Amendment to Annual Report — [x] Reg. S-K Item 405 — Form 10-K
Filing Table of Contents
Document/Exhibit Description Pages Size
1: 10-K405/A Cephalon, Inc. Form 10-K405/A Amendment No. 1 7 42K
2: EX-4.3(B) Form of Revenue Sharing Senior Secured Note 49 186K
7: EX-10.12 Toll Manufacturing and Packaging Agreement 30 99K
3: EX-10.5H Amendment No. 5 to License Agreement 3 16K
4: EX-10.5I Amendment No. 6 to License Agreement 3 15K
5: EX-10.5J Amendment No. 3 to Trademark Agreement 2 8K
6: EX-10.5K Amendment No. 4 to Trademark Agreement 2 10K
EX-10.12 — Toll Manufacturing and Packaging Agreement
Exhibit Table of Contents
Exhibit 10.12*
TOLL MANUFACTURING AND PACKAGING AGREEMENT
This Toll Manufacturing and Packaging Agreement is made as of this 24/th/
day of February, 1998, by and between Cephalon, Inc., 145 Brandywine Parkway,
West Chester, PA 19380-4245 ("CEPHALON") and Circa Pharmaceuticals, Inc., 33
Ralph Avenue, P.O. Box 30, Copiague, NY 11726-0030 ("CIRCA"').
WHEREAS, CEPHALON holds certain rights to manufacture, market and sell in
the United States, Mexico, Japan, the United Kingdom and Ireland, the
pharmaceutical product modafinil;
WHEREAS, CEPHALON possesses certain know how and other confidential and
proprietary information relating to the process of manufacturing and packaging
modafinil in finished dosage form;
WHEREAS, CEPHALON previously has engaged CIRCA to perform certain
manufacturing and consulting activities relating to the supply of modafinil, and
now wishes to engage CIRCA on a long-term basis to formulate and package
modafinil tablets in dosage form for subsequent sale by CEPHALON in the United
States, Mexico, Japan, the United Kingdom and Ireland, and for certain clinical
and other purposes; and
WHEREAS, CIRCA has suitable facilities and equipment and sufficient
qualified personnel at its plant in Copiague, New York to formulate and package
commercial quantities of modafinil in dosage form, and is willing to provide
such services on the terms and conditions set forth below.
NOW, THEREFORE, the parties hereto agree as follows:
I. DEFINITIONS
As Used in this Agreement:
1.1 "Active Drug Substance" means the compound modafinil having those
specifications as set forth on Schedule A hereto.
1.2 "Adverse Experience" or "AE" shall mean any unfavorable and unintended
change in the structure (signs), function (symptoms), or chemistry (laboratory
data) of the body temporally associated with any use of a Product or of a
derivative thereof, whether or not the adverse experience is considered to be
related to the use of the Product, including but not limited to any of the
following: an unexpected side effect, injury, toxicity or sensitivity reaction,
which may include an experience of unexpected incidence and severity; an adverse
experience occurring in the course of the use of a drug product in professional
practice; an adverse experience occurring in clinical studies; an adverse
experience occurring from drug overdose; whether accidental or intentional; an
adverse experience occurring from drug abuse; an adverse experience occurring
from drug withdrawal; and any significant failure of expected pharmacological
action.
* Certain portions of this exhibit have been omitted based upon a request
for confidential treatment that has been filed with the Commission. The
omitted portions have been filed separately with the Commission.
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1.3 "Affiliate" means any corporation or other business entity which,
directly or indirectly, is controlled by, controls, or is under common control
with CEPHALON or CIRCA. For this purpose, "control" shall be deemed to mean
ownership of fifty percent (50%) or more of the stock or other equity of such
entity.
1.4 "Confidential Information" means any confidential or proprietary
information relating to the manufacture and packaging of the Product.
1.5 "Product" means modafinil in final packaged dosage forms meeting the
Product specifications established in Schedule B hereto.
1.6 "Starting Material" means certain interactive raw material (including
without limitation, compressil) necessary to formulate and package the Product
to be acquired directly CIRCA, as set forth in Schedule A hereto.
1.7 "Trademark" or "Trademarks" shall mean Provigil(R), as well as any
other trademark owned or used by CEPHALON in connection with the Product and
listed on Schedule A hereto.
II. APPOINTMENT AND TERM
2.1 Appointment. CEPHALON hereby appoints CIRCA, and CIRCA hereby
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accepts appointment, as a toll manufacturer to formulate and package the
Product.
2.2 Manufacturing and Packaging Services. During the term of this
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Agreement, CIRCA shall formulate Product, which shall include the validation of
commercial batches of the Product in accordance with the procedures established
in Schedule D hereto, and the preparation of the Product for commercial sale to
customers by CEPHALON. In addition, Circa shall label and package Product in
accordance with instructions provided by CEPHALON. CEPHALON will supply masters
for labels, package inserts and packaging. The content of the labels, package
inserts and packaging shall be the sole and exclusive responsibility of
CEPHALON. CIRCA will procure, test, inspect and approve all labels, package
inserts and packaging used for this Product. CIRCA will submit all new labels,
package inserts and packaging used for Product to CEPHALON for approval prior to
use.
2.3 Specific Duties. In addition to its general obligations relating to
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formulating and packaging, CIRCA shall perform the following services:
(i) receiving and storing all Active Drug Substance;
(ii) placing orders for, acquiring and storing all Starting Material
and packaging components;
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(iii) quality control and testing of all Active Drug Substance,
Starting Material in process materials, bulk tablets, finished
dosage Product and packaging components, in order to assure
compliance with all applicable standards and specifications;
(iv) managing clearance of customs for all Starting Materials and
packaging components, as necessary;
(v) conducting stability testing of Product in accordance with the
procedures established in Schedule D hereto; and
(vi) performing such other services as agreed upon in writing by the
parties.
2.4 Term. Unless terminated in accordance with the provisions of Article
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XX, this Agreement will remain in effect for a period of three (3) years from
the date hereof (the "Initial Term"), and shall automatically be renewed for
consecutive terms of one year.
III. PRODUCT QUANTITY, QUALITY AND MANUFACTURING PROCESSES
3.1 Quantity. CIRCA will manufacture, package and supply to CEPHALON all
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quantities of Product ordered by CEPHALON or an Affiliate thereof for
subsequent sale by CEPHALON or an Affiliate or agent thereof in the United
States, Mexico, Japan, the United Kingdom or Ireland, and for certain clinical
or other purposes as may be determined by CEPHALON. The parties acknowledge
that, during the pendency of this Agreement, CIRCA shall serve as the
manufacturer of a majority of Product produced for sale by CEPHALON in such
geographic ares, provided however, that CEPHALON shall have no obligation to
place any orders for any minimum quantities of Product, and provided further,
that CEPHALON may in its sole discretion engage a second toll manufacturer and
packager to produce Product for sale in such areas.
3.2 Quality. All Product manufactured by CIRCA for CEPHALON under this
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Agreement will meet the Product specifications established in Schedule B hereto
(the Specifications"), as well as the quality assurance standards established in
Schedule C hereto (the "Technical Agreement"). Such Specifications, as well as
the terms and conditions of the Technical Agreement, will be provided by
CEPHALON, agreed upon by CIRCA, and are subject to modification from time to
time by mutual agreement of the parties.
3.3 Manufacturing Processes. Circa has furnished CEPHALON with a copy of
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its production procedures and has identified to CEPHALON the equipment to be
used to produce the Product, all as set forth in Schedule C hereto. CIRCA agrees
that it will not modify these procedures, nor modify any method of formulation,
packaging, labeling or testing the Product (including analytical procedures,
components, process, Specifications, controls, storage, stability protocols),
without notifying CEPHALON or obtaining CEPHALON's prior written consent as
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required in Schedule C hereto. Costs incurred by CIRCA as a result of any such
changes or modifications requested by the FDA or by CEPHALON and relating solely
to the production of the Product will be borne by CEPHALON; costs for other
changes will be borne by CIRCA.
IV. TOLLING FEES
For each unit of Product made and supplied to CEPHALON under this Agreement
(provided it meets the quality requirements established herein) CEPHALON will
pay CIRCA a tolling fee in accordance with the terms established in Schedule E
hereto.
V. CONFIDENTIAL INFORMATION AND KNOW-HOW
5.1 The parties acknowledge that CEPHALON has provided Confidential
Information to CIRCA in connection with the formulation and packaging of the
Product, and further acknowledge that all such Confidential Information (as well
as any additional Confidential information provided to CIRCA by CEPHALON
hereunder) shall be subject to the provisions of the Article V. Any and all
information, knowledge, technology, and trade secrets relating to the Product or
the production, packaging, labeling or testing thereof, including any of the
foregoing that is obtained or developed by CIRCA in the performance of this
Agreement (herein the "Know-How") shall be held in confidence by CIRCA, and
CIRCA shall not use such Know-How for itself or for any third party nor disclose
the same to any third party except as provided below.
5.2 CIRCA will disclose to CEPHALON all Confidential Information and Know-
How developed by or for CIRCA during the term of this Agreement, promptly as it
is developed. CIRCA agrees and acknowledges that any Confidential Information
and Know-How, whether developed by CEPHALON, by CIRCA, or by CEPHALON and CIRCA
in collaboration hereunder, shall be the property of CEPHALON, and the CIRCA
shall have no rights or claims to any such Know-How except insofar as it shall
have access to and use of such Know-How to fulfill its obligations hereunder. If
any such Know-How is considered to be a patentable invention, CEPHALON shall be
responsible for the preparation, filing, prosecution and maintenance of all
patent applications and patents covering such invention as provided below.
5.3 All Know-How or other Confidential Information, disclosed or confirmed
in writing and designated as confidential by CEPHALON, shall be held in
confidence by CIRCA, shall not be used by CIRCA for any purpose except as
provided hereunder and shall not be disclosed to third parties except for
disclosure to its Affiliates or governmental authorities, or except as otherwise
necessary to carry out CIRCA's obligations under this Agreement. If CIRCA finds
it necessary to disclose such Confidential Information or Know-How to a third
party, CIRCA will not do so without first obtaining the written consent of
CEPHALON and entering into an agreement with the third party which binds the
third party to the same obligations of restricted use and disclosure as are
undertaken by CIRCA in this Agreement.
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5.4 CIRCA shall keep all such Know-How and Confidential Information in a
special file which shall be solely under the direction and control of CIRCA's
senior management. CIRCA shall not distribute any such Know-How or Confidential
Information except to its employees who have a need to know in connection with
the performance of their duties in satisfying the obligations of CIRCA
hereunder. Any CIRCA employee who receives such Know-How or Confidential
Information shall be advised as to the confidential nature thereof and the
prohibitions contained herein. CIRCA will use its best efforts to keep a record
of those individuals who have received copies of the Know-How and Confidential
Information or any portions thereof, and all copies of any portions thereof will
be identified by CIRCA as confidential. Upon termination of this Agreement, and
upon the request of CEPHALON, CIRCA shall return or destroy all such Know-How
and Confidential Information and any copies thereof in its possession.
5.5 Termination of this Agreement shall not operate to extinguish CIRCA's
obligation to treat Know-How and Confidential Information as provided herein,
and the same shall continue in effect in accordance with the Article for ten
(10) years with respect to such Confidential Information, and until such
Know-How is otherwise disclosed, as the case may be.
5.6 Nothing contained herein shall be deemed to grant to CIRCA, either
expressed or implied, a license or other right or interest in the Know-How or in
any patent, trademark or other similar property of CEPHALON other than as
expressly provided hereunder.
5.7 CIRCA shall not use the name of CEPHALON, or disclose the existence of
this Agreement for any marketing, advertising or promotional purpose, without
CEPHALON's prior written consent.
5.8 If CEPHALON learns of any confidential or proprietary information of
CIRCA that does not relate to the manufacture or packaging of the Product, then
the provisions of this Article V shall apply to govern CEPHALON with respect to
the treatment of such information.
VI. COMPONENT SUPPLY
6.1 Active Drug Substance. CEPHALON will provide free of charge, and
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deliver to CIRCA at its designated production facility not less than thirty
(30) days in advance of the date of production of Product, appropriate
quantities of Active Drug Substance which meets the specifications established
in Schedule A. Following such delivery, CIRCA shall assume full responsibility
for the safekeeping and safe handling, and shall bear all risk of loss, of all
such Active Drug Substance that is in its possession. Legal title to all Active
Drug Substance will remain with CEPHALON, provided however, that CIRCA shall
reimburse CEPHALON for the replacement cost of any Active Drug Substance that is
lost, contaminated, or destroyed while in the possession of CIRCA. CIRCA will
use its best efforts to obtain maximum yield of Product from the Active Drug
Substance provided by CEPHALON in connection with the formulation and packaging
services provided hereunder. The parties anticipate that the combined yield loss
suffered in the course of formulating and packaging the Product in any given lot
shall not exceed
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five percent (5%). Notwithstanding the above, if the yield loss over any given
twelve month period during the term hereof exceeds five percent (5%), then CIRCA
will reimburse CEPHALON for its costs for that amount of Active Drug Substance
lost that exceeds the aforementioned five percent (5%) maximum threshold.
Notwithstanding the above, the parties agree to calculate the actual yield loss
after production by CIRCA of the first ten (10) batches of Product, and to
negotiate in good faith to adjust the aforementioned yield loss threshold if the
actual yield loss proves to be substantially more than or less than five percent
(5%).
6.2 Starting Material. CIRCA will obtain at its expense Starting Material
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which meets the specifications established in Scheduled A. CIRCA assumes full
responsibility and liability for the storage and handling of all Starting
Material.
6.3 Packaging Components. Product will be labeled and packaged in
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accordance with instructions provided by CEPHALON. CIRCA will provide to
CEPHALON master samples of all labels, package inserts and packaging prior to
use and CEPHALON thereafter promptly will approve said master samples. Upon
approval by CEPHALON, CIRCA will procure, test, inspect and approve all labels,
package inserts and packaging used in connection with the Products.
VII. FORECASTS AND ORDERS
7.1 Orders. CEPHALON will submit firm written purchase orders to CIRCA
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not less than ninety (90) days in advance of the required date of shipment.
CEPHALON must deliver all Active Drug Substance necessary to formulate Product
for any given shipment to CIRCA not less than ninety (90) days in advance of
said date of shipment.
7.2 Forecasts and Forecast Changes. CEPHALON will provide CIRCA with an
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initial volume forecast setting forth CEPHALON's anticipated quantity
requirements for the forthcoming twelve (12) months on or about the Effective
Date, and with rolling, updated volume forecasts on a quarterly basis
thereafter. Forecasts provided by CEPHALON to CIRCA hereunder are for planning
purposes only. CEPHALON can increase or decrease its firm order quantities with
CIRCA's prior agreement and CIRCA can adjust its shipping quantities with
CEPHALON'S prior agreeement. Both parties shall accommodate reasonable change
requests from the other.
VIII. SHIPMENT AND PAYMENT
8.1 CIRCA's Responsibilities. CIRCA will properly prepare the Product so
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that it may be lawfully and safely shipped to warehouse locations in the United
States, Mexico, Japan, the United Kingdom and Ireland as designated by CEPHALON.
CIRCA will prepare and execute all necessary shipping documents. CEPHALON will
choose the carrier by indicating same on its purchase order provided to CIRCA.
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8.2 Terms of Shipment. CIRCA will ship Product ex factory to CEPHALON's
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warehouse or other designated sites. All transport costs and risk of loss during
shipment will be borne by CEPHALON.
8.3 Terms of Payment. CEPHALON will pay CIRCA the toll fee within thirty
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(30) days after the date on which CEPHALON receives said invoice from CIRCA,
together with copies of all documentation required for Product release as
provided in Schedule C hereto.
XI. INSPECTION AND ANALYSIS
9.1 Inspection by CIRCA. CIRCA will analyze each Product lot for
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compliance with the Specifications established in Schedule B. CIRCA will send to
CEPHALON a certificate of analysis and a certificate of release (together with
any other documentation required under procedures established in Schedule C
hereto) prior to, or together with, each shipment of Product. In this regard,
CIRCA agrees to retain all records and documents necessary to fulfill the
requirements established by all applicable regulatory agencies. The parties
acknowledge that, subject to the terms set forth in Schedule C hereof, under the
laws and regulations of the United Kingdom and Ireland, CEPHALON or its
authorized agent shall serve as the designated "Qualified Person" under the laws
and regulation for the European Union for purposes of releasing the Product into
the market.
9.2 Inspection by CEPHALON. CEPHALON or its authorized representative will
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inspect all shipments upon their receipt and will report any reasonably
discernible defects in the Product to CIRCA within sixty (60) days of its
receipt of the Product and related records. Any defects not reasonable
discernible will be reported to CIRCA by CEPHALON within thirty (30) days of
CEPHALON's discovery of same.
9.3 Non-Conforming Product. If CEPHALON notifies CIRCA in writing that any
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Product lot does not meet Product Specifications established in Schedule B or
in the Technical Agreement set forth in Schedule C as determined by CEPHALON's
testing and inspection of the Product, then solely at its option CEPHALON may
either (i) demand that CIRCA remanufacture or repackage (as appropriate) said
Product at no charge to CEPHALON and pay all round-trip shipping charges to and
from the destination of the original shipment, or (ii) be relieved of any
obligation to pay CIRCA the toll fees otherwise payable for the manufacture of
said Product, and CIRCA shall reimburse CEPHALON for the costs incurred by
CEPHALON in properly disposing of the Product. In any event, CIRCA shall not be
liable for reimbursing CEPHALON its cost of Active Drug Substance used in
formulating such non-conforming Product, provided however, that nothing herein
shall be construed to limit CIRCA's obligations established in Section 6.1
hereof.
9.4 Independent Testing. If CEPHALON notifies CIRCA that any Product does
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not meet applicable Specifications or quality assurance guidelines, and CIRCA
does not agree with CEPHALON'S position, the parties will attempt to reach a
mutually acceptable resolution of the dispute. If they are unable to do so after
a reasonable period of time (such period not to exceed three months from the
date of original notification), the matter will be submitted to an
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independent testing laboratory acceptable to both parties. Both parties will
accept the judgement of the independent laboratory. The cost of such testing
will be borne by the party whose position is determined to have been in error.
If the Product is determined by said independent laboratory to have been
conforming, then the provisions of Section 9.3 hereof shall not apply, and
CEPHALON shall not be relieved of its obligations to pay CIRCA for the
production of such Product.
X. REPRESENTATIONS AND WARRANTIES
10.1 General. CIRCA represents and warrants to CEPHALON that (i) it has
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and will maintain throughout the pendency of this Agreement, the expertise, with
respect to personnel and equipment, to fulfill the obligations established
hereunder, and has obtained all requisite licenses, authorizations and approvals
required by federal, state or local government authorities to manufacture the
Product; (ii) the production facility, equipment and personnel to be employed to
formulate and package the Product will be qualified to manufacture GMP grade
product at the time each such batch of Product is produced, and that the
production facility to be employed is in compliance with all applicable laws and
regulations, provided however, that CEPHALON acknowledges that CIRCA shall not
be required to establish or to maintain a dedicated production facility solely
on the basis of this representation; (iii) there are no pending or uncorrected
citations or adverse conditions noted in any inspection of the production
facility to be employed which would cause the Product to be misbranded or
adulterated within the meaning of the federal Food, Drug and Cosmetic Act, as
amended; (iv) it has provided to CEPHALON all FDA inspection reports and FORM
483s received by CIRCA in the last two (2) years, and that the documents
provided are true and complete copies thereof (except as noted); (v) the
execution, delivery and performance of this Agreement by CIRCA does not conflict
with, or constitute a breach of any order, judgement, agreement, or instrument
to which CIRCA is a party; (vi) the execution, delivery and performance of this
Agreement by CIRCA does not require the consent of any person or the
authorization of (by notice or otherwise) any governmental or regulatory
authority (other than those relating to the granting of approval to
commercialize the Product); and (vii) CIRCA has not been debarred by the United
States Food & Drug Administration ("FDA") under the General Drug Enforcement Act
of 1992 (or by any analogous agency or under any analogous law or regulation),
and neither it nor any of its officers or directors has ever been convicted of a
felony under the laws of the United States or of the Territory for conduct
relating to the development or approval of a drug product or relating to the
marketing or sale of a drug product, and further that no individual or firm
debarred by any governmental authority will participate in the performance,
supervision, management or review of the production of Product supplied to
CEPHALON under this Agreement.
10.2 Manufacturing Warranty. CIRCA warrants that all products supplied to
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CEPHALON will be manufactured in accordance with current good manufacturing
practices as specified by the applicable laws and regulations of the United
States, Mexico, Japan, the European Union, the United Kingdom and of Ireland (as
may be applicable), at the time of manufacture. A statement to this effect shall
be printed on CIRCA'S certificate of analysis for each batch of Product
delivered. Moreover, CIRCA will provide to CEPHALON concurrent with each invoice
the applicable batch records and test results establishing such compliance, as
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provided in Schedule C hereto.
10.3 Product Warranty. CIRCA hereby warrants that all Product delivered to
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CEPHALON (i) will not be adulterated, misbranded, or otherwise prohibited within
the meaning of any European Union, national, state or local law or regulation,
(ii) will be free from defects in materials (so long as such materials are
within the control of CIRCA during the manufacturing process) and manufacture,
(iii) will conform to the specification set forth in the applicable Product
registration on file with the FDA, the Japanese Ministry of Health and Welfare,
the European Medicines Evaluative Agency, any other authority, and (iv) will
conform to Specifications as established in Schedule B hereto.
10.4 Environmental Warranty. CIRCA warrants that all waste generated in
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operations under this Agreement will be stored, transported and disposed of in a
safe and environmentally sound manner consistent with all federal, state and
local laws and regulations. CIRCA further warrants that it will conduct its
business so as to comply with the terms and conditions of all air pollution
control permits, sanitary sewer discharge permits, and authorizations required
by applicable federal, state and local laws, rules and regulations relating to
the protection of the environment. CIRCA will not undertake any production or
development activities for itself or on behalf of a third party which, together
with the emissions from activities under this Agreement, would cause air
emissions from isopropyl alcohol or any other substance to exceed any applicable
legal limits.
10.5 Technology Warranty. CEPHALON hereby represents and warrants to CIRCA
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that the technology established in the Specifications, or as otherwise disclosed
hereunder (collectively, the "Technology") is, to the best knowledge of
CEPHALON, sufficient to enable CIRCA to manufacture and package the Product as
contemplated hereunder. Except as otherwise disclosed to CIRCA, CEPHALON owns
all right, title and interest to said Technology, free and clear of any adverse
ownership claims Except as otherwise disclosed to CIRCA, CEPHALON has not
received any notice that any portion of the Technology infringes upon the
patent, trade secret or other intellectual property rights or interests of any
third party and, to the best knowledge of CEPHALON, there has been no such
infringement.
XI. QUALITY CONTROL, RECORDS AND INSPECTIONS
11.1 Product and Component Samples. CIRCA will maintain a sample of each
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chemical component (including Active Drug Substance) as required by applicable
regulatory standards or as otherwise mutually agreed by CEPHALON and CIRCA.
