Exhibit 10.41
Confidential Materials omitted and filed separately with the
Securities and Exchange Commission. Askterisks denote omissions.
AGREEMENT
FOR
MANUFACTURING AND SUPPLY OF ZILEUTON
Made as of February 8, 2005 (the "Effective Date")
by and between
CRITICAL THERAPEUTICS, INC., (hereinafter referred to as "CTI"), a corporation
duly organized and validly existing under the laws of the State of Delaware with
its principal offices at 00 Xxxxxxxx Xxxxxx, Xxxxxxxxx, XX 00000 XXX
and
RHODIA PHARMA SOLUTIONS LTD., (hereinafter referred to as "RPS"), a corporation
duly organized and validly existing under the laws of England, with its
principal offices at Dudley, Xxxxxxxxxxx, Xxxxxxxxxxxxxx, XX00 0XX, Xxxxxxx
WHEREAS, CTI and RPS and RPS' affiliate, Rhodia Pharma Solutions Inc. are
parties to a certain Confidential Proposal Agreement ANNSEN22032004A dated March
23, 2004, under which RPS and Rhodia Pharma Solutions Inc. provided CTI with
certain research and development services concerning the manufacturing of the
Compound (as defined below); and
WHEREAS, CTI and RPS desire to enter into a contract for the supply of
commercial scale Compound batches manufactured by RPS at its Manufacturing Site
(as defined below), subject to the terms and conditions contained herein.
NOW, THEREFORE, CTI and RPS hereby agree as follows:
1.0 DEFINITIONS
Unless otherwise specifically set forth herein, the following terms shall
have the meanings set forth below:
1.1 Affiliate
Shall mean in relation to a party, any other entity controlled, directly
or indirectly, by a Party at the time in question or controlling that
Party or controlled directly or indirectly by an entity controlling the
Party, and where the term "control" means the holding of more than 50% of
the equity of an entity or having the right to appoint and/or remove more
than 50% of its board of directors or like penultimate governing body.
1.2 Agreement
Shall mean this Agreement for the Manufacturing and Supply of ZILEUTON and
all annexes hereto.
1.3 Annual Contract Volume
Shall mean for any Calendar Year, the lesser of (i) [**] percent ([**]%)
of the commercial scale volume of Compound required by CTI and its
Affiliates in that
Calendar Year for the manufacture of Drug Products plus any Excess
Compound Demand that RPS is entitled to produce in accordance with Section
2.1(b)(iii) below, and (ii) the [**] at the Manufacturing Site at Annan
during such Calendar Year.
1.4 cGMP
Shall mean the current good manufacturing practices promulgated by
Governmental Authorities and the International Conference on Harmonisation
("ICH"), including ICH guideline Q7A.
1.5 Compound
Shall mean the compound (+)-1-(1-benzo[b]thien-2-ylethyl)-1-hydroxyurea,
also known as zileuton.
1.6 Confidential Information
Shall mean all information, whether technical or non-technical, trade
secrets, discoveries, data, drawings, techniques, documents, models,
samples and know-how, whether or not patented or patentable, owned or
possessed by a Party on the date of this Agreement or later developed by
them that is not in the public domain. CTI's Confidential Information
shall include Intellectual Work Product (as defined in Section 8.1 (a).
1.7 Contract Year
Shall mean each calendar year during the Term hereof beginning upon
January 1st and ending upon December 31st of such year.
1.8 Drug Product
Shall mean any and all pharmaceutical preparations suitable for human use
manufactured by or for CTI that contain the Compound.
1.9 EMEA Territories
Shall mean the European countries of Austria, Belgium, Cyprus, Czech
Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary,
Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, the Netherlands,
Norway, Poland, Portugal, Slovakia, Slovenia, Spain, Sweden and the United
Kingdom, and such other countries as may from time to time become member
states of the European Union.
1.10 European Union
Shall mean the European countries of Austria, Belgium, Cyprus, Czech
Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary,
Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, the
Netherlands, Poland, Portugal, Slovakia, Slovenia, Spain, Sweden and the
United Kingdom, and such other countries as may from time to time become
member states of the European Union.
1.11 Excess Compound Demand
As defined in Section 2.1(b)(iv) below.
1.12 FDA
Shall mean the United States Food and Drug Administration, or any
successor entity.
1.13 Governmental Approval
Shall mean all authorizations by the appropriate Governmental Authorities
that are required for the manufacture (other than manufacturing facility
licenses, approvals, or authorizations), marketing, promotion, and sale of
the Compound in the United States and the European Union.
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1.14 Governmental Authority
Shall mean any national, supra-national, regional, state, or local
regulatory agency, department, bureau, commission, council, or other
governmental entity in the United States or the European Union involved in
the granting of Governmental Approval for the Compound, including, without
limitation, the FDA and the EMEA.
1.15 Initial Delivery Period
Shall mean the period commencing with the Effective Date and ending upon
December 31, 2006.
1.16 Manufacturing Site
Shall mean one or both of RPS' manufacturing facilities located at Dudley,
Xxxxxxxxxxx, Xxxxxxxxxxxxxx, XX00 0XX, Xxxxxxx and Xxxxx Xxxxx Xxxx,
Xxxxxx, Xxxxx, Xxxxxxxxxxxxx, XX00 0XXX, Xxxxxxxx
1.17 Manufacturing Site Capital Project
Shall mean the capital build-out projects at the Manufacturing Site at
Annan, Scotland required to increase RPS' Compound manufacturing capacity
at the Manufacturing Site at Annan from [**] to [**] of Compound per
Calendar Year sites, together with the estimated costs and expenses of
such project and the estimated project timeline shown on Annex 12 attached
hereto.
1.18 Party
Shall mean CTI or RPS, and when used in the plural form both CTI and RPS.
1.19 Proposal Agreement
Shall mean the Confidential Proposal Agreement described in the preamble
of this Agreement together with any amendments and change orders agreed to
in writing between the Parties, a copy of which is attached hereto at
Annex 11.
1.20 Quality Agreement
Shall mean the written quality agreement for the manufacturing of the
Compound agreed between the Parties and attached hereto as Annex 9, as
such agreement shall be amended from time to time in writing by the
Parties.
1.21 Raw Materials
Shall mean all materials, chemicals and solvents used in the production of
the Compound by RPS hereunder.
1.22 Recall
Shall mean any action by CTI and its Affiliates or RPS and its Affiliates,
to recover title or possession or halt distribution, prescription, or
consumption of the Compound or any Drug Product sold or shipped to Third
Parties. The term "Recall" also applies to Compound or Drug Products that
would have been subject to recall if the Compound or Drug Products, as the
case may be, had been shipped.
1.23 Seizure
Shall mean any action by the FDA or other governmental authority to detain
or destroy the Compound or the Drug Products or prevent the distribution,
prescription, consumption, or release of the Compound or Drug Products.
1.24 Specifications
Shall mean the specifications for the Compound attached hereto in Annex 1.
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1.25 Supply Chain Introduction Date
Shall mean the date, for a given drum of Compound that is shipped by RPS
hereunder, upon which CTI or CTI's designated agent first breaks the seal
of such drum.
1.26 Term
Shall mean the duration of this Agreement as provided in Section 10.1
hereof.
1.27 Third Party
Shall mean any party other than CTI and its Affiliates and RPS and its
Affiliates.
1.28 Validations
Shall mean process validation, test method validation, milling validation
and cleaning validation, contemplated by the Parties to be undertaken for
preparation of the Process Validation Report.
1.29 Process Validation Report
Shall mean a written report prepared by RPS in consultation with CTI
evidencing the repeatability of Compound quality and stability over the
production of [**] Compound batches, as required for commercial release of
the Compound under applicable Government Approvals, and all Validations
and the achievement of any other production validation criteria so
required and as the Parties shall mutually agree, and which report shall,
subject to Section 10.6, be attached hereto at Annex 10 upon completion
and sign off, in writing, by both Parties.
1.30 Validation Schedule and Timeline
Shall mean the schedule of work and timelines for the Validations and the
manufacture by RPS of Phase 1 validation batches of Compound, described at
Annex 3 hereto.
1.31 Validation Success Criteria
Shall mean the criteria agreed between the parties for the Validations and
the successful completion of the manufacture by RPS of validation batches
of Compound, as set forth in the Validation Schedule and Timeline.
1.32 Vendors
Shall mean any and all Third Party suppliers of materials, processing
services and/or testing services engaged by RPS in connection with this
Agreement.
2.0 AGREEMENT SCOPE AND MANUFACTURE AND SUPPLY OF COMPOUND
2.1 (a) Phase 1 - Validation Batches of Compound.
During the Term, RPS will manufacture at the Manufacturing Site under cGMP
[**] validation batches of the Compound from the Manufacturing Site at
Xxxxxx and [**] validation batches of the Compound from the Manufacturing
Site at Annan in accordance with the Proposal Agreement, the Validation
Schedule and Timeline and the Validation Success Criteria. Should any such
validation batch be prepared under conditions determined not to meet the
Validation Success Criteria to the mutual satisfaction of the Parties, RPS
shall manufacture a new validation batch or batches. The price for these
Phase 1 validation batches of Compound is set forth in the Proposal
Agreement; provided, however, that CTI shall only be responsible for
paying for the [**] validation batches from the Manufacturing Site at
Xxxxxx and the [**] validation batches from the Manufacturing Site at
Annan as outlined in the
4
Proposal Agreement regardless of how many validation batches are needed to
be produced to achieve [**] validation batches that meet the Validation
Success Criteria. Further, the foregoing price shall be inclusive of the
cost of the Process Validation Report and all validation batches,
excluding the cost of the milling part of the Validations to the extent
any milling is done by a Third Party, in which case, the cost of such
milling by a Third Party shall be the sole responsibility of CTI. For the
milling validation part of the Validations, the extent of the milling
required of Compound from the foregoing validation batches, including, but
not limited to, how much Compound to be milled and the timing thereof,
shall be determined by CTI, in its reasonable discretion, in consultation
with RPS.
(b) Phase 2 - Commercial Batches of Compound.
(i) Price: The price for commercial scale batches of Compound shall be
US$[**] per kilo, [**] (per INCOTERMS 2000), during the Initial Delivery
Period. The foregoing price is inclusive of CTI's obligation to [**], but
not more than $[**], of (i) any costs and expenses incurred by RPS in
connection with the work described in the Manufacturing Site Capital
Project Project and (ii) the reasonable out-of-pocket cost of [**] any
such capital improvements that RPS must undertake, provided that CTI
performs its [**] per Section 2.1(b)(ii) below. The price for commercial
scale batches during any Calendar Year thereafter shall vary as provided
in Schedule 13 attached hereto depending upon the volume of Compound
ordered by CTI for such Calendar Year. The Parties shall meet no less than
once a Calendar Year to review Compound pricing under Schedule 13 of this
Agreement with a goal of achieving a Compound price of US$[**] per kilo
for Calendar Year volumes of Compound equal to or greater than [**] metric
tons, provided that no adjustments or changes to Schedule 13 pricing will
be binding upon the Partiers absent an amendment to Schedule 13 signed by
both of the Parties.
(ii) Compound Delivery Volumes: Subject to the terms of this Agreement,
during the Initial Delivery Period, RPS will manufacture at the
Manufacturing Site under cGMP, and CTI will purchase, [**] metric tons of
commercial scale batches of Compound Subject to the terms of this
Agreement, during each Calendar Year after the Initial Delivery Period,
RPS will manufacture at the Manufacturing Site under cGMP, and CTI will
purchase, the Annual Contract Volume.
(iii) Orders: If CTI has not already done so as of the Effective Date, CTI
will provide RPS with a written, rolling, twenty-four month forecast of
its Compound requirements no later than [**] months prior to the first
date proposed for delivery by RPS of commercial scale Compound batches
hereunder and shall provide an update of such forecast on or before the
first [**] thereafter during the Term of this Agreement (e.g., [**]). Such
forecasts shall constitute [**] months of firm orders from CTI for the
requested volume of Compound and shall then include [**] months of pro
forma volumes of Compound and [**] months of Compound delivery planning
horizon. The latter [**] months of each such forecast shall be
non-binding, subject always to CTI's minimum Compound volume purchase
obligations hereunder. RPS shall advise CTI if it cannot meet any of the
proposed delivery dates for Compound contained in CTI's newly forecasted
[**] within fifteen (15) business days of receiving each [**] updated
forecast, and the Parties shall negotiate mutually agreeable alternative
delivery dates. For the avoidance of doubt, once RPS has agreed that it
can accommodate the delivery dates for the first [**] months of CTI's
forecasts delivered as above, RPS shall only be able to object to the
delivery dates proposed in the updated forecast next due from CTI for the
[**] months immediately following the [**] months of firm orders then
pending under CTI's forecast. CTI's forecasts will also forecast the total
Compound requirements for CTI and its Affiliates over the forecast period
to the extent not reflected in CTI's firm orders. It is understood and
agreed between the
5
Parties that, for any Compound needed by CTI for commercial production of
Drug Product, RPS shall be the sole and exclusive supplier of Compound to
CTI and its Affiliates until the end of the Initial Delivery Period.
(iv) Right of First Refusal: Beginning with the Calendar Year 2007, CTI
hereby grants to RPS the right of first refusal to supply CTI and its
Affiliates with an additional [**] percent ([**]%) of their total annual
Compound requirements above [**] percent ([**]%) of such volume under this
Agreement ("Excess Compound Demand"), which right shall be exercisable by
RPS for all or any part of such Excess Compound Demand that RPS is capable
of producing subject to the capacity limitations at the Manufacturing Site
for any such Calendar Year by written notice issued to CTI within fifteen
(15) days after the date that RPS first receives from CTI firm orders for
Compound for that Calendar Year under Section 2.1(b)(iii) above (i.e.,
forecast due date from CTI of April 1st of each Calendar Year covering the
twenty-four (24) month period commencing with July 1st of that year) (the
"Exercise Period"). If RPS has received written notice from CTI on or
prior to an Exercise Period, containing reasonably detailed information
and supporting documents for RPS' evaluation (subject always to any
confidentiality obligations to Third Parties to which CTI or its
Affiliates may be bound), that CTI and/or one or more of its Affiliates
have received a written offer, binding upon a Third Party supplier(s) of
Compound, to supply CTI and/or its Affiliates with between [**] percent
([**]%) and [**] percent ([**]%) of its Compound requirements for the
succeeding Calendar Year and such offer, or offers on average if there are
more than one, evidence a lower price delivered to the final destination
designated by CTI than that which will be payable hereunder during such
succeeding Calendar Year, taking into account [**], then RPS' right of
first refusal for the Excess Compound Demand represented by such offer(s)
shall be subject to RPS' agreement to supply such Excess Compound Demand
hereunder at a price that is more favorable to CTI than such offered
price. If RPS does not exercise its right of first refusal with an
agreement by RPS to supply all or any part of such Excess Compound Demand
at a price that is more favorable to CTI than the offered price, then CTI
shall be free to purchase any Excess Compound Demand so declined by RPS
for the relevant succeeding Calendar Year from the Third Party supplier(s)
who has made the competitive offer.
(c) Compound Deliveries
All deliveries of Compound shall be made by RPS to CTI, either [**].
facility of RPS' Affiliate, Rhodia Pharma Solutions Inc. [**] to the
carrier nominated by CTI or its designated agent or [**] (per INCOTERMS
2000) as the Parties shall agree based upon CTI's firm Compound orders,
and title and risk of loss to the Compound shall pass from RPS to CTI upon
completion of delivery as aforesaid. CTI shall be the importer of record
and shall be responsible for paying all customs duties and any other
importation charges and fees on any Compound brought into the United
States, including without limitation any [**] that RPS must maintain at
[**] per Section 2.1(d) below, but CTI shall not take title to the
Compound until delivered to the carrier selected by CTI and/or its
designated agent at [**].
It is expressly understood by the Parties that [**] in the [**] hereunder
or [**] agreed between the Parties.
(d) [**]
During the Term of this Agreement, RPS agrees to [**], as requested by
CTI, an [**] RPS' then-current monthly production capacity of Compound at
the Manufacturing
6
Site, or [**] agreed between the Parties ("[**]") to support RPS' [**]
hereunder; provided, however, that after the milling portion of the
Validations is complete, a [**] of the [**] in [**] Compound to be
processed by CTI or its designated agents into Drug Product in the United
States, as advised by CTI to RPS with appropriate advance notice, shall
[**] unless otherwise agreed in writing by the Parties (e.g. if [**] of
CTI's [**] are for the processing of Drug Products in the United States,
then [**] of the [**] will be [**]). Notwithstanding the foregoing, CTI
agrees that RPS will not be obligated to have such [**] until [**], and
that [**], RPS shall only be required to [**] a [**] of [**] as a [**].
CTI further agrees that RPS may supply Compound to CTI [**], including for
milling validation as described in section 2.1(a), but shall [**] to the
extent necessary to have the [**]; provided, however, the [**] by RPS [**]
will, if reasonably required by CTI, be [**] by RPS, at RPS' sole expense,
[**] to CTI to [**] that the [**]. Title and risk of loss to Compound [**]
shall at all times remain with RPS prior to the delivery to CTI of such
Compound by RPS. CTI shall purchase [**] from RPS at the termination of
this Agreement for any reason whatsoever, at RPS's cost of [**] unless
[**] from CTI to be filled by RPS during the termination periods set forth
in Sections 10.2, 10.5 and 10.6 below or as otherwise agreed between the
Parties in which case [**] by CTI at the price for [**] hereunder.
CTI shall be provided with all batch records related to the [**] and shall
be agreed between the Parties as contemplated in Section 2.2(b) below.
(e) Price Adjustments [**]
After the Initial Delivery Period, RPS shall be allowed to [**] the
Compound price each Calendar Year by [**]. By way of example only, if
[**], RPS will be entitled to [**] the Compound price [**]. RPS will
advise CTI in writing of any such [**] during the term of this Agreement,
and will adjust any invoices already submitted to CTI for Compound
produced during the new Calendar Year that do not reflect such [**] and
shall submit a [**] to the next succeeding Compound invoice following such
written notice to CTI. [**]
(f) Price Adjustment for [**]
In the event that RPS [**] the cost of the [**] Compound hereunder to a
price, delivered to the Manufacturing Site, to [**], whether through the
[**] or otherwise, then [**] percent ([**]%) of such [**] shall be [**]
through [**] the purchase price per kilogram for the Compound.
2.2 (a) All Compound shall be manufactured to meet the Specifications
indicated in Annex 1. Any reasonable changes in Annexes 1, 2, 4, 5, 6, 9
and/or 10 provided by CTI, or required due to new or changed governmental
laws rules or regulations that come into force during the term hereof,
shall be adopted and the relevant Annex shall be amended by a signed
written amendment to this Agreement to reflect the change, provided that
CTI shall reimburse RPS, on terms designated by RPS, for any and all
increased costs and expenses that RPS incurs to produce Compound in
compliance with such changes. In the event that RPS wishes, in its
reasonable discretion, to amend Annexes 1, 2, 4, 5, 6, 9 and/or 10, RPS
shall provide such proposed amendment to CTI and the terms of such changes
will be evidenced in a signed, written amendment to this Agreement
negotiated between CTI and RPS and the costs and expenses of producing
Compound in compliance with such changes shall be for RPS account. All Raw
Materials and intermediates necessary for the manufacturing by RPS of the
Compound at the Manufacturing Site will be supplied by
7
RPS without additional charge to CTI. A list of critical Raw Materials
necessary for the manufacture of the Compound by RPS is set forth at Annex
2 hereto.
(b) Batch records, specifications for Raw Materials and intermediates to
be used in the manufacture by RPS of the Compound and the analytical test
methods for same will be developed by RPS in consultation with CTI during
the Phase 1 stage of this Agreement, and shall be reduced to writing and
attached hereto at Annex 4. [**]. All batch record forms, specifications
for Raw Materials and intermediates to be used in the manufacture by RPS
of the Compound and the analytical test methods for same must be approved
in writing by CTI prior to use by RPS, which approval will not be
unreasonably withheld or delayed. Any material changes in the batch
records, specifications for Raw Materials and intermediates to be used in
the manufacture by RPS of the Compound and the analytical test methods for
same or equipment specifically used for the Compound by RPS at the
Manufacturing Site will require prior written approval by CTI as per the
Quality Agreement attached hereto at Annex 9. RPS will provide a
Certificate of Analysis and a Certificate of Compliance with cGMP in the
forms shown at Annex 5 attached hereto and executed batch record(s) in the
then agreed form with each shipment of the Compound hereunder.
(c) RPS shall follow the Procedures for Release of Compound attached at
Annex 6 hereto prior to delivery of any Compound to CTI. The procedures to
be followed upon the occurrence of an Out of Specification ("OOS") event
are contained in the standard operating procedures ("SOPs") for the
Manufacturing Site. Current copies of such SOPs will be provided by RPS to
CTI and shall be reviewed by CTI and shall be subject to CTI's approval
before implementation in relation to this Agreement, which approval will
not be unreasonably withheld or delayed. No new SOP shall be adopted by
RPS in relation to this Agreement without the express written approval of
CTI, which approval will not be unreasonably withheld or delayed. RPS will
promptly provide CTI with any changes to such SOPs that RPS desires to
make in relation to this Agreement. Such changes shall be reviewed by CTI
and shall be subject to CTI's approval before implementation with respect
to this Agreement, which approval will not be unreasonably withheld or
delayed. These procedures contain specific timelines for investigation of
OOS events. Procedures to be followed for a batch failure due to
circumstances other than OOS events shall also be contained in the SOPs
for the Manufacturing Site. As outlined in the Quality Agreement, RPS will
retain samples of each batch of Compound and samples of all Raw Materials
and intermediates used in the manufacturing thereof hereunder for a period
of at least five (5) years following the expiry of the last Drug Product
incorporating such Compound. Prior to the destruction or disposal of any
such retained samples, RPS shall notify CTI and CTI shall have the option
to take possession of such retained samples at CTI's expense.
(d) RPS shall be responsible for conducting an approval program for
Vendors utilized by RPS in connection with manufacturing of the Compound
as required to comply with cGMP. CTI shall also have the right, but not
the obligation, to independently audit the Vendors; provided, however,
that, in the case of Vendors of materials used by RPS in the manufacture
of the Compound, CTI shall only have such audit right with respect to the
Vendors of critical Raw Materials as listed in Annex 2; further provided
that RPS will not have any liability to CTI in the event that any such
Vendor refuses to permit CTI to conduct such an audit. Where RPS conducts
an audit of a vendor, RPS will provide CTI with a copy of RPS' audit
procedures and analytical approval process, and any updates or amendments
to such procedures and process. CTI shall have the right, during audits of
the Manufacturing Site conducted by CTI as permitted hereunder, to review
the records for all Vendor audits conducted by RPS. In addition, CTI shall
also have the right to
8
review the qualification records (as required by cGMP) of the Vendors for
the Raw Materials for the Compound, provided the Raw Materials are
produced under cGMP. RPS shall promptly inform CTI in the event of a
concern with the quality or manufacturing compliance with respect to a Raw
Material used in the manufacture of the Compound and RPS will coordinate
with CTI to assure a prompt resolution of any such concern. RPS shall
provide CTI with copies of the results of all Vendor audits conducted by
RPS upon CTI's request.
(e) Under no circumstances, shall RPS change a Vendor of critical Raw
Materials identified on Annex 2 hereto, or process or testing Vendor
without the prior written consent of CTI, which consent shall not be
unreasonably withheld or delayed.
2.3 Payment for all Compound purchased from RPS by CTI in accordance with this
Agreement, and any other sums that may be payable by CTI to RPS hereunder,
shall be made within thirty (30) days after the date of RPS' invoice, by
wire transfer in immediately available funds to RPS' bank account set
forth in Annex 7 hereto, or as RPS shall otherwise direct payment to be
made in writing. RPS will be entitled to charge interest on late payments
at the rate of two percent (2%) per annum above the base lending rate
charged by HSBC Bank plc prevailing from time to time, both before and
after judgment, from the date due until the date cleared funds are
received by RPS. RPS shall not invoice CTI for any batch of Compound prior
to the issuance of the batch records and the Certificates of Analysis and
Compliance for such batch.
2.4 During the term of this Agreement and for a period of at least five (5)
years thereafter, RPS shall maintain records of inspection and testing,
lab notebooks and procedures made in connection with the Compound
manufacturing work conducted under this Agreement. Prior to the
destruction or disposal of any such records, RPS shall notify CTI and CTI
shall have the option to take possession of such records at CTI's expense.
RPS shall provide CTI with the necessary information that would be
included in a Drug Manufacturing File ("DMF") or in support of a Chemistry
and Master Controls ("CMC") portion of an NDA or equivalent filing so that
such information can be included by CTI in its NDA or equivalent filing in
the United States, the European Union, or such other location designated
by CTI. [**]
2.5 RPS shall keep CTI regularly informed of the status and progress of all
stages of Phases 1 and 2 through regular telephone or e-mail updates,
[**], and through written summaries. During all periods that RPS is
conducting any manufacturing for CTI, RPS shall perform an annual product
review, including a review of production history, deviations (if any), OOS
events, investigation programs adopted and the outcome of any
investigations, any reprocessing conducted, and ongoing stability results,
if generated at an RPS site. This review shall comply with section 2.50 of
ICH Q7a and a copy shall be provided to CTI one month prior to the
regulatory annual report due date. This review shall list all of the
changes made during the year that impact on regulatory submissions and
also summarize the stability data generated during the year in question.
Additional review(s) will be undertaken if necessary to comply with cGMP.
3.0 INSPECTIONS AND CONTROLS
3.1 Subject to confidentiality obligations contained in Section 7, RPS agrees,
without additional charge to CTI, to allow inspections of the
Manufacturing Site by representatives of CTI or its agents during normal
working hours upon prior written notice to RPS, which notice will occur at
least three (3) days in advance of the inspection, unless not possible due
to an inspection on the same date by a
9
Governmental Authority. RPS shall grant access to such premises and to the
documentation necessary for or appropriate to the manufacturing and
quality control of the Compound including, but not limited to, full copies
of all batch records. During such visits, RPS shall make sure that at
least one technical person from its quality assurance/control department
and, if reasonably possible, that appropriate RPS product management
personnel are present to answer questions or discuss matters of concern
with the CTI personnel conducting such audit or inspection.
3.2 RPS shall ensure all relevant and/or critical Compound manufacturing, test
and inspection equipment at the Manufacturing Site is maintained under a
documented calibration and maintenance program. This includes providing
equipment calibration certifications as required.
3.3 RPS will maintain environmental controls, including particulate and
bioburden monitoring, pest controls and housekeeping procedures in
accordance with cGMP. The use of supplies of process water, air and
particulate handling, etc., for manufacture of the Compound, shall be
consistent with relevant cGMP specifications and guidelines.
3.4 RPS shall maintain a quality assurance/control department, which is a
distinct department separate from manufacturing. RPS quality
assurance/control personnel will perform incoming, in-process and finished
product inspections, review records, perform line clearance inspections,
maintain batch history records, provide batch history records for review
and accuracy and completeness and provide product release services, all in
accordance with the Quality Agreement and the Procedures for Release of
Compound. RPS quality assurance/control personnel will also manage the
storage and handling of all Raw Materials and intermediates used in the
manufacture of the Compound, as well as any finished batches of Compound,
in accordance with the Quality Agreement.
3.5 RPS will promptly notify CTI of any FDA or other material Governmental
Authority inspection of the Manufacturing Site related, directly or
indirectly, to the Compound, and will promptly provide CTI with a copy of
any non-privileged documentation relating to such inspection. CTI shall
have the right to communicate at any time with the FDA or any Governmental
Authority regarding such matters, provided any such communication is done
after consultation with RPS and is coordinated with RPS. CTI will provide
appropriate support for any such inspection, including data and
information relating to critical parameters and other information relevant
to the Compound.
3.6 At all times during the term of this Agreement, each of the Parties shall
carry and keep in force a general liability insurance policy, in support
of their liability obligations to one another hereunder. The policy
maintained by the Parties shall afford limits of not less than five (5)
million dollars (US $5,000,000) in the case of CTI, and five million Euros
((euro)5,000,000) in the case of RPS, for each occurrence and not less
than seven and a half (7.5) million dollars (US $7.5,000,000) in the case
of CTI, and seven and a half (7.5) million Euros ((euro)7,500,000) in the
case of RPS, in the annual aggregate in respect of products and completed
operations liability. In the event that such policy is written on a
claims-made basis, such policy shall provide no less than twelve (12)
months extended reporting period from the date of termination of this
Agreement. A Certificate of Insurance evidencing RPS' coverage and a
Certificate of Insurance evidencing CTI's coverage are attached hereto as
Annex 8 hereto.
4.0 WARRANTIES/LIMITATIONS
10
4.1 (a) Product Warranty
RPS warrants and represents that the Compound manufactured by RPS and
delivered to CTI shall conform to the Specifications when delivered and be
manufactured in accordance with cGMP and all other applicable Governmental
Approvals, and was not and will not be adulterated or misbranded while in
the possession of RPS (as the terms "adulterated" and "misbranded" are
used and interpreted under the U.S. Food, Drug and Cosmetic Act). RPS will
maintain at least 25 to 50 grams of the Compound from each batch produced
as a retained sample. Such retained sample will be maintained at the
Manufacturing Site or other RPS facility and RPS will store such retained
sample under storage conditions set forth in the Quality Agreement.
EXCEPT FOR THE FOREGOING AND RPS' WARRANTY IN SECTION 4.3 BELOW, RPS MAKES
NO WARRANTY OR REPRESENTATION OF ANY KIND, EITHER EXPRESS OR IMPLIED,
INCLUDING, BUT NOT LIMITED TO, THE WARRANTIES OF MERCHANTABILITY AND
FITNESS FOR A PARTICULAR PURPOSE AND ANY REPRESENTATION OR ANY WARRANTY
THAT USE OF THE PROCESS FOR MANUFACTURE OF THE COMPOUND OR USE OR SALE OF
THE COMPOUND, WHETHER OR NOT SUCH COMPOUND IS MADE BY THE PROCESS FOR
MANUFACTURE OF THE COMPOUND, WILL NOT INFRINGE THE CLAIMS UNDER ANY PATENT
OR OTHER INTELLECTUAL PROPERTY RIGHT OF ANY THIRD PARTY.
(b) Limitations
RPS'S SOLE LIABILITY AND CTI'S EXCLUSIVE REMEDY IN THE CASE OF COMPOUND
DELIVERED HEREUNDER TO CTI THAT DOES NOT MEET THE SPECIFICATIONS SHALL BE,
AT CTI'S OPTION, FOR RPS TO USE COMMERCIALLY REASONABLE EFFORTS TO REPLACE
THE DEFECTIVE COMPOUND WITH COMPOUND THAT CONFORMS WITH THE SPECIFICATIONS
OR FOR RPS TO REFUND THE PURCHASE PRICE PAID TO RPS FOR SUCH
NON-CONFORMING COMPOUND. ALL CLAIMS CONCERNING COMPOUND DELIVERED TO CTI
HEREUNDER MUST BE MADE IN WRITING RECEIVED BY RPS WITHIN THE EARLIER OF
(A) NINETY (90) DAYS AFTER THE SUPPLY CHAIN INTRODUCTION DATE AND (B)
TWELVE (12) MONTHS AFTER THE DATE OF DELIVERY TO CTI OR ITS DESIGNATED
AGENT, FAILING WHICH CLAIM NOTICE SUCH COMPOUND SHALL BE DEEMED ACCEPTED
BY CTI "AS IS" AND ALL CLAIMS BY CTI IN RELATION TO SUCH DELIVERED
COMPOUND SHALL BE DEEMED WAIVED, EXCEPT IN RESPECT TO DEFECTS IN COMPOUND
QUALITY THAT COULD NOT HAVE BEEN DISCOVERED BY CTI PRIOR TO THE EXPIRATION
OF THE EARLIER TO OCCUR OF SUCH NINETY (90) DAY AND TWELVE (12) MONTH
PERIODS THROUGH THE EXERCISE OF COMMERCIAL DILIGENCE REQUIRED OF
MANUFACTURERS OF DRUG END PRODUCTS FOR HUMAN CONSUMPTION FOR SALE IN THE
UNITED STATES AND THE EUROPEAN UNION.
IN NO EVENT SHALL EITHER RPS OR CTI BE LIABLE TO THE OTHER FOR INDIRECT,
SPECIAL, CONSEQUENTIAL (INCLUDING WITHOUT LIMITATION LOST PROFITS UNDER
SEC. 2-715 OF THE UNIFORM COMMERCIAL CODE), PUNITIVE OR INCIDENTAL DAMAGES
IN ANY WAY ASSOCIATED WITH THIS AGREEMENT, REGARDLESS OF THE FORM OR BASIS
OF ANY CLAIM OR ACTION.
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NOTWITHSTANDING ANYTHING TO THE CONTRARY HEREIN CONTAINED, THE FOREGOING
LIMITATIONS IN THIS SECTION 4.1(B) (I) DO NOT APPLY TO THE OBLIGATIONS OF
THE PARTIES CONTAINED IN SECTION 9 (INDEMNIFICATION) OF THIS AