being executed
in
the same manner at both sites. Second, carefully controlled and split samples
should be sent from one site to another in an attempt to reach an agreement.
Should there be a failure to achieve resolution, analysts from both parties
will
be required to meet to work through the analysis of a mutually agreeable
sample.
If these actions fail to achieve resolution, and only after these avenues
have
been exhausted, will the parties apply the terms of the API Supply Agreement
regarding resolution of API.
|
10.10
|
Regulatory
Inspections
|
NEW
RIVER’s Vice President of Product Development or designate will be notified as
soon as reasonably possible of any Regulatory Inspections related to NEW
RIVER
API, and ORGANICHEM will permit a representative from NEW RIVER to be present
on
site for consultation, if requested by NEW RIVER. ORGANICHEM will notify
NEW
RIVER of any requests for information, notices of violations, or other
communication from FDA relating directly to NEW RIVER API.
| 10.11 |
Regulatory
Actions at NEW RIVER
|
NEW
RIVER
or its affiliates will notify ORGANICHEM of any regulatory actions on the
API
that may impact ORGANICHEM. Additionally, NEW RIVER will immediately forward
any
regulatory correspondence on the APIs to ORGANICHEM.
|
10.12
|
Regulatory
Investigations
|
ORGANICHEM
is responsible for supporting all batch record investigations associated
with
regulatory actions. NEW RIVER will be notified of any such events
[***]
12
|
10.13
|
Manufacturing
Audits (MA)
|
|
10.13.1
|
ORGANICHEM
will allow and support one routine quality audit by NEW RIVER per
calendar
year per facility.
|
|
10.13.2
|
ORGANICHEM
will allow and support additional audits as requested by NEW RIVER
(for
cause only),
and as mutually agreed to by ORGANICHEM, to address specific quality
problems related to the API or in direct response to FDA requirements,
for
circumstances where NEW RIVER and ORGANICHEM reasonably believe
that
significant quality and/or compliance issues
exist.
|
|
10.13.3
|
Correspondence.
Each Party shall promptly notify the other Party of, and shall
provide
such other Party with copies of, any correspondence and other
documentation received or prepared by the notifying Party in connection
with any of the following events:
|
|
10.13.3.1
|
Receipt
of a 483 Observation Letter or “Warning Letter” from the FDA or any other
regulatory authority or any relevant foreign equivalent outside
the USA in
connection with the Manufacture, packaging, testing, storage or
security
of the API;
|
|
10.13.3.2
|
Any
field alert, recall, market withdrawal or correction of any Batch
of the
API; or
|
|
10.13.3.3
|
Any
regulatory comments relating to the Manufacture of the API requiring
a
response or action by the notifying
Party.
|
|
10.14
|
Right
to Audit
|
|
10.14.1
|
NEW
RIVER or its affiliate’s representatives will be escorted at all times by
ORGANICHEM personnel.
|
|
10.14.2
|
Audit
Procedures
|
|
10.14.2.1
|
An
exit meeting will be held with representatives from ORGANICHEM
and NEW
RIVER to discuss significant audit
observations.
|
|
10.14.2.2
|
NEW
RIVER will provide a written report of all observations [***] to
ORGANICHEM. [***] of audit report receipt, ORGANICHEM will provide
a
written response to all findings that details corrective action
to be
implemented. ORGANICHEM will follow-up to ensure that all corrective
actions are implemented.
|
|
10.15
|
Product
Complaints, Recall
|
|
10.15.1
|
Product
Complaints
|
NEW
RIVER
Quality Assurance or its affiliates shall maintain complaint files with respect
to the API in accordance with cGMP’s. NEW RIVER or its affiliates are
responsible for receiving and initially investigating any API complaints
and
will notify ORGANICHEM of any complaint that may impact the API quality.
ORGANICHEM will investigate any API complaints and provide a report to NEW
RIVER
promptly but [***] from receipt. The investigation shall be completed in
accordance with all cGMP regulations and any other applicable regulations.
