1
Certain confidential material
contained in this document
has been omitted and
filed separately with the
Securities and Exchange Commission
EXHIBIT 10.4
MANUFACTURING AND SUPPLY AGREEMENT
UNITED STATES
This MANUFACTURING AND SUPPLY AGREEMENT ("Agreement") is made as of July
31, 1998, by between RENAGEL LLC, a Delaware limited liability company
("Customer") and CIRCA PHARMACEUTICALS, INC., a New York corporation ("Circa").
RECITALS:
A. Circa owns and operates a pharmaceutical manufacturing and packaging
facility located at 33 Ralph Avenue, Copiague, New York, and wishes to perform
certain manufacturing and packaging services for Customer.
B. Customer requires a manufacturer to perform the following services:
compounding, encapsulating, packaging, labeling, analytical and stability
testing; and Circa is willing to perform such services for and on behalf of
Customer, all subject to the terms and conditions of this Agreement.
NOW, THEREFORE, in consideration of the promises contained herein and
other valuable considerations, and intending to be bound hereby, the parties
agree as follows:
1. DEFINITIONS.
1.1 DEFINITIONS. As used in this Agreement, the following terms shall
have the corresponding meanings set forth below:
(a) "FDA" means the U.S. Food and Drug Administration.
(b) "GMPs" means the current Good Manufacturing Practices
promulgated by the FDA.
(c) "BULK PRODUCT" means sevelamer hydrochloride as described
in EXHIBIT A hereto, with such amendments thereto as the parties may from time
to time approve in writing.
(d) "PPI" means the Producer Price Index for finished
pharmaceutical preparations, ethical, as published by the Bureau of Labor
Statistics of the U.S. Department of Labor.
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(e) "PRODUCTION FACILITY" means the facility of Circa located
in Copiague, New York.
(f) "PRODUCTION PROCEDURES" means the procedures used to
compound and encapsulate, the Bulk Product and package the Final Product into
bottles conducted in accordance with GMP's and Circa's standard operating
procedures as provided to Customer.
(g) "BULK SPECIFICATIONS" means the specifications for the
Bulk Product as described in EXHIBIT A, with such amendments thereto as the
parties may from time to time approve.
(h) "PRODUCT" shall mean collectively, the Bulk Product and
the Final Product.
(i) "FINAL PRODUCT" means the finished product in 403 mg
capsule form as described in the Final Specifications and in EXHIBIT B hereto,
with such amendments thereto as the parties may from time to time approve in
writing.
(j) "REGULATORY STANDARDS" means (i) the facility license
requirements of the FDA and other regulatory agencies applicable to the
Production Facility or Circa's production, storage or handling of Bulk Product
or Final Product at the Production Facility, and (ii) any standards and
regulations of any governmental authority, whether within or outside the United
States (including, without limitation, the Environmental Protection Agency,
OSHA, the Food and Drug Administration, and state and local authorities), that
apply to the Production Facility or Circa's production, storage or handling of
Bulk Product or Final Product.
(k) "TECHNICAL AGREEMENT" means the Technical Agreement for
the Commercial Manufacture and Testing of RenaGel(R) Drug Product attached
hereto as Exhibit D. The terms and conditions of the Technical Agreement are
incorporated herein by reference.
(l) "FINAL SPECIFICATIONS" means the production and quality
control specifications for the Final Product, all as set forth in EXHIBIT B
hereto with such amendments thereto as the parties may from time to time approve
in writing.
(m) "TERRITORY" means the United States.
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2.0 TERMS OF ENGAGEMENT.
2.1 Subject to the provisions of this Agreement, Customer hereby
appoints Circa as a non-exclusive manufacturer of the Final Product for the
Territory, and Circa hereby accepts such appointment and agrees to act as such
non-exclusive manufacturer.
2.2 Customer agrees that the annual minimum amount of Final Product
which Customer is obligated to order and purchase from Circa during each
calendar year during the term of this Agreement shall be *********************
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2.3 For purposes of the Agreement, Customer shall supply, or cause
its contract manufacturer to supply, Circa with sufficient quantities of tested
and released Bulk Product which meet the Bulk Specifications, the costs of which
shall be borne by Customer. All such supplies shall be sent to Circa at
Customer's expense, F.O.B. the Production Facility of Circa. All other materials
required for the production, labeling and shipping of the Final Product for
Customer will be supplied by Circa, and the parties acknowledge that the cost of
such materials is included in the batch pricing listed on Exhibit C. Circa
agrees that the labels utilized in packaging the Final Product will conform to
the label copy provided by Customer.
2.4 Circa agrees that it will use reasonable commercial efforts to
minimize the Bulk Product waste associated with the manufacture of Final
Product. Promptly after Circa has completed the manufacture of a total of ten
(10) batches of Final Product, including batches manufactured for validation
purposes, the parties shall establish a required Bulk Product to Final Product
yield and shall attach such requirements as Exhibit E hereto. Should Circa fail
to achieve the required yield, Circa shall be responsible for compensating
Customer for the wasted Bulk Product either through a credit on the cost of
Final Product, or through reimbursement directly to Customer, at Customer's
discretion. In the event that Circa fails to achieve the required yield with
respect to more than ***************** of the batches produced during any one
period of *
* Confidential Information omitted and filed separately with the Commission.