CIRCA will be responsible for maintaining retention samples of the Product as
may be required by applicable regulatory standards.
11.2 Validation. CIRCA will validate all process, methods, equipment
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utilities, facilities and computers used in the formulation, packaging, storage,
testing and release of Product in conformance with the provisions of Schedule D
hereto, and all applicable laws and regulations. CEPHALON will have the right to
review the results of said validation upon request.
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11.3 Quality Compliance. CIRCA will provide CEPHALON with timely
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notification of all significant deviations, notes to file, and other
deficiencies that may impact the quality of the Product, as well as all FDA
reports regarding testing, manufacture, packaging, or labeling of the Product or
the production facility.
11.4 Manufacturing Records. CIRCA will maintain complete and accurate
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records relating to the Product and the manufacture, packaging, labeling and
testing thereof for the period required by applicable Regulatory Standards, and
CIRCA shall provide copies thereof to CEPHALON upon CEPHALON's request. The
records shall be subject to audit and inspection under this Article XI.
11.5 Batch Records. CIRCA will supply for each batch of Product, including
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each pilot batch, complete batch production and control records. Records which
include the information relating to the manufacturing, packaging and quality
operation for each lot of Product will be prepared by CIRCA at the time such
operations occur. The records will include, without limitation, mixing and
filling records; container and component traceability records; equipment usage
records; in-process and final laboratory testing results; in-process and final
Product physical inspection results; yield reconciliation for bulk and finished
Product; labeling and packaging records; and records relating to deviations from
approved procedure, as well as CIRCA's investigation and corrective actions.
Copies of batch records will be forwarded to CEPHALON prior to or along with
shipment of each Product lot.
11.6 Records Retention. CIRCA will retain records and documents for
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periods meeting all applicable regulations of the FDA and other applicable
regulatory agencies.
11.7 Regulatory Inspections. CIRCA will promptly inform CEPHALON of any
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contact, inspection or audit by any governmental agency, related to or affecting
the Product. CIRCA will promptly provide CEPHALON with copies of any
government-issued inspection observation reports (including without limitation
FDA Form 483s) and agency correspondence, that may affect the Product. CIRCA and
CEPHALON will cooperate in resolving any concerns with any governmental agency.
CIRCA will also inform CEPHALON of any action taken by any governmental agency
against CIRCA or any of its officers and employees, within 24 hours after the
action is taken.
11.8 CEPHALON Inspections. CEPAHLON or its authorized representative will
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have the right during normal business hours, at reasonable intervals and on
reasonable prior notice, to inspect CIRCA's facilities used in the
manufacturing, packaging, storage, testing, shipping or receiving of Product and
Product components. Such inspections may include GMP inspections and system
audits. Representatives of CEPHALON (and its designated Affiliate) will have
access during audits to all documents, records, reports, data, procedures,
facilities, regulatory submissions, and all other information required to be
maintained by applicable government regulations. CIRCA shall take appropriate
actions to adopt reasonable suggestions of CEPHALON to correct any deficiencies
identified by such inspection or audit. In addition, CEPHALON shall have the
right to observe from time to time the manufacture, packaging and quality
control testing of the Product by CIRCA, including without limitation, the right
to
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arrange, at its cost and expense, to have a CEPHALON employee or other
representative located on the premises of CIRCA's production facility to
participate in the monitoring of Product production, testing, packaging and
labeling under this Agreement. No testing of the Product by CEPHALON and no
inspection or audit by CEPHALON of the CIRCA production facility under this
Agreement shall operate as a waiver of or otherwise diminish CIRCA's
responsibility to ensure Product quality under this Agreement.
XII. COMPLAINTS, ADVERSE EXPERIENCES AND RECALLS
12.1 Product Complaints and AE's. CEPHALON will correspond with
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complainants as to any complaints associated with Product, whether received
during or after the term hereof. CIRCA will assist CEPHALON in investigating
Product complaints by analyzing Product, manufacturing processes and components
to determine the nature and cause of an alleged Product manufacturing defect or
alleged Product failure. CIRCA will also assist CEPHALON in the investigation of
any Adverse Experience (AE) reported to either party when such AEs are believed
to be attributable to the Product. If CEPHALON determines that any reasonable
pyhsical, chemical, biological or other evaluation should be conducted in
relation to an AE or Product compliant, CIRCA will conduct the evaluation and
provide CEPHALON with a written report of such evaluation within thirty (30)
days from receipt of CEPHALON's written request for same, together with samples
of the Product from the relevant lot. CIRCA will notify CEPHALON within 24 hours
of any Product that fails to meet the Specifications set forth in Schedule B
hereto.
12.2 AE Reports. CEPHALON or its Affiliates will file any AE Reports
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required under United States or foreign laws and regulations for the Product.
CIRCA will notify CEPHALON by facsimile transmission of all Product complaints
and AEs received within two (2) days of its receipt thereof. All such notices
shall be sent to the attention of the Director, Medical Affairs at CEPHALON,
facsimile number (610) 738-6313.
12.3 Recall Action. If CEPHALON should elect or be required to initiate a
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Product recall, withdrawal or field correction because of (i) supply by CIRCA of
Product that does not conform to the Specifications and warranties established
by this Agreement or (ii) the negligent or intentional wrongful act or omission
of CIRCA, CEPHALON will notify CIRCA and provide a copy of its recall
letter prior to initiation of the recall. CIRCA will assist CEPHALON (and its
designated Affiliate) in any investigation to determine the cause and extent of
the problem. All regulatory authority contacts and coordination of any recall
activities will be initiated by CEPHALON.
12.4 Recall Expenses. If any Product is recalled as a result of (i)
----------------
supply by CIRCA of Product that does not conform to the warranties in this
Agreement or (ii) the negligent or intentional wrongful act or omission of
CIRCA, then CIRCA will bear all costs and expenses of such recall. Recalls for
any other reason will be at CEPHALON's expense. If each Party contributes to
the cause for a recall, the cost will be shared in proportion to each Party's
contribution.
-11-
12.5 Recall Records. CIRCA will maintain complete and accurate records
---------------
for such periods as may be required by applicable law or regulation, but not
less than three (3) years following the applicable date of expiration of a given
Product lot, or all Product supplied under this Agreement.
XIII. EQUIPMENT
Notwithstanding anything to the contrary herein, the parties acknowledge
that CEPHALON will reimburse CIRCA for its out-of-pocket expenses incurred in
connection with the purchase of certain tablet tooling equipment required for
the manufacture, packaging and labeling of the Product (the "Equipment"),
including without limitation punches and dies for tablet presses, and special
change parts for bottle handling. The parties shall agree in writing on the
specifications and costs of any such Equipment and related materials prior to
such purchase. CIRCA agrees to use said Equipment solely in connection with the
performance of its duties and obligations established hereunder. CIRCA shall
maintain all such Equipment in good working order. CEPHALON will be responsible
for the cost of purchasing replacement Equipment at the end of its useful life,
provided however that CIRCA will be responsible for any such costs stemming from
damage or premature or undue wear and tear to the Equipment based upon neglect
for misuse by CIRCA. CEPHALON shall retain title to such Equipment, which will
be returned by CIRCA at the request of CEPHALON following termination of this
Agreement.
XIV. INSURANCE
During the term hereof, CIRCA shall maintain product liability/completed
operations insurance for and providing coverage of not less than TEN MILLION AND
00/100 DOLLARS ($10,000,000.00) per occurrence and in the aggregate providing a
defense for and insuring CIRCA against all costs, fees, judgments, and
liabilities arising out of or alleged to rise out of its obligations and
representations and warranties under this Agreement. In addition, CIRCA will
maintain at all times sufficient property casualty insurance to cover the total
quantity of Active Drug Substance and Product on hand at its full cost of
replacement. CIRCA will provide to CEPHALON, upon request, evidence of such
insurance overages. CIRCA further agrees to cause such policies to name CEPHALON
as an additional insured at no cost to CEPHALON.
XV. TRADEMARKS
15.1 CIRCA shall have the non-exclusive right to use the Trademarks in
packaging the Product in connection with fulfilling its obligations hereunder.
The rights granted CIRCA hereunder to use the Trademarks shall in no way affect
CEPHALON's ownership of such Trademarks. No other right, title or interest in
the Trademarks is established hereby, and nothing herein shall be construed to
grant any right or license to CIRCA to use the CEPHALON trademark or the name
CEPHALON, other than as specifically set forth herein.
-12-
15.2 CIRCA shall not make any use or take any action with respect to the
Trademarks to prejudice or infringe CEPHALON's rights thereto including the use
of any confusingly similar trademark and shall forthwith, upon objection by
CEPHALON, desist from any use thereof or action therewith which is in violation
of this Agreement.
15.3 CIRCA will only market the Product using the relevant Trademarks as
listed in Schedule A during the term of this Agreement. Upon termination of
this Agreement, CIRCA will cease all use of the Trademarks and cancel any
license to such Trademarks granted hereunder.
15.4 CIRCA will use the Trademarks in strict accordance with the
instructions given by CEPHALON, and shall refrain from making any changes in
connection therewith without first obtaining CEPHALON's written consent. CIRCA
further agrees that at all times the Trademarks shall be used in accordance with
good trademark practice, including notation of the fact that they are trademarks
and use of the appropriate notice of registration. CEPHALON reserves the right
to unilaterally determine the adequacy of the use and protection given the
Trademarks by CIRCA as set forth herein.
15.5 CIRCA shall notify CEPHALON, in writing, of any conflicting use of
and applications or registrations for, any of the Trademarks, or any acts of
infringements, or acts of unfair competition involving the Trademark, promptly
after such matters are brought to its attention or its has knowledge thereof.
CIRCA further agrees to assist CEPHALON, at CEPHALON's expense, in registering
or perfecting CEPHALON's rights to the Trademarks in the Territory.
15.6 In the event of any claim or litigation by a third party against
CIRCA alleging that any of the Trademarks initiates or infringes a trademark of
such third party or is invalid, CIRCA shall promptly give notice of such claims
or litigation to CEPHALON and CEPHALON shall assume responsibility for and
control of the handling, defense or settlement thereof. CIRCA shall cooperation
fully with CEPHALON during the pendency of any such claim or litigation.
CEPHALON shall keep CIRCA notified of the current status of any trademark claim,
litigation or infringement of any of the Trademarks and shall permit CIRCA to
assume the handling, defense or settlement thereof if CEPHALON declines to do
so. CEPHALON may at any time modify adopt or withdraw from use of any Trademark
without any liability to CIRCA.
XVI. INVENTIONS
Any inventions or discoveries made by CIRCA in the performance of this
Agreement that relate to the Product (including any new use or change in the
method of producing, testing or storing the Product) shall be owned by CEPHALON.
Any other invention or discovery made by CIRCA in the performance of this
Agreement shall be owned by CIRCA, but CEPHALON shall have a nonexclusive,
perpetual, nontransferable, paid-up license to use any such invention to make or
have made the Product. Each party shall execute such instruments as shall be
required to evidence or effectuate the other party's ownership of any such
inventions, and shall cooperate upon reasonable request (and at the expense of
the requesting party) in the prosecution of patents
-13-
and other intellectual property rights related to any such invention.
XVII. INDEMNIFICATION
17.1 By CIRCA. CIRCA will indemnify and hold CEPHALON harmless from
---------
any and all liability, damage, loss, cost, or expense (including reasonable
attorneys' fees) which arise from (i) CIRCA'S breach of any of the
covenants, warranties, and representations contained herein, or (ii) CIRCA's
negligence or other wrongful conduct as determined by a court of competent
jurisdiction.
17.2 By CHEPHALON. CEPHALON will indemnify and hold CIRCA harmless
-------------
from any and all liability, damage, loss, cost, or expense (including reasonable
attorneys' fees) which arise from (i) CEPHALON'S breach of any of the covenants,
warranties, and representations contained herein, or (ii) CEPHALON's negligence
or other wrongful conduct as determined by a court of competent jurisdiction, or
(iii) a claim that the manufacture of the Product by CIRCA in accordance with
this Agreement infringes a patent registered in the United States, or any other
jurisdiction.
17.3 By Each Party. In the event that negligence or willful
--------------
misconduct of both CIRCA and CEPHALON contribute to any such loss, damage,
claim, injury, cost or expense, CIRCA and CEPHALON will each indemnify and hold
harmless the other with respect to that portion of the loss, damage, claim,
injury, cost or expense attributable to its negligence or willful misconduct.
17.4 Procedures. In the event that one party receives notice of a
-----------
claim, lawsuit, or liability for which it is entitled to indemnification by the
other party, the party receiving notice shall give prompt notification to the
indemnifying party. The party being indemnified shall cooperate fully with the
indemnifying party throughout the pendency of the claim, lawsuit or liability,
and the indemnifying party shall have complete control over the conduct and
disposition of the claim, lawsuit, or liability including the retention of legal
counsel engaged to handle such matter. The indemnifying party hereunder will be
liable for any costs associated with the settlement of any claim or action
brought against it or other party unless it has received prior notice of the
settlement negotiations and has agreed to the settlement.
XVIII. FURTHER ENGAGEMENTS
If CEPHALON develops a revised formulation of the Product, or otherwise
desires to engage CIRCA to formulate or package pharmaceutical products other
than the Product, then the parties will negotiate in good faith to reach
agreement on mutually acceptable terms and conditions under which this Agreement
shall be expanded to cover such additional engagement(s).
-14-
XIX. TERMINATION
19.1 Without Cause. CEPHALON may terminate this Agreement, effective on
--------------
the third anniversary of the date hereof or on subsequent anniversary date(s),
if applicable, by giving three (3) months written notice to CIRCA.
19.2 Breach. If either party hereto commits a material breach of any of
-------
its obligations hereunder, the non-breaching party may, at its option, terminate
this Agreement by giving the other party at least sixty (60) days prior written
notice of its intent to terminate this Agreement, which notice shall specify the
breach and the termination date, unless the breaching party cures said breach
prior to the specified termination date (or prior to the expiration of a longer
period as may be reasonably necessary to cure such breach, provided that the
breaching party is making diligent efforts to cure such breach, and provided
further that such longer period shall not in any event exceed one hundred twenty
(120) days from the date of notice.)
19.3 Insolvency. Either party may terminate this Agreement immediately in
-----------
its entirety if the other Party files a petition of bankruptcy, is adjudged
bankrupt, takes advantage of any insolvency act, or executes a bill of sale,
deed of trust, or assignment for the benefit of creditors.
19.4 Survival. The rights and obligations contained in sections covering
---------
representations and warranties, indemnification and confidentiality will survive
termination of this Agreement, as will any rights to payment or other rights or
obligations that have accrued under this Agreement prior to termination.
Termination will not affect the liability of either party by reason of any act,
default, or occurrence prior to said termination.
19.5 Transfer. If either party terminates this Agreement, CIRCA will upon
---------
request provide reasonable assistance in transferring production of Product to a
facility owned by CEPHALON or a third party selected by CEPHALON.
19.6 Return of Product and Components. Upon termination under this
--------------------------------
Article, CIRCA shall return promptly to CEPHALON all Product, Active Drug
Substance, and packaging components in its possession on the effective date of
termination.
XX. ALTERNATE DISPUTE RESOLUTION
Any dispute concerning or arising out of this Agreement or concerning the
existence or validity hereof, shall be determined by the following procedure.
20.1 Both parties understand and appreciate that their long term mutual
interest will be best served by affecting a rapid and fair resolution of any
claims or disputes which may arise out of services performed under this contract
or from any dispute concerning contract terms. Therefore, both parties agree to
use their best efforts to resolve all such disputes as rapidly as possible on a
fair and equitable basis. Toward this end, both parties agree to develop and
follow a process for presenting, rapidly assessing, and settling claims on a
fair and equitable basis.
-15-
20.2 If any dispute or claim arising under this contract cannot be
readily resolved by the parties pursuant to the process described in Section
21.1, the parties agree to refer the matter to a panel consisting of one (1)
senior executive employed by each party who is not directly involved in the
claim or dispute for review and resolution. A copy of the contract terms, agreed
upon facts (and areas of disagreement), and concise summary of the basis for
each side's contentions will be provided to both such senior executives who
shall review the same, confer, and attempt to reach a mutual resolution of the
issue.
20.3 If the matter has not been resolved utilizing the process set forth
in this Article XXI, and the parties are unwilling to accept the non-binding
decision of the panel, either or both parties may elect to pursue resolution
through litigation, or other legal remedies available to the parties.
XXI. MISCELLANEOUS
21.1 Headings. The headings and captions used herein are for the
--------
convenience of the parties only and are not to be construed to define, limit or
affect the construction or interpretation hereof.
21.2 Severability. In the event that any provision of this Agreement is
------------
found to be invalid or unenforceable, then the offending provision shall not
render any other provision of this Agreement invalid or unenforceable, and all
other provisions shall remain in full force and effect and shall be
enforceable, unless the provisions which have been found to be invalid or
unenforceable shall substantially affect the remaining rights or obligations
granted or undertaken by either party.
21.3 Entire Agreement. This Agreement, including all those Schedules
----------------
appended hereto, contains the entire agreement of the Parties regarding the
subject matter hereof and supersedes all prior agreements, understandings or
conditions (whether oral or written) regarding the same, including without
limitation that certain Manufacturing Agreement between the parties dated as of
November 14, 1994 (except for those provisions thereof that were designated by
the parties to survive termination of said Manufacturing Agreement). Further,
this Agreement may not be changed, modified, amended or supplemented except by
written instrument signed by both parties.
21.4 Assignability. This Agreement and the rights hereunder may not be
-------------
assigned or transferred by either party without the prior written consent of the
other party (other than for rights to payment), provided however, that either
party may assign this Agreement to an Affiliate, and provided further that in
the event of a merger, acquisition or sale of substantially all of the assets of
CEPHALON, the rights and obligations of CEPHALON under this Agreement may be
assigned to the survivor or purchaser in that transaction. In the event that
this Agreement is assigned, it shall be binding upon and inure to the benefit of
the parties and their respective successors and assigns.
-16-
21.5 Further Assurances. Each party hereto agrees to execute, acknowledge
------------------
and deliver such further instruments, and to take such other actions, as may be
necessary or appropriate in order to carry out the purposes and intent of this
Agreement.
21.6 Waiver. The waiver by either party of a breach of any provisions
------
contained herein shall be effective only if made in writing and shall in no way
be construed as a waiver of any succeeding breach of such provision or waiver of
the provision of itself.
21.7 Force Majeure. A party shall not be liable for nonperformance or
-------------
delay in performance (other than of obligations regarding any payments or of
confidentiality) caused by any event reasonably beyond the control of such party
including, without limitation, wars, hostilities, revolutions, riots, civil
disturbances, national emergencies, strikes, lockouts, unavailability of
supplies, epidemics, fires, floods, earthquakes, other forces of nature,
explosions, embargoes, or any other Acts of God, or any laws, proclamations,
regulations, ordinances, or other acts or orders of any court, government or
governmental agency. Any occurrence of Force Majeure shall be reported promptly
to the other party. A party whose performance has been excused will perform such
obligations as soon as is reasonably practicable after the termination or
cessation of such event or circumstance.
21.8 Remedies. CIRCA agrees and acknowledges that its failure to produce
--------
Product, its disclosure of Confidential Information, or the breach of any other
provision set forth in this Agreement may cause irreparable harm to CEPHALON,
and therefore that any such breach or threatened breach will entitle CEPHALON to
injunctive relief, in addition to any other legal remedies available to
CEPHALON in a court of competent jurisdiction.
21.9 Governing Law. This Agreement shall in all respects be construed and
-------------
enforced in accordance with the laws of the State of Delaware.
21.10 Independent Contractors. The parties are independent contractors
-----------------------
under this Agreement. Nothing contained in this Agreement is to be construed so
as to constitute CEPHALON and CIRCA as partners, agents or employees of the
other, including with respect to this Agreement. Neither party hereto shall have
any express or implied right or authority to assume or create any obligations on
behalf of, or in the name of, the other party or to bind the other party to any
contract, agreement or undertaking with any third party unless expressly so
authorized in writing by the other party.
21.11 Counterparts. This Agreement may be executed in multiple
------------
counterparts, each of which shall be considered and shall have the force and
effect of an original.
21.12 Notices. Except as set forth in Section 12.2 above, or as otherwise
-------
stated herein, all notices, consents or approvals required by this Agreement
shall be in writing and sent by certified or registered air mail, postage
prepaid or by facsimile or cable (confirmed by such certified or registered
mail) to the parties at the following addresses or such other addresses as may
be designated in writing by the respective parties. Notices shall be deemed
effective on the date of mailing.
-17-
Director, Technical Operations
Cephalon, Inc.
145 Brandywine Parkway
West Chester, PA 19380-4245
Facsimile: (610) 344-7563
General Manager
Circa Pharmaceuticals, Inc.
33 Ralph Avenue
P.O. Box 30
Copiague, New York 11726-0030
Facsimile: (516) 842-8630
IN WITNESS WHEREOF, the undersigned parties have caused this Agreement to
be executed as of the date first above written.
CEPHALON, INC.
By: /s/ Bruce A. Peacock
------------------------------------
Bruce A. Peacock
CIRCA PHARMACEUTICALS, INC.
By: /s/ Stan J. Martinez
------------------------------------
-18-
SCHEDULE A
----------
ACTIVE DRUG SUBSTANCE AND STARTING MATERIAL SPECIFICATIONS; TRADEMARKS
----------------------------------------------------------------------
The parties have agreed upon all those applicable specifications for the
Active Drug Substance and Starting Materials as set forth in the following
documents. Any modifications to any such specifications shall be agreed upon by
the parties.
[Download Table]
DCRA # DOCUMENT # TITLE
------ ---------- -----
893 PKG/CAPLINER Packaging Component - Cap Liner (PE)
892 PKG/DESS Packaging Component - Desiccant Canister
891 PKG/HDPE Packaging Component - HDPE Container
894 PKG/RAYON Packaging Component - Rayon Coil
865 RM/CRMLNA Raw Material - Croscarmellose Sodium, NF
864 RM/CRN STR Raw Material - Corn Starch
917 RM/IPA Raw Material - Isopropyl Alcohol
867 RM/LACHY Raw Material - Lactose Monohydrate, NF
929 RM/MAGSIL Raw Material - Magnesium Silicate Compressil RM 274
869 RM/MAGSTR Raw Material - Magnesium Stearate, NF
873 RM/MODAF Raw Material - Modafinil
870 RM/PVP Raw Material - Povidone, USP
907 RM/PWATER Raw Material - Purified Water, USP
872 RM/TALC Raw Material - Talc, USP
875 STD/MODAF Requalification of Standard - Modafinil
876 VQ/MODAF Vendor Qualification - Modafinil
-19-
Int. Cl.: 42
Prior U.S. Cls.: 100 and 101
Reg. No. 1,983,615
United States Patent and Trademark Office Registered July 2, 1996
-----------------------------------------------------------------------
SERVICE MARK
PRINCIPAL REGISTER
[LOGO]
CEPHALON, INC. (DELAWARE CORPORATION)
145 BRANDYWINE PARKWAY
WEST CHESTER, PA 19380
FOR: BIOFILARMACEUTICAL RESEARCH AND DEVELOPMENT SERVICES, NAMELY DEVELOPING
FOR OTHERS DIAGNOSTIC AND THERAPEUTIC AGENTS FOR DISEASES OF ANIMALS AND HUMANS,
IN CLASS 42 (U.S. CLS. 100 AND 101).
FIRST USE 6-0-1988: IN COMMERCE 6-0-1988
THE STIPPLING IN THE DRAWING IS FOR SHADING PURPOSES ONLY.
THE MARK IS A STYLIZED LETTER "C" DESIGN
SER. NO. 74-622-072, FILED 1-17-1995
DAVID H. STINE, EXAMINING ATTORNEY
Provigil(R)
Cephalon(R)
-20-
SCHEDULE B
----------
PRODUCT SPECIFICATIONS
----------------------
The parties have agreed upon all those applicable specifications for the
Product as set forth in the following documents. Any modifications to any such
specifications shall be agreed upon by the parties.
[Download Table]
DCRA # DOCUMENT # TITLE
------ ---------- -----
877 BL/MODAF Master Blend - Modafinil Tablets
878 FP/100MODAF Finished Product - Modafinil 100 mg Tablets
890 FP/100MODAFEUR Finished Product Modafinil 100 mg Tablets (European)
879 FP/100MODAFIPA Finished Product - Residual Isopropyl Alcohol in
Modafinil 100 mg Tablets
881 FP/200MODAF Finished Product - Modafinil 200 mg Tablets
882 FP/200MODAFIPA Finished Product - Residual Isopropyl Alcohol in
Modafinil 200 mg Tablets
875 STD/MODAF Requalification of Standard - Modafinil
-21-
SCHEDULE C
----------
TECHNICAL AGREEMENT
-------------------
-22-
[LOGO OF CIRCA PHARMACEUTICALS, INC.]
CEPHALON - CIRCA TECHNICAL AGREEMENT
FOR THE COMMERCIAL MANUFACTURING AND TESTING
OF PROVIGIL(R) DRUG PRODUCT
I. PURPOSE AND SCOPE
This is the Quality Assurance policy between Cephalon and Circa. This agreement
specifies the QA responsibilities and requirements of each party for the
commercial manufacturing and testing of Provigil(R) Drug Product. This policy
also specifies the Provigil related requirements for record keeping, quality
reporting, and change control.
II. DEPARTMENTS AFFECTED
Quality Assurance - Cephalon Quality Assurance - Circa
Commerical Operations - Cephalon Quality Control - Circa
Regulatory Affairs - Cephalon Manufacturing Operations - Circa
Regulatory Affairs - Circa
III. RESPONSIBILITY
It is the responsibility of the Quality Assurance management at Cephalon and
Circa, in cooperation with Manufacturing Operations, Quality Control and
Regulatory Affairs, to assure compliance with this agreement.
IV. RESPONSIBILITIES AND REQUIREMENTS - CIRCA
A. Circa Responsibilities
. Manufacture and test Provigil Drug Product in accordance with cGMP and the
approved Provigil marketing applications.
. Perform a Quality review of every lot of Provigil drug product and
subsequently release or reject the lot in accordance with cGMP.
. All initial and stability testing of both active and inactive components and
finished dosage forms are performed in-house by the staff of the Circa
Quality Control Department in accordance with approved specifications and
procedures (as listed in this agreement) and/or the approved Provigil
marketing applications and protocols for Provigil drug product.
[LOGO OF CIRCA APPEARS HERE]
. Quality Control Raw Material Report for release of each lot of modafinil
drug substance tested and released for use in the manufacturing of Provigil
drug product.
. Quality Control Release Report for each lot of Provigil Master Blend used
in the manufacturing of Provigil drug product.
. Quality Control Release Report for each lot of Provigil Compression Process
used in the manufacture of Provigil drug product.
. Certificate of Release (to Cephalon) for each labeled and packaged lot of
Provigil final drug product.
. All investigations, incident reports, anomaly reports, associated with the
manufacturing and testing of every lot of Provigil.
The following documents shall be provided to Cephalon on a schedule mutually
agreed to by Circa and Cephalon or on an as need basis:
. Stability Reports
. Product Quality Review Reports (Summarized annually as the "Annual Product
Review)"
- Summary Report - Product complaints
- Summary Report - Incident reports and anomaly explanation reports
- Summary Report - Production deviations
- Summary Report - Out-of-specification results
- Summary Report - QA product disposition
- Summary Report - In-process and finished product data trends
- Summary Report - Retain sample evaluation
V. RESPONSIBILITIES AND REQUIREMENTS - CEPHALON
A. RESPONSIBILITIES
. Cephalon's QA shall review the Provigil summary lot file documentation
prior to market distribution. Documentation of the sponsor review and
disposition will be provided to Circa prior to the shipment of the lot to
the designated distributor.
[LOGO OF CIRCA APPEARS HERE]
. To assure that all raw materials and packaging components are tested and
released, as per the most current Specifications and Procedures (as listed
in this agreement), and/or the approved Provigil marketing applications and
Standard Operating Procedures, prior to usage in the manufacturing of
Provigil drug product.
. The manufacturing and packaging is to be executed under the most current
Master Batch and Packaging Records (as listed in this agreement), that are
controlled through Circa's internal change control procedure.
. Compile and report the following Provigil specific information necessary
for the periodic product quality assessment:
- Investigations;
- Deviations;
- List of Provigil Lots Released;
- List of Provigil Lots Rejected;
- Product Complaints; and
- Product Stability
- In-Process and Finished Product Data Trends
- Retain Sample Evaluation
B. Change Control - Circa
Circa shall not implement, modify or delete any specification, process, or
procedure directly related to the manufacture or testing of Provigil Drug
Product, or change the equipment used, or change the vendors, without notifying
Cephalon or without prior written approval from Cephalon.
The following require joint Cephalon - Circa approval prior to implementation,
-------------------------
modification or deletion:
. Master Batch Formula: Master Blend
. Master Batch Formula: 100 mg Compression Process
. Master Batch Formula: 200 mg Compression Process
. Modafinil Raw Material Specification and Procedure: RM/MODAF
. In-Process Specification and Procedure: BL/MODAF
. Finish Product Specification and Procedure, Provigil Tablets, 100 mg FP/100
MODAF
. Finished Product Specification and Procedure, Provigil Tablets, 200 mg
FP/200 MODAF
. Stability Specification and Procedure, Provigil Tablets, 100 mg STAB/100
MODAF
. Stability Specification and Procedure, Provigil Tablets, 200 mg STAB/200
MODAF
. Raw Material Specification and Procedure for Magnesium Silicate (Compressil
RM 274)
RM/MAGSIL
. Master Packaging Record: Provigil Tablets, 100 mg Capsule Shaped
[LOGO OF CIRCA APPEARS HERE]
. Master Packaging Record: Provigil Tablets, 200 mg
. Other procedures, processes, and documentation exclusive to Provigil
manufacturing and testing operations...for example:
- Provigil Process Validation
- Provigil Cleaning Validation
The following require Cephalon notification prior to implementation,
---------------------
modification or deletion:
. "Spec & Pros" specific (but not exclusive) to the manufacturing and testing
operations of Provigil Drug Product.
. Raw Material Specifications and Procedure for the following:
Purified Water, USP: RM/Water <USP>
Isopropyl Alcohol, USP: RM/IPA
Providone K90D, USP: RM/PVP
Lactose Monohydrate, NF: RM/LACHY
Corn Starch, NF: RM/CRNSTR
Croscarmellose Sodium NF: RM/CRMLNA
Talc USP: RM/TALC
Magnesium Stearate, NF: RM/MAGSTR
. Other procedures, processes, and documentation specific to Provigil or the
Cephalon sponsored drug product applications...for example:
- Addition or deletion of a Circa qualified outside testing
laboratory
- Circa's facilities and equipment specific in the manufacturing
and testing of Provigil, including but not limited to:
[*]
C. SUMMARY DOCUMENTATION AND REPORTS - CIRCA
Circa shall provide Cephalon with documentation specific to the manufacturing
testing and quality review of Provigil drug product as indicated below. Upon
request, Circa shall provide any and all Provigil specific manufacturing,
testing, QA and distribution documentation (Lot File documentation).
At a minimum, a copy of the following documents shall be provided to Cephalon
prior to the initial shipment of each lot of Provigil final product:
* THE CONFIDENTIAL MATERIAL CONTAINED HEREIN HAS
BEEN OMITTED AND HAS BEEN FILED SEPARATELY
WITH THE COMMISSION.
[LOGO OF CIRCA APPEARS HERE]
Cephalon's Professional Services will receive and report adverse drug
experiences (ADEs). All spontaneous reports of adverse events received by Circa
or Cephalon will be directed to Cephalon as follows:
Cephalon, Inc.
Professional Services Representative
145 Brandywine Parkway
West Chester, PA 19380-4245
Telephone: 1-800-896-5855 Fax: 610-738-6313
. Cephalon's Professional Services will receive product quality complaints.
All product complaints received by Circa or Cephalon will be directed to
Cephalon's Professional Services as specified above. Cephalon will forward
all product quality complaints to Circa and processed in accordance with
Circa's drug quality complaint procedure.
. Cephalon's Quality Assurance is ultimately responsible for all Provigil
recall activities.
. Cephalon's will periodically monitor and audit Circa's manufacturing and
testing operations for compliance to the Provigil NDA and for compliance to
cGMP.
B. DOCUMENTATION AND REPORTS
. A copy of the Cephalon QA Provigil final product disposition will be sent
to Circa to effect the shipment of same lot to the designated distributor
(CORD).
. Cephalon will report all Provigil product quality complaints to Circa
within 10 working days of receipt.
/s/ Robert Urban 9/17/97
---------------------------------------------- ---------
Cephalon, Inc. Manufacturing Operations Date
/s/ Doug Claney 9/17/97
---------------------------------------------- ---------
Cephalon, Inc. Quality Assurance Date
/s/ [SIGNATURE ILLEGIBLE] 9/16/97
---------------------------------------------- ---------
Circa Pharmaceuticals, Inc. Regulatory Affairs Date
/s/ [SIGNATURE ILLEGIBLE] 9/16/97
---------------------------------------------- ---------
Circa Pharmaceuticals, Inc Quality Assurance Date
SCHEDULE D
----------
PRODUCT VALIDATION AND STABILITY TESTING PROCEDURES
---------------------------------------------------
The parties have agreed upon all those applicable specifications for Product
validation and stability testing as set forth in the following documents. Any
modifications to any such specifications shall be agreed upon by the parties.
DCRA # DOCUMENT # TITLE
------ ---------- -----
874 RD/RA/MODAF Residual Active Assay - Modafinil Cleaning
Validation
880 STAB/100MODAF Stability - Modafinil 100 mg Tablets
889 STAB/100MODAFEU Stability - Modafinil 100 mg Tablets (European)
883 STAB/200MODAF Stability - Modafinil 200 mg Tablets
875 STD/MODAF Requalification of Standard - Modafinil
PV-001-10047 Process Validation Protocol - Master Blend for
Modafinil 100 mg & 200 mg Tablets
PV-002-11047 Process Validation Protocol - Compression Process
for Modafinil 100 mg Tablets
PV-003-11047 Process Validation Protocol - Compression Process
for Modafinil 200 mg Tablets
PV-004-06057 Process Validation Protocol - Packaging Process for
Modafinil 100 mg & 200 mg Tablets
CV-003-21047 Cleaning Validation Protocol - Modafinil 200 mg
Tablets
-23-
SCHEDULE E
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TOLLING FEES
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CEPHALON shall pay CIRCA the following amounts in consideration of the
formulation and packaging services rendered hereunder:
BATCH PRICING COST/BATCH
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. A single lot per P.O. and delivery Date:
Provigil(R) 100 mg packed in 100 counts [*]
Provigil(R) 100 mg packed in 12 counts
Provigil(R) 200 mg packed in 100 counts
Provigil(R) 200 mg packed in 6 counts
. 3 or more of the same batch on a single P.O. with the same
delivery date:
Provigil(R) 100 mg packed in 100 counts [*]
Provigil(R) 100 mg packed in 12 counts
Provigil(R) 200 mg packed in 100 counts
Provigil(R) 200 mg packed in 6 counts
VOLUME DISCOUNTS:
----------------
A volume discount will be applied when a determined quantity of batches has been
purchased in a 12-month period starting with the anniversary date of the first
commercial batch. The determined quantities for the volume discounts are as
follows:
. [*] Batches: A [*] credit will be applied toward the next P.O.
for commercial batches.
. [*] Batches: A [*] credit will be applied toward the next P.O.
for commercial batches.
Beginning on the first anniversary of the effective date of this
Agreement and on each anniversary thereafter, the above tolling fees shall be
increased or decreased (as the case may be) by the percentage change from the
immediately proceeding anniversary date in the Producer Price Index (PPI) for
finished pharmaceutical preparations, ethical, as published by the Bureau of
Labor Statistics of the U.S. Department of Labor for the region in which the
production facility is located.
* THE CONFIDENTIAL MATERIAL CONTAINED HEREIN HAS
BEEN OMITTED AND HAS BEEN FILED SEPARATELY
WITH THE COMMISSION.
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Page 1 of 2
BUREAU OF LABOR STATISTICS DATA [LOGO]
DATA EXTRACTED ON: FEBRUARY 27, 1998 (11:28 AM)
PRODUCER PRICE INDEX-COMMODITIES
SERIES CATALOG:
Series ID: wpu06.35
Not Seasonally Adjusted
Group: Chemicals and allied products
Item: Preparations, ethical (prescription)
Base Date: 8200
DATA:
[Enlarge/Download Table]
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YEAR JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC ANN
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1998 162.6 163.4 166.0 167.1 168.2 167.5 168.9 169.8 172.0 172.6 175.1 174.5 169.0
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1989 177.4 177.6 180.3 182.1 182.1 183.4 184.6 187.4 187.7 189.0 190.0 191.1 184.4
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1990 193.1 196.4 197.4 199.5 201.2 199.4 201.0 202.4 202.4 204.4 205.4 206.5 200.8
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1991 208.7 211.5 212.1 216.6 216.7 216.8 219.4 220.8 219.5 223.2 222.5 222.6 217.5
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1992 225.2 227.5 228.5 230.5 230.8 231.3 232.3 234.4 233.2 235.0 234.4 236.9 231.7
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1993 237.2 239.7 240.0 242.1 241.5 241.7 242.8 244.2 243.5 244.9 244.0 244.5 242.2
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1994 247.9 248.5 248.6 249.2 250.7 250.3 249.2 250.2 250.7 250.3 251.9 252.0 250.0
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1995 251.3 253.6 253.3 256.2 255.9 255.4 256.8 257.1 258.8 261.3 261.6 262.6 257.0
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1996 262.3 262.2 263.1 263.4 265.6 266.3 267.1 266.9 266.5 266.6 266.6 267.9 265.4
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1997 270.2 271.0 271.9 271.6 272.7 273.2 273.4 273.5 273.9 275.4(P) 276.4(P) 276.9(P) 273.3(P)
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1998 279.4(P)
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P: Preliminary. All indexes are subject to revision four months after original
publication.
[GRAPH APPEARS HERE] DATA HOME PAGE
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Dates Referenced Herein and Documents Incorporated by Reference
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