NEW
RIVER shall have responsibility for reporting all complaints relating to
the API
to the FDA and any other regulatory authority, including, but not limited
to,
complaints relating to the Manufacture of the API. NEW RIVER shall have the
responsibility for reporting all complaints relating to adverse drug experience
(ADE) reports.
13
|
10.15.2
|
Product
Recall
|
NEW
RIVER
or its affiliates are responsible for instituting a product recall due to
any
defect considered sufficiently serious. NEW RIVER will notify ORGANICHEM
of any
recall that may be due to the manufacture of the API. ORGANICHEM will work
with
NEW RIVER and its affiliates to investigate and coordinate the recall.
ORGANICHEM will provide a rapid initial response and a full report
[***].
|
10.16
|
Compliance
Deficiencies
|
Should
ORGANICHEM become aware of any issues that could affect the quality, safety,
identity or efficacy of any NEW RIVER API produced at their facility, ORGANICHEM
will notify NEW RIVER in writing [***].
|
11.
|
CHANGE
MANAGEMENT
|
Master
Production Records and the API Monograph will be approved by both NEW RIVER’s
Quality Assurance Department and ORGANICHEM’s Quality Assurance Department. No
changes to the above documents may be implemented without the signed
authorization from an authorized member of the NEW RIVER Quality Assurance
Department. All required regulatory approvals will be obtained prior to
implementation. Variations to established production procedures may be initiated
by either party, but must be agreed to in writing by the authorized members
of
the Quality Assurance Departments of both companies before
implementation.
|
12.
|
API
AND PROCESS VALIDATION
|
|
12.1
|
Process
|
ORGANICHEM
is responsible for ensuring that the manufacturing process is validated.
The
validation should ensure that the process is capable of consistently achieving
the API acceptance Specification. ORGANICHEM will not use any validation
protocol or issue a report unless NEW RIVER technical personnel have first
reviewed and provided comment (as appropriate). NEW RIVER will review all
protocols and validation reports [***]
|
12.2
|
Cleaning
Validation
|
ORGANICHEM
is responsible for ensuring that adequate cleaning is carried out between
batches of different APIs to prevent cross-contamination. NEW RIVER may review
(on-site during the annual compliance audit) ORGANICHEM’s overall or Master
Cleaning Validation Program, which may include equipment logs, cleaning
validation SOPs, equipment cleaning procedures or SOPs, analytical method
specificity, rationale for equipment release criteria and classifications
of
other products or raw materials used in the same equipment.
14
|
12.3
|
Equipment,
Computer, Facility, and Utilities
Qualification
|
ORGANICHEM
is responsible for the safe and efficient working of all equipment, computer,
utility, and facility qualification activities associated with the API including
maintenance. ORGANICHEM is also responsible for the validation and qualification
of all equipment, computer, and utilities associated with the API.
|
12.4
|
Laboratory
Qualification
|
ORGANICHEM
is responsible for ensuring that any contract laboratories used are compliant
with cGMPs and are qualified in all of the methodology associated with the
API.
If analytical work is performed at ORGANICHEM, then NEW RIVER will also provide
any existing analytical documentation to assist in methods transfer or methods
validation. ORGANICHEM will not use any validation protocol or issue a report
unless NEW RIVER technical personnel have first reviewed and provided comment
(as appropriate). NEW RIVER will review all protocols and reports [***] [***].
In addition, if analytical work is not performed at ORGANICHEM’s site,
ORGANICHEM may elect to perform an audit on vendors to be used for analytical
testing. Should ORGANICHEM decide to sub-contract out any analytical testing,
prior approval from NEW RIVER QA or designee will be required.
|
13.
|
PRODUCT
QUALITY REVIEW AND ANNUAL
REPORTS
|
|
13.1
|
Product
Quality Review
|
ORGANICHEM
will perform a product quality review according to ICH Q7A (section 2.5)
and
will provide to NEW RIVER, upon request, a summary of what is required by
NEW
RIVER for a CMC section of an annual report (as per CDER’s Guidance for
Industry, “Format and Content for the CMC Section of an Annual Report).
|
13.2
|
Annual
Reports
|
NEW
RIVER
is responsible for preparing any Annual Report as required by applicable
regulations, including 21 CFR 314.7 (g)(3), 314.81 (b)(2), and/or 601.12
(d),
(f)(3). [***] before the Annual Report due date, NEW RIVER shall request
in
writing from ORGANICHEM any information in addition to ORGANICHEM’s Annual
Report that ORGANICHEM may possess that may be useful in NEW RIVER’s preparation
of its Annual Report.
|
14.
|
STORAGE
AND SHIPPING
|
|
14.1
|
Storage
|
ORGANICHEM
will ensure that during storage of the API that there is no possibility of
deterioration, interference, theft, material contamination or admixture with
any
other materials. NEW RIVER will provide details of any labeling requirements
and
container sealing and integrity.
|
14.2
|
Packing
and Labeling for Transit
|
The
API
will be suitably packed for transit, each pallet or outer container being
labeled in accordance with the approved specifications.
15
|
14.3
|
Shipment
of API to NEW RIVER or Third Party
|
Only
approved, finished (unless required by NEW RIVER), labeled API will be shipped
by ORGANICHEM to NEW RIVER or a Third Party as indicated on a Purchase Order.
Any shipment of API from ORGANICHEM that is unapproved or under quarantine
requires prior written consent by NEW RIVER’s Quality Unit. This authorization
will be on a lot by lot basis.
16
|
15.
|
CONTRACTUAL
AGREEMENT
|
Established
at NEW RIVER PHARMACEUTICALS INC., 0000 Xxxxx Xxxxxx, Xxxxxxx, Xxxxxxxx
00000
For
and
on behalf of NEW RIVER PHARMACEUTICALS INC.:
|
|
|
|||
|
|
||||
|
NAME
|
TITLE
|
SIGNATURE
|
For
and
on behalf of ORGANICHEM CORPORATION:
|
|
|
|||
|
|
||||
|
NAME
|
TITLE
|
SIGNATURE
|
17
APENDIX
I
Quality
Assurance Responsibilities Matrix
18
Responsibilities
Matrix
ORGANICHEM
is responsible for all the operations that are marked with "X" in the column
titled "ORGANICHEM" and NEW RIVER is responsible for all the operations that
are
marked with "X" in the column titled "NEW RIVER." The designated party that
does
not have the primary responsibility, however will need to cooperate. Reference
to QA or MSA correlates the location of this responsibility to the body of
the
Quality Agreement (Section or Appendix) or the Master Services Agreement
(MSA)
location.
Administrative
or Overall
|
Reference
QA or MSA
|
NEW
RIVER
|
ORGANICHEM
|
||
|
1.
|
Manufacture
and package API according to the Specifications.
|
QA
Appendix III
|
X
|
|
|
2.
|
Permit
cGMP audits of all relevant premises, procedures and documentation
by NEW
RIVER (once annually or for cause) and permit inspection by regulatory
authorities.
|
QA
Section 10.10 to 10.13
|
X
|
|
|
3.
|
Will
not subcontract any of the work to a third party without prior
written
consent of NEW RIVER.
|
QA
Section 9.1 and 12.4
|
X
|
|
|
4.
|
Provide
a summary upon request by NEW RIVER for the annual update to the
CMC
section.
|
QA
Section 13.1
|
X
|
|
|
5.
|
Provide
copies of information and correspondence necessary to support the
Annual
Report when requested by NEW RIVER.
|
QA
Section 13.2
|
X
|
|
|
6.
|
Notify
and obtain approval from NEW RIVER before initiating any proposed
changes
to the Master Production Records and API Monograph that may affect
the
API.
|
QA
Section 11
|
X
|
|
|
7.
|
NEW
RIVER will have [***] to provide such approval of Master Batch
Records and
API Monograph (unless otherwise mutually agreed to). NEW RIVER
approval
will not be unreasonably withheld.
|
QA
Section 9.5
|
X
|
|
|
8.
|
Notify
and obtain approval from ORGANICHEM of any proposed changes to
the
process, materials, testing, or Specifications that may affect
the API.