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*********** such consistent failure shall be considered to be a material breach
of this Agreement.
2.5 Customer shall be invoiced at Circa's out-of-pocket costs for any
tooling and materials required for the manufacture, testing and packaging of the
Products in accordance with the terms of this Agreement, provided that prior to
such purchase, Circa and Customer shall agree in writing on the specifications
and cost of any such equipment and materials, and provided further, that
Customer shall only be responsible for the cost of tooling and materials that
will be used exclusively for the manufacture, testing and packaging of the
Products.
2.6 Prior to the execution of this Agreement, Customer purchased an
*******************************************************************************
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purpose of manufacturing Final Product for Customer under the terms of this
Agreement. Notwithstanding Circa's use of the ***** Customer shall at all times
remain the owner of the ****. Circa shall, at its expense, service and maintain
the **** in a manner consistent with the way in which it services and maintains
the machinery located at the Production Facility and owned by Circa. At such
time as Circa is no longer producing product for Customer under this Agreement,
Customer shall have the right to enter the Production Facility and remove the
****.
3.0 MANUFACTURE OF PRODUCT
3.1 During the term of this Agreement, Circa shall receive Bulk
Product from Customer or Customer's contract manufacturer and shall test such
Bulk Product for conformance to the Bulk Specifications. Upon acceptance, Circa
shall store Bulk Product in accordance with Regulatory Standards. Circa shall
complete the testing of Bulk Product within fifty (50) days of its receipt. If
Circa determines that the Bulk Product does not conform to the Specifications or
if the shipment of Bulk Product contains a quantity of Bulk Product that is less
than the reported or expected amount, Circa shall provide written notice to
Customer of such defect, nonconformance and/or shortage within fifty-five (55)
days of Circa's receipt of the Bulk Product. Simultaneously with the provision
of notice to Customer, Circa shall provide written notice of the defect,
nonconformance and/or shortage to the Customer's Bulk Product contract
manufacturer. Customer shall provide Circa with written instructions regarding
the address for such notice.
3.2 During the term of this Agreement, Circa will manufacture and
deliver to Customer the Final Product ordered by Customer pursuant to the terms
of this Agreement. All Final Product shall be produced at the Production
Facility. All Final Product produced by Circa under this Agreement shall be
produced in accordance with
* Confidential information omitted and filed separately with the Commission.
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the Production Procedures, the Final Specifications, GMP's and all other
applicable regulatory requirements, and the Technical Agreement.
4.0 FEE PRICE AND PAYMENT TERMS.
4.1 As set forth in Exhibit C.
4.2 Beginning on the first anniversary of the initial shipment of the
Final Product by Circa and on each such anniversary thereafter, the Fee shall be
increased or decreased by the percentage change in *************************
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***********************************************************************
**************************** For example, ******************************
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******** for the second year of the term of this Agreement over the price
charged in the preceding year.
4.3 Except as set forth in Section 13.5, payment for each delivery of
the Final Product to Customer will be made within thirty (30) days after the
date of Circa's invoice, to be rendered concurrently with delivery of the Final
Product. All payments required to be paid hereunder shall be made by corporate
check or by wire transfer of immediately available funds to the financial
institution, account number, and account party's name designated in writing by
Circa to Customer at the place of payment.
4.4 Customer shall reimburse Circa for any federal, state, or local
excise or other tax or assessment, which Circa may be required to pay upon the
sale, production, transportation, or use of the Product (excluding taxes based
on Circa's income or Circa's franchise fees or taxes).
5.0 RESPONSIBILITIES OF CUSTOMER; WARRANTIES.
5.1 Customer will supply the Bulk Specifications and the Final
Specifications and all necessary quality control test specifications for the
Product, which must be approved by Circa (which approval will not be
unreasonably withheld or delayed).
5.2 Customer represents that Circa is not required to maintain a
dedicated facility for the manufacture of the Product.
5.3 Circa will be responsible for maintaining, on behalf of Customer,
the retention samples of the Final Product required by applicable Regulatory
Standards.
* Confidential information omitted and filed separately with the Commission.
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6.0 RESPONSIBILITIES OF CIRCA; WARRANTIES.
6.1 Circa represents and warrants that the testing of the Bulk
Product will conform to the applicable requirement of the Regulatory Standards
and that the Bulk Product will be stored and controlled by Circa in accordance
with applicable Regulatory Standards.
6.2 Circa represents and warrants that its production procedures
(including the Production Procedures) will conform to the applicable
requirements of the Regulatory Standards. Circa warrants that each shipment of
the Final Product will conform to the Final Specifications and will be made,
stored and controlled by Circa in accordance with applicable Regulatory
Standards and the process and procedures contained in the Production Procedures
and the Technical Agreement.
6.3 Circa represents and warrants that the Final Product shall (i) be
free from defects in material and workmanship, (ii) not be adulterated or
misbranded and (iii) be sold free and clear of any liens, claims or
encumbrances, and that the labels obtained by Circa will conform to the label
copy provided and approved by Customer.
6.4 Circa has previously furnished Customer with a copy of its
Production Procedures and has identified to Customer the equipment to be used to
produce the Final Product. Circa shall not (i) modify the Production Procedures,
(ii) modify any method of manufacturing or testing the Bulk Product or the Final
Product, (iii) change or relocate any equipment used in the production of a
Product, or (iv) change a vendor for any components or raw materials used in the
Final Product, in each case, without obtaining Customer's prior written consent.
6.5 Customer or its authorized designee will have the right, during
Circa's normal hours of operation, to inspect the Production Facility and
Circa's records relating to Circa's manufacturing, packaging, and testing of the
Product. Circa shall take appropriate actions to adopt reasonable suggestions of
Customer to correct any deficiencies identified by such inspection or audit. To
supplement this provision, Customer also may arrange, at its cost and expense,
to have a Customer employee or other representative located on the premises of
the Production Facility participate in the monitoring of Product production,
testing and packaging under this Agreement. All information acquired pursuant to
the provisions of this paragraph are subject to the requirements of
confidentiality as contained in the Confidentiality Agreement of even date
herewith.
6.6 Circa will cooperate with Customer and any governmental authority
in evaluating any complaint, claim, or adverse drug reaction report related to
the production
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of a Product, and shall provide information and data and take such other steps
as may be appropriate to resolve any identified problems.
6.7 As may be further discussed in the Technical Agreement, Circa
will provide Customer with timely notification of all 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.
7.0 RECORDS, REGULATORY MATTERS.
7.1 Circa will maintain complete and accurate records relating to the
Product and the manufacture, packaging, and testing thereof for the period
required by applicable Regulatory Standards, and Circa shall provide copies
thereof to Customer upon Customer's request. Without limiting the generality of
the foregoing, Circa shall (i) perform quality assurance and control tests on
each lot of Final Product manufactured before delivery and shall prepare and
deliver to Customer a written report of the results of such tests, with each
report setting forth for each lot delivered the items tested, specifications and
results in a certificate of analysis containing the type of information which is
required by the Federal Food and Drug Administration ("FDA") and (ii) prepare
and maintain for a period of no less than five (5) years and for so long as
required under applicable requirements of the FDA for each lot of Final Product
manufactured a certificate of manufacturing compliance containing the types of
information that is required by the FDA, which certificate will certify that the
lot of Final Product was manufactured in accordance with the Final
Specifications and GMPs.
7.2 Circa will supply for each batch of Final Product, including each
pilot batch, complete batch production and control records.
7.3 Circa shall ensure that the Production Facility and the equipment
and personnel used to manufacture Product are now, and at the time each batch of
Final Product is produced shall be, maintained in a professional and workmanlike
manner, consistent with generally accepted industry standards. Circa represents
and warrants that (i) the Production Facility is in compliance with all
applicable material requirements of the Regulatory Standards, and (ii) there are
no pending or uncorrected citations or adverse conditions noted in any
inspection of the Production Facility which would cause the Final Product to be
misbranded or adultered within the meaning of the Act.
7.4 In addition to any authorizations required under Section 7.3,
Circa has obtained all other licenses, authorizations and approvals required by
any federal, state or local governmental authority for the production of the
Product, and the Production Facility complies with all laws, rules and
regulations applicable to it,
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7.5 Circa shall promptly notify Customer if the FDA or other
regulatory authority visits or makes written or oral inquiries about the
Production Facility or Circa's procedures to the production, testing, packaging,
labeling, storage or handling of a Product. Circa shall furnish Customer, within
thirty (30) days after receipt, a copy of any report or correspondence issued by
the governmental authority in connection with such visit or inquiry, purged only
of confidential information that is unrelated to the Product or the activities
under this Agreement.
8.0 TERM.
8.1 This Agreement shall be effective as of the date hereof and shall
continue for ********* from the first shipment of the Final Product in
interstate commerce with FDA approval, subject to earlier termination in
accordance with the terms hereof. Thereafter it will be automatically renewed
for successive one (1) year terms unless terminated by Customer by written
notice given no less than *********** before the end of the term or any renewal
term hereof.
9.0 DELIVERY.
9.1 To assist Circa in scheduling production for the manufacture of
the Final Product, Customer shall provide to Circa, quarterly, a nine month
rolling forecast of its requirements for a Final Product. The first forecast
shall be provided by Customer to Circa approximately six months prior to the
anticipated market launch of the Final Product, as reasonably estimated by the
parties, and thereafter shall be provided to Circa on or before the 20th day of
the first month of each successive quarterly period (to forecast the
requirements for the next nine succeeding calendar months). It is understood and
agreed that all forecasts are estimates only and Customer shall only be bound to
purchase the Final Product pursuant to orders submitted by it to Circa. All
purchase orders shall be for minimum batch size quantities reasonably agreed by
the parties and shall anticipate an order/production/availability cycle of
approximately *************.
9.2 Circa will arrange for shipping and/or transportation for the
Final Product from Circa's Production Facility; provided, however, that Customer
may provide Circa with specific shipping instructions and direct the use of a
specific carrier, and Customer will reimburse Circa for all shipping and related
costs. Risk of loss and title to the Final Product shall pass to Customer upon
pick-up of the Final Product by, on behalf of, or for the account of Customer at
Circa's Production Facility.
10.0 INVENTIONS.
10.1 Any inventions or discoveries made by Circa in the performance of
this
* Confidential information omitted and filed separately with the Commission.
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Agreement that relate exclusively to the Product (including any new use or any
change in the method of producing, testing or storing the Product) shall be
owned by Customer. Any other invention or discovery made by Circa in the
performance of this Agreement shall be owned by Circa, but Customer shall have a
nonexclusive, perpetual, nontransferable, paid-up license (with the right to
sublicense) to use any such worldwide 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 and other intellectual property rights
related to any such invention.
11.0 GENERAL INDEMNITIES.
11.1 Circa will indemnify and hold Customer harmless from any and all
liability, damage, loss, cost, or expense (including reasonable attorney's fees)
which arise from (i) Circa's breach of any of its agreements, representations,
or warranties contained herein, (ii) Circa's negligence or other wrongful
conduct as determined by a court of competent jurisdiction or (iii) a claim that
the Production Procedures utilized by Circa to manufacture the Final Product
infringe a United States patent or any other proprietary rights of any third
party. Upon learning of any such claim or suit, Customer shall immediately
notify Circa.
11.2 Customer will indemnify and hold Circa harmless from any and all
liability, damage, loss, cost, or expense (including reasonable attorneys' fees)
which arise from (i) Customer's breach of any of its agreements,
representations, or warrants contained herein, (ii) Customer's negligence or
Customer's other wrongful conduct as determined by a court of competent
jurisdiction or (iii) a claim (other than a claim that is covered by Section
11.1 (iii) above, that the manufacture of the Product by Circa in accordance
with this Agreement infringes a United States patent or any other proprietary
rights of any third party. Upon learning of any such claim or suit against it,
Circa shall immediately notify Customer.
11.3 The parties will cooperate with each other in the defense of any
claim or action.
11.4 No indemnifying party hereunder will be liable for any costs
associated with the settlement of any claim or action brought against it or the
other party unless it has received prior notice of the settlement negotiations
and has agreed to the settlement in writing.
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12.0 INSURANCE.
12.1 Each of Circa and Customer (or Customer's Members) shall carry
product liability insurance in an amount at least equal to *********** with an
insurance carrier reasonably acceptable to the other party, such insurance to be
in place at times reasonably acceptable to the parties, but not later than the
date of the first commercial sale of a Product. Each party shall promptly
furnish the other evidence of the maintenance of the insurance required
hereunder and shall name the other as an "additional insured" under such
insurance policy. Each party's coverage shall (i) include broad form vendor
coverage and such other provisions as are typical in the industry and (ii) name
the other party as an additional insured thereunder.
13.0 PRODUCT ACCEPTANCE.
13.1 Circa shall manufacture the Final Product and make it available
for pick up in accordance with all applicable laws, rules and regulations
including, without limitation, the Final Specifications and all other applicable
requirements of the FDA and other governmental authorities having jurisdiction.
All Products shipped to Customer shall be accompanied by quality control
certificates of analysis signed by a duly authorized laboratory official of
Circa confirming that each batch of Products covered by such certificate meets
its release Final Specifications and shall be deemed accepted by it unless
Customer, acting reasonably and in good faith, shall give written notice of
rejection (hereafter referred to as a "Rejection Notice") to Circa within 35
days after pick up of the Product by, on behalf of, or for the account of
Customer at Circa's facility.
13.2 The Rejection Notice shall state in reasonable detail (sufficient
to enable Circa to identify the nature of the problem and the tests or studies
to be conducted by or on its behalf to confirm or dispute same) the reason why
the Final Product is not acceptable to Customer. If the Final Product meets the
applicable provisions of the Final Specifications, has been manufactured in
accordance with representations and warranties provided herein is labeled as
required by the Customer and is provided in quantities specified in a purchase
order, Customer shall not be entitled to reject it. Any Rejection Notice shall
be accompanied by copies of all written reports relating to tests, studies or
investigations performed to that date by or for Customer on the Final Product
batch rejected.
13.3 Upon receipt of such Rejection Notice, Circa may require Customer
to return the rejected Final Product or samples thereof to Circa for further
testing, in which event such Final Product or samples thereof as the case may
be, shall be returned by Customer to Circa. If it is later determined by the
parties or by an independent laboratory or consultant that Customer was not
justified in rejecting the Final Product or that Customer was the cause of or
was responsible for the problem, Customer shall reimburse
* Confidential information omitted and filed separately with the Commission.
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Circa for the costs of the return, as well as any other costs or expenses
incurred by Circa as a result of the rejection or return.
13.4 Customer's test results or basis for rejection shall be
conclusive unless Circa notifies Customer, within 35 days of receipt by Circa of
the rejected Final Products or samples that it disagrees with such test results
or its responsibility for the problem in question. In the event of such a notice
by Circa, representative samples of the batch of the Final Products in question
shall be submitted to a mutually acceptable independent laboratory or consultant
(if not a laboratory analysis issue) for analysis or review, the costs of which
shall be paid by the party that is determined by the independent laboratory or
consultant to have been incorrect in its determination of whether the Final
Product should be rejected.
13.5 If any order of Final Product is rejected by Customer, Customer's
duty to pay all amounts payable to Circa in respect of the rejected Final
Product shall be suspended until such time as it is determined (i) by an
independent laboratory or consultant that the Final Products in question should
not have been rejected by Customer or (ii) by the parties or by any arbitration
conducted pursuant hereto or by a final order of a court of competent
jurisdiction (which is not subject to further appeal) that any act or omission
of, on behalf of or for which Customer is responsible was the cause of the
problem that was the basis for the rejection. If only a portion of an order is
rejected, only the duty to pay the amount allocable to such portion shall be
suspended.
13.6 In the event any Final Product is appropriately rejected by
Customer, Circa shall replace such Final Product with conforming goods and shall
be fully responsible for all costs associated with replacing such Final Product,
including the cost of the Bulk Product required to replace the Final Product or,
if requested by Customer, shall provide a credit to Customer for the amount, if
any, previously paid by Customer to Circa on account of the Final Product in
question and for the full cost of replacing the Bulk Product utilized in the
manufacture of the Final Product in question, including any wasted Bulk Product.
The credit shall be provided by Circa to Customer immediately following the
expiration of the period during which Circa may dispute a Rejection Notice as
contemplated above (unless the Rejection Notice is disputed by Circa, in which
event such credit shall be given only if the dispute is resolved in favor of
Customer). Replacement Products, as aforesaid, shall be delivered to Customer at
no cost to Customer if Customer has already paid for the rejected Products and
not received a credit therefor, as aforesaid. All delivery costs, including
insurance, incident to the return of Final Products to Circa and delivery of the
replacement Final Products to Customer's order shall be paid by Circa, unless
the rejection is determined not to have been appropriately rejected, in which
case Customer shall reimburse Circa for the costs of the return, as well as any
other costs or expenses incurred by Circa as a result of the rejection or
return.
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14.0 FORCE MAJEURE.
14.1 Neither Customer nor Circa shall be in default in the performance
of their obligations hereunder to the extent that such performance is delayed or
prevented by an act of God, weather conditions, strikes, lockouts, inability to
procure labor, materials, or fuels due to shortages, fires, riots, interference
by civil or military authorities, or acts of war (declared or undeclared), or
any other cause which is beyond the reasonable control of either party; provided
however, that should Circa experience a Force Majeure event which results in its
inability to perform under this Agreement, Customer's minimum purchase
obligations set forth in Section 2.2 shall be waived for the period during which
the Force Majeure event continues and the annual minimum purchase obligation
shall be adjusted accordingly. Should Circa be unable to perform hereunder due
to a Force Majeure event that continues for more than ****************, Customer
shall be entitled to terminate this Agreement immediately thereafter.
15.0 TERMINATION.
15.1 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 the breach
prior to the termination date (or such longer period not to exceed an additional
sixty (60) days after the end of the aforementioned 60-day period reasonably
necessary to cure such breach, provided that the breaching party is making
diligent efforts to cure such breach), the Agreement shall terminate.
15.2 Notwithstanding the foregoing, (i) if Customer fails to pay any
sums owed hereunder within thirty (30) days after Circa has notified Customer
that such sums are past due, Circa may terminate this Agreement immediately, and
(ii) if either party should become insolvent or seek relief under any
bankruptcy, debtor relief, or similar law or if any proceeding against either
party under any such law remains in effect for a period of thirty (30)
consecutive days, the other party may terminate this Agreement immediately.
15.3 Any termination of the Agreement shall not release the parties
from any liabilities and obligations accrued as of the date thereof.
15.4 Sections 10.0, 11.0, 12.0 and this 15.4 and any other provisions
required to interpret and enforce the parties' rights and obligations under this
Agreement shall survive the termination of this Agreement to the extent required
for the full observation and performance of this Agreement by the parties in
accordance with its terms.
* Confidential information omitted and filed separately with the Commission.
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16.0 NON-WAIVER OF RIGHTS.
16.1 Failure by Circa or Customer to enforce the terms and conditions
of the Agreement shall not affect or impair such terms or conditions, or the
right of Circa or Customer to avail itself of such remedies as it may have for
any breach of such terms or conditions under the provisions of this Agreement,
in equity or at law.
17.0 NOTICES.
17.1 Any notice given under this Agreement shall be deemed adequate if
made by facsimile (with confirmation of transmission), and certified mail or
registered mail, return receipt requested, postage prepaid, or by reputable
overnight courier (with evidence of delivery), and addressed as follows:
TO CIRCA: CIRCA PHARMACEUTICALS, INC.
33 Ralph Avenue
Copiague, New York 11726-0030
Attention: Steven J. Martinez
Telephone Number: 516-842-8383
Facsimile Number: 516-842-8630
TO CUSTOMER: RENAGEL LLC.
c/o GelTex Pharmaceuticals, Inc.
Nine Fourth Avenue
Waltham, Massachusetts 02154
Attention: Joseph E. Tyler
Telephone Number: 781-290-5888
Facsimile Number: 781-290-5890
or to such other address as either of the parties shall designate by notice
given as herein required.
18.0 AMENDMENTS AND WAIVER.
18.1 This Agreement cannot be amended in any respect except in writing
duly executed by both parties. No waiver of compliance with any provisions or
conditions of this Agreement and no approvals provided for in this Agreement
shall be effective unless evidenced by a written instrument executed by the
party waiving or approving, as applicable.
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19.0 ASSIGNMENT.
19.1 Neither party hereto shall assign this Agreement or any part
thereof or any interest herein without the written approval of the other party
hereto; however, in the event of a merger, acquisition or sale substantially of
all the assets of Customer, the rights and obligations of Customer under this
Agreement may be assigned to the survivor or purchaser in the transaction.
20.0 GOVERNING LAW.
20.1 This Agreement shall be governed by the law of the State of New
York, without respect to conflict of law principles.
21.0 ENTIRE AGREEMENT.
21.1 This writing and the Confidentiality Agreement of even date
herewith constitute the entire understanding between the parties and shall
supersede any prior agreements between them. Each party acknowledges that there
are no other understandings which relate to the matters covered herein or in
such Confidentiality Agreement or which are inconsistent with any provisions of
the Agreement.
22.0 PARTIES INDEPENDENT.
22.1 In making and performing this Agreement, the parties act and
shall act at all times as independent entities and nothing contained in this
Agreement shall be construed or implied to create an agency, partnership or
employer and employee relationship between Circa and Customer. Except as
specifically provided herein, at no time shall either party make commitments or
incur any charges or expenses for or in the name of the other party.
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IN WITNESS WHEREOF, the parties hereto have executed this Agreement in
duplicate as of on the date and year written.
CIRCA PHARMACEUTICALS, INC.
By: /s/ Steven J. Martinez
---------------------------------
Steven J. Martinez
Vice President/General Manager
RENAGEL LLC
By: GELTEX PHARMACEUTICALS, INC.,
Its Member
By: /s/ Mark Skaletsky
---------------------------------
Name: Mark Skaletsky
---------------------------------
Title: President
---------------------------------
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EXHIBIT A
BULK PRODUCT DESCRIPTION AND SPECIFICATIONS
SEVELAMER HCL
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************ ******** ********
**************** ********* ********
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******************** *************************** ********
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********* ************* *******
**************** ********* *******
************** ***************************************** *******
*********
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***** ******************************************************************
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****************************.
* Confidential information omitted and filed separately with the Commission.
16
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EXHIBIT B
FINAL PRODUCT DESCRIPTION AND SPECIFICATIONS
RENAGEL(R) 403 MG CAPSULES
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* Confidential information omitted and filed separately with the Commission.
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18
EXHIBIT C
FEES & PAYMENT TERMS
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* *****************************
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* *****************************************
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* *********** ******************************************************
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* ************************************************************************
************
* Confidential information omitted and filed separately with the Commission.
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19
EXHIBIT D
RENAGEL - CIRCA TECHNICAL AGREEMENT
FOR THE COMMERCIAL MANUFACTURING AND TESTING
OF RENAGEL(R) DRUG PRODUCT
1. PURPOSE AND SCOPE
This document serves to define the quality responsibilities and requirements
between RenaGel LLC and Circa Pharmaceuticals, Inc. ("Circa") for the commercial
production of RenaGel(R) capsules for distribution in the United States. RenaGel
LLC and Circa agree that GelTex Pharmaceuticals, Inc. ("GelTex"), a Member of
RenaGel LLC, will be responsible for all obligations that would otherwise be
assigned to RenaGel LLC, and will be the recipient of all notices Circa agrees
to provide hereunder. GelTex, by signature below, acknowledges these obligations
and agrees to perform the functions detailed below and agrees to receive notices
on behalf of RenaGel LLC. GelTex is the sponsor of the RenaGel NDA, 20-926, in
which the chemistry, manufacture, and control of RenaGel capsules is described.
Circa is a commercial manufacturer of RenaGel capsules. This document is
attached to the Manufacturing and Supply Agreement between RenaGel LLC and Circa
and the terms and conditions are incorporated therein by reference.
2. DEPARTMENTS AFFECTED
Quality Assurance - GelTex Quality Assurance - Circa
Operations - GelTex Quality Control - Circa
Regulatory Affairs - GelTex Operations - Circa
Regulatory Affairs - Circa
3. RESPONSIBILITY
GelTex is the NDA sponsor and is responsible for the adherence, maintenance and
upkeep of the NDA. Circa is a listed manufacturer of RenaGel capsules and is
responsible for the manufacture, testing, and packaging of RenaGel capsules in
compliance with the NDA. It is the responsibility of the Quality Assurance
management at GelTex and Circa, in cooperation with Manufacturing Operations,
Quality Control and Regulatory Affairs, to assure compliance with this
agreement.
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4. CIRCA PHARMACEUTICALS RESPONSIBILITIES
Circa will follow its own internal Standard Operating Procedures (SOPs) in the
fulfillment of its responsibilities. Execution of these responsibilities are in
accordance with all pertinent federal regulations and guidelines and the
approved RenaGel NDA, 20-926.
4.1. Production
- Manufacture and test RenaGel drug product in accordance with
GMPs, applicable contracts, approved RenaGel NDA, and any other
regulatory filings.
- Perform a Quality review of every lot of RenaGel drug product and
subsequently release or reject the lot in accordance with GMPs.
- All initial and stability testing of both active ingredient and
finished dosage forms and release and retest of inactive
components are performed by the Circa Quality Control Department
or approved designees as cited in the NDA in accordance with
approved specifications and procedures as submitted in the
approved RenaGel marketing applications and protocols for RenaGel
drug product.
- To assure that all packaging components are tested and released
as per the most current Specifications and Procedures and/or the
approved RenaGel marketing applications and Standard Operating
Procedures, prior to usage in the packaging of RenaGel drug
product.
- The manufacturing and packaging is to be executed under the most
current Master Batch and Packaging Records.
4.2. Change Control
Circa Pharmaceuticals will notify GelTex Pharmaceuticals of any proposed
change in the manufacturing, testing, or packaging of RenaGel capsules,
prior to implementation, which may affect the quality of RenaGel
capsules or impact any applicable contracts, the RenaGel NDA, or other
RenaGel regulatory filings. Circa Pharmaceuticals will not implement any
changes in the manufacturing, testing, or packaging of RenaGel capsules
without GelTex Pharmaceuticals' written approval.
The following require GelTex Pharmaceuticals' approval prior to
implementation, modification or deletion including, but not limited to:
21
- Master Batch Formula
- Sevelamer Hydrochloride Raw Material Specification and Procedure
- In-Process Specification and Procedures
- Finished Product Specification and Procedure, RenaGel capsules,
403 mg
- Stability Specification and Procedure, RenaGel capsules, 403 mg
- Master Packaging Record: RenaGel Capsules, 403 mg, 60 units
- Master Packaging Record: RenaGel Capsules, 403 mg, 200 units
- Label Text and Design
- Excipient Manufacturers
- Outside Laboratories
- Packaging and Labeling Manufacturers and Materials
- Other procedures, processes, and documentation exclusive to RenaGel
manufacturing and testing operations...for example:
- RenaGel Process Validation
- RenaGel Cleaning Validation
- Other Operations described in the RenaGel NDA
The following require GELTEX NOTIFICATION prior to implementation,
modification or deletion:
- Inactive raw materials specifications and procedures.
- Circa's facilities and equipment applicable to the manufacturing
and testing of RenaGel.
4.3. Deviations
Circa Pharmaceuticals will notify GelTex Pharmaceuticals of deviations
in the manufacture and testing of RenaGel capsules prior to deciding the
outcome of the deviation, unless the nature of the deviation requires
immediate determination. If the disposition determination requires
immediate action, Circa Pharmaceuticals will notify GelTex
Pharmaceuticals as soon as reasonably possible after the deviation has
occurred.
4.4. Regulatory Inspections
Circa Pharmaceuticals will notify GelTex Pharmaceuticals of any
impending inspection by a regulatory agency or unannounced regulatory
inspection, which is related to the RenaGel NDA or other RenaGel
regulatory documents. Circa Pharmaceuticals will inform GelTex
Pharmaceuticals as to the outcome of any regulatory inspection within
ten business days.
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4.5. Postmarketing Adverse Events and Complaints
Circa Pharmaceuticals' representative will notify Genzyme of any product
quality complaints pertaining to RenaGel capsules within ten business
days. Complaints which may constitute an NDA field alert per 21 CFR
314.80 will be reported to Genzyme within 48 hours. GelTex
Pharmaceuticals is responsible for recalls.
Circa Pharmaceuticals will notify Genzyme Corporation of any adverse
events, serious adverse event within 48 hours.
4.6. Annual Reports
Circa Pharmaceuticals will supply to GelTex Pharmaceuticals with annual
report data summarizing the manufacture and testing of RenaGel capsules
thirty to sixty days prior to the annual RenaGel NDA approval
anniversary or other regulatory filing anniversaries.
4.7. Annual Product Review Report
The RenaGel specific information necessary for the periodic product
quality assessment (at least annually) includes, but is not limited to:
- Investigations
- Deviations
- Out-of-specification results
- QA product disposition
- List of RenaGel Lots Released
- List of RenaGel Lots Rejected
- Product Complaints, and
- Product Stability
- In-Process and Finished Product Data Trends
- Retain Sample Evaluation
4.8. Summary Documentation and Reports
Circa Pharmaceuticals shall provide GelTex Pharmaceuticals with
documentation specific to the manufacturing, testing and quality review
of RenaGel capsules as indicated below prior to distribution of the drug
product. Circa shall not release for shipment a lot of RenaGel capsules
prior to written approval for GelTex Pharmaceuticals.
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At a minimum, a copy of the following documents shall be provided to
GelTex prior to the initial shipment of each lot of RenaGel final
product:
- Quality Control Raw Material Release Report of each lot of sevelamer
hydrochloride drug substance, stearic acid, colloidal silicon
dioxide, and hard gelatin capsules tested and released for use in
the manufacturing of RenaGel drug product.
- Quality Control Release Report for each lot of RenaGel drug product.
- The executed batch record for every lot of RenaGel drug product.
- The executed packaging record for every lot of RenaGel drug
product(s).
- Circa's release documentation for manufactured and packaged RenaGel
drug product.
- All investigations, incident reports, anomaly reports associated
with the manufacturing, testing, and packaging of every lot of
RenaGel.
The following documents shall be provided to GelTex Pharmaceuticals on a
schedule mutually agreed to by Circa Pharmaceuticals and GelTex
Pharmaceuticals or on an as needed basis:
- Stability Reports
5. GELTEX PHARMACEUTICALS RESPONSIBILITIES
GelTex Pharmaceuticals and GelTex Pharmaceuticals representatives will follow
their own internal Standard Operating Protocols (SOPs) in the fulfillment of its
responsibilities. Execution of these responsibilities will be in accordance with
all pertinent federal regulations and guidelines and the approved RenaGel NDA,
20-926.
5.1. Lot Disposition
GelTex Pharmaceuticals Quality Assurance shall review the RenaGel
summary lot file documentation prior to market distribution.
Documentation of the sponsor review and disposition will be provided to
Circa Pharmaceuticals prior to the shipment of the lot to the designated
distributor.
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5.2. Audits
GelTex Pharmaceuticals and/or a GelTex Pharmaceuticals representative
will periodically audit Circa Pharmaceuticals to ensure compliance with
this document, cGMPs, RenaGel NDA, and any other RenaGel regulatory
filings.
5.3. Postmarketing Adverse Events and Complaints
GelTex Pharmaceuticals or a GelTex Pharmaceuticals representative will
notify Circa Pharmaceuticals of any product quality complaints
pertaining to RenaGel capsules within ten business days.
Complaints which may constitute an NDA field alert per 21 CFR 314.80
will be reported to Circa within 48 hours. GelTex Pharmaceuticals is
responsible for recalls.
GelTex Pharmaceuticals or a GelTex Pharmaceuticals representative will
notify Circa Pharmaceuticals of any adverse events, serious adverse
event within 48 hours.
5.4. Change Control
GelTex Pharmaceuticals or a GelTex Pharmaceuticals representative will
notify Circa Pharmaceuticals prior to implementation of any changes in
the RenaGel NDA, other regulatory filings, or commitments made to the
regulatory authorities pertaining to the manufacture, testing, and
packaging of RenaGel capsules. GelTex Pharmaceuticals will be
responsible for notifying of the other regulatory filings, or
commitments made to the regulatory authorities pertaining to Circa's
manufacture, testing and packaging of control or RenaGel capsules.
GelTex Pharmaceuticals will not implement any significant changes in the
manufacture and testing of RenaGel capsules without Circa
Pharmaceuticals' prior written approval.
5.5. Postmarketing Regulatory Reporting
GelTex Pharmaceuticals is responsible for submitting any required
postmarketing regulatory reports to the approved RenaGel NDA pertaining
to the manufacture, testing, and packaging of RenaGel capsules.
Postmarketing RenaGel regulatory reports related to Circa
Pharmaceuticals' manufacture and testing of RenaGel capsules will be
forwarded to Circa Pharmaceuticals.
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Acknowledged and agreed to:
GelTex Pharmaceuticals, Inc.
By: /s/ Mark Skaletsky
----------------------------------------------
Its: President
----------------------------------------------
Acknowledged and agreed to:
By:
/s/ [illegible] August 3, 1998
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GelTex Manufacturing Operations Date
/s/ [illegible] August 3, 1998
---------------------------------------------- -----------------
GelTex Quality Assurance Date
/s/ [illegible] August 3, 1998
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GelTex Regulatory Affairs Date
/s/ [illegible] July 31, 1998
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Circa Pharmaceuticals, Inc. Regulatory Affairs Date
/s/ [illegible] July 31, 1998
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Circa Pharmaceuticals, Inc. Quality Assurance Date
/s/ [illegible] July 29, 1998
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Circa Pharmaceuticals, Inc. Operations Date