ORGANICHEM approval will not be unreasonably withheld.
|
QA
Section 11
|
X
|
|
|
9.
|
Notify
NEW RIVER promptly of receipt of any FDA Form 483's, warning letters
or
the like from regulatory agencies relating specifically to: (i)
the API;
(ii) the supply of API. ORGANICHEM reserves the right to respond
to such
regulatory agencies without approval, if, in the reasonable opinion
of
ORGANICHEM’S counsel, it is required to do so.
|
QA
Section 10.13.3
|
(X)
|
X
|
|
10.
|
Notify
NEW RIVER [***] of any regulatory authority requests for samples,
batch
documentation, or other information related specifically to the
API.
|
QA
Section 10.12
|
X
|
|
|
11.
|
Conduct
operations in compliance with applicable cGMP regulations.
|
QA
Section 2.1 & 9.1.2Article 2 of MSA
|
X
|
|
|
12.
|
Investigate
all complaints related to the Manufacturing of the API.
|
QA
Section 10.15
|
X
|
(X)
|
|
13.
|
Investigate
all Manufacturing complaints at NEW RIVER’S request.
|
QA
Section 10.15
|
X
|
|
|
14.
|
Notify
other party promptly of receipt of information meeting NDA Field
Alert
criteria as defined in 21 CFR 314.81(b)(1).
|
QA
Section 10.13.3
|
X
|
X
|
|
15.
|
Initiate
NDA Field Alert reports.
|
QA
Section 10.13.3
|
X
|
|
|
16.
|
Initiate
and manage Drug Product recalls.
|
QA
Section 10.15.2
|
X
|
|
|
17.
|
Timely
liaise with Regulatory Authorities for approval, maintenance, and
updating
of marketing approval.
|
QA
Section 10.10 to 10.16
|
X
|
19
| (b) |
Validation
and Process Testing Activities
|
|
Reference
QA or MSA
|
NEW
RIVER
|
ORGANICHEM
|
||
|
1.
|
Establish
applicable master validation plans.
|
QA
Section 12
|
X
|
|
|
2.
|
Maintain
a validation program for the API.
|
QA
Section 12.1
|
(X)
|
X
|
|
3.
|
Qualify
(IQ/OQ) facilities, utilities, laboratory equipment and process
equipment.
|
QA
Section 12.3
|
X
|
|
|
4.
|
Calibrate
instrumentation and qualify computer systems used in the Manufacture
and
testing of the API.
|
QA
Section 12.3
|
X
|
|
|
5.
|
Prepare
all Validation Protocols and reports for Manufacturing and packaging
operations.
|
QA
Section 12.1
|
X
|
|
|
6.
|
Review
NRP104 process validation plan, Validation Protocols, and reports
for
Manufacturing and packaging of the API. Provide comments and feedback
as
applicable.
|
QA
Section 12.1
|
X
|
|
|
7.
|
Approve
NRP104 process validation plan, and Validation Protocols and reports
for
Manufacturing and packaging of the API.
|
QA
Section 12.1
|
X
|
|
|
8.
|
Maintain
appropriate equipment cleaning procedures and cleaning validation
program.
|
QA
Section 12.2
|
X
|
|
|
9.
|
Provide
toxicological information to be used in the development of a cleaning
program.
|
QA
Section 12.2
|
X
|
|
|
10.
|
Assure
analytical test methods for finished API have been adequately validated
for use at Organichem.
|
QA
Section 12.4
|
(X)
|
X
|
20
| (c) |
Raw
Materials
|
|
Reference
QA or MSA
|
NEW
RIVER
|
ORGANICHEM
|
||
|
1.
|
Provide
all Batch Records (including Master Batch Records) including Xxxx
of
Materials.
|
QA
Section 9.2
|
X
|
|
|
2.
|
ORGANICHEM
to qualify and approve all Raw Material suppliers and ensure cGMP
compliance where applicable. Critical material suppliers considered
will
be identified and changes to these approved Specifications will
be routed
through NEW RIVER and associated change control. NEW RIVER approval
of
said changes will not be reasonably withheld (attached hereto as
Schedule
C).
|
QA
Section 9.2.2
|
(X)
|
X
|
|
3.
|
Analyze
and release API to NEW RIVER or assigned third party.
|
QA
Section 9.0
|
X
|
|
|
4.
|
Retain
reference sample of API for a [***] past the expiry date or such
longer
period required by law.
|
QA
Section 10.5.1
|
X
|
|
|
5.
|
Procure
Raw Materials (including Certificates of Analysis and Certificates
of
Compliance, where applicable).
|
QA
Section 9.4
|
X
|
|
|
6.
|
Analyze
and release Raw Materials.
|
QA
Section 9.4
|
X
|
|
|
7.
|
Retain
reference samples (non hazardous) of Raw Materials for a period
as defined
by ORGANICHEM procedures. Maintain all testing records for raw
materials
(hazardous and non hazardous) for [***].
|
QA
Section 10.5.1
|
X
|
|
|
8.
|
At
NEW RIVER’S request, confirm that all [***] Raw Materials purchased by
ORGANICHEM for the Manufacture of API have a [***] certificate
of
compliance from the Raw Material supplier.
|
QA
Section 9.2.2.1
|
X
|
21
| (d) |
Bulk
Manufacture
|
|
Reference
QA or MSA
|
NEW
RIVER
|
ORGANICHEM
|
||
|
1.
|
Create,
control, issue and execute Master Batch Record (production
instructions).
|
QA
Section 9.2
|
X
|
|
|
2.
|
Approve
master production and packaging instructions (New River shall have
[***]
provide approval, unless otherwise agreed upon).
|
QA
Section 9.5
|
X
|
X
|
|
3.
|
Document,
investigate, and resolve deviations affecting a Regulatory filing
from
approved Manufacturing instructions or Specifications.
|
QA
Section 10.7.1
|
(X)
|
X
|
| (e) |
Packaging
|
|
Reference
QA or MSA
|
NEW
RIVER
|
ORGANICHEM
|
||
|
1.
|
Provide
Specifications for packaging components.
|
QA
Appendix III
|
(X)
|
X
|
|
2.
|
Provide
labeling text (label, pallet etc.) Specifications.
|
QA
Section 9.2.2.2
|
X
|
|
|
3.
|
Create,
control, issue, and execute master packaging record (may be part
of master
production instructions).
|
QA
Section 9.2
|
X
|
|
|
4.
|
Approve
master packaging record (may be part of master production instructions)
(NEW RIVER shall have [***] [***] to provide approval, unless otherwise
agreed upon).
|
QA
Section 9.5
|
X
|
X
|
|
5.
|
ORGANICHEM
to assure that “product contact” packaging components meet all cGMP
requirements (as applicable).
|
QA
Section 9.2.2.3
|
X
|
|
|
6.
|
Provide
test methods for packaging components.
|
QA
Section 9.2.2.3
|
X
|
|
|
7.
|
Procure
packaging components.
|
QA
Section 9.2.2.3
|
X
|
|
|
8.
|
Analyze
and release packaging components (as applicable).
|
QA
Section 9.2.2.3
|
X
|
|
|
9.
|
Maintain
records and evidence on the testing of packaging/labeling materials
for
[***] after the materials were last used in the packaging/labeling
of the
API.
|
QA
Section 10.4
|
X
|
|
|
10.
|
Document,
investigate, and resolve any deviation from approved packaging
instructions or specifications.
|
QA
Section 10.7
|
X
|
22
| (f) |
Testing
& Release of Finished Drug Substance
|
|
Reference
QA or MSA
|
NEW
RIVER
|
ORGANICHEM
|
|||
|
1.
|
Provide
API Specifications.
|
QA
Appendix III
|
(X)
|
X
|
|
|
2.
|
Supply/develop
analytical test methods specific to API.
|
QA
Section 9.7
|
(X)
|
X
|
|
|
3.
|
Test
finished API. Issue CoA/CoC.
|
QA
Appendix IV
|
X
|
||
|
4.
|
Maintain
all batch records for a minimum of [***] past API expiry or retest
date.
|
QA
Section 10.4
|
X
|
||
|
5.
|
Supply
copies of all batch records to NEW RIVER upon request.
|
QA
Section 10.4.1 and Appendix V
|
X
|
||
|
6.
|
Notify
NEW RIVER QA of confirmed Out-Of-Specification results within
[***]
|
QA
Section 10.7.2
|
X
|
||
|
7.
|
Resolve
Out-Of-Specifications results and supply Investigation Report with
Batch
Documentation.
|
QA
Section 10.7.2
|
X
|
||
|
8.
|
Retain
reference samples of drug substance for a [***] past retest or
expiration
date.
|
QA
Section 10.5.1
|
X
|
||
| (g) |
Stability
Testing
|
|
Reference
QA or MSA
|
NEW
RIVER
|
ORGANICHEM
|
|||
|
1.
|
Provide
stability testing protocol for finished API.
|
QA
Section 10.6
|
(X)
|
X
|
|
|
2.
|
Store
stability samples according to ICH conditions.
|
QA
Section 10.6
|
X
|
||
|
3.
|
Assure
that a validated stability indicating assay is being performed
for
stability testing.
|
QA
Section 10.6
|
X
|
(X)
|
|
|
3.
|
Qualify
or transfer stability indicating assay.
|
QA
Section 10.6
|
X
|
||
|
4.
|
Perform
stability testing [***] of stability pull or as indicated per approved
site SOP or approved Stability Protocol.
|
QA
Section 10.6
|
X
|
||
|
5.
|
Notify
NEW RIVER of any confirmed stability failure for API supplied to
NEW RIVER
[***].
|
QA
Section 10.6
|
X
|
||
23
APENDIX
II
List
of Contacts
(Name,
[***])
|
ISSUE
|
NEW
RIVER or Affiliates
|
ORGANICHEM
|
|
Product
Release
|
Xxxx
Xxxxxxxx
[***]
|
Xxxxx
Xxxxxx
[***]
|
|
Investigations
|
Xxxxxx
Xxxxxxxxx
[***]
|
Xxxxx
Xxxxxx
[***]
|
|
Stability
|
Xxxxxx
Xxxxxxxxx
[***]
|
Xxxxxxx
Xxxxxxx
[***]
|
|
Regulatory
Inspections
|
Xxxx
Xxxxxxxx
[***]
|
Xxxxxxxx
Xxxxx
[***]
|
|
Complaints
|
Xxxx
Xxxxxxxx
[***]
|
Xxxx
Xxxx
[***]
|
|
Change
Management
|
Xxxxxx
Xxxxxxxxx
[***]
|
Xxxxx
Xxxxxx
[***]
|
|
Audits
|
Xxxxxx
Xxxxxxxxx
[***]
|
Xxxxxxx
Xxxxxxx
[***]
|
|
Regulatory
Affairs
|
Xxxx
Xxxxxxxx
[***]
|
Xxxx
Xxxx
[***]
|
|
Emergency
|
Xxxxxx
Xxxxxxxxx
[***]
|
Xxxxx
Xxxxxx
[***]
|
24
APPENDIX
III
NRP104
Drug Substance and Packaging Specifications
And
Approved
Critical Raw Material and Product Contact Packaging Component
Suppliers
25
Product
Name: NRP104
Replaces: July
20,
2004
Effective: November
18, 2005
[***]
SPECIFICATIONS:
[***]
26
ORGANICHEM
CORP. BULK CHEMICAL PACKAGING SPECIFICATIONS
[***]
|
PRODUCT
IDENTIFICATION:
NRP104
|
PRODUCTION
PACKAGING SPECIFICATIONS
|
MATERIALS
PACKAGING SPECIFICATION
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
27
|
Critical
Material
|
Suppliers
|
|
[***]
|
[***]
|
|
[***]
|
[***]
|
|
[***]
|
[***]
|
28
APPENDIX
IV
Release
Documentation
All
Batches
The
release documentation will include a Certificate of Analysis (COA) and a
Certificate of Conformance (COC).
List
of
all batch deviations planned and unplanned.
A
Certificate of Analysis (COA)
This
document will list the following:
|
·
|
The
API Name
|
|
·
|
The
Batch/Control Number
|
|
·
|
The
Date of Manufacture
|
|
·
|
All
Analytical Test Results
|
|
·
|
All
Microbiological Test Results (as
applicable)
|
|
·
|
Issue
Date
|
|
·
|
Retest
Date
|
|
·
|
Approval
Signature
|
A
Certificate of Conformance (COC)
This
document will attest to the fact that the batch of API was made in accordance
with all applicable regulations, licenses, and company policies statement
confirming that the batch record has been reviewed and approved by ORGANICHEM’s
Quality Assurance.
The
above
certificates will be signed by ORGANICHEM’s authorized personnel.
29
APPENDIX
V
Batch
Document Audit Schedule
The
primary responsibility for batch document review resides with Organichem.
New
River has every confidence in Organichem’s expertise and ability to review and
approve batch documents as part of the release of API to New River or it’s
affiliates. However to demonstrate this [***]. This will supplement the annual
cGMP audit, or any other investigations related to quality or batch
incidents.
The
following table outlines the plans for New River or it’s affiliates review of
batch documentation:
|
[***]
|
[***]
|
[***]
|
|
|
[***]
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
[***]
|
[***]
30
APPENDIX
D
- List of Schedules.
Schedule
A: Xxxx of Materials
Schedule
B: Exclusive Component Purchasing Summary for Key or Critical raw
materials
Schedule
C: Shipping Logistics Protocol
31
Schedule
A: Xxxx of Materials
The
materials required to produce one [***] of NRP104 are summarized in the table
below:
|
Raw
Material
|
ORGANICHEM
Item
Code #
|
Estimated
Required
Mass
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
|
[***]
|
[***]
|
[***]
|
32
Schedule
B: Exclusive Component Purchasing Summary for Key or Critical
Raw
Materials.
The
materials determined to be critical and therefore requiring NEW RIVER
participation in the change control process. These items are summarized in
the
table below:
|
Critical
Material
|
ORGANICHEM
Item
Code #
|
|
[***]
|
[***]
|
|
[***]
|
[***]
|
|
[***]
|
[***]
|
33
Schedule
C: Shipping Logistics Protocol
All
materials must be properly classified, packaged, labeled and shipped according
to all applicable national governmental regulations. A packing list and
appropriate certificates of analysis must be included with each shipment.
Shipments shall be made using carriers identified by NEW RIVER according
to FCA
Rensselaer shipping terms. Materials shall be shipped according to NEW RIVER’s
written instructions as specified on the purchase order and any third party
recipients shall require contact information including name, phone number
and
extension, and delivery address. Copies of all relevant shipping documents
and
Certificates of Analysis shall be provided to NEW RIVER.
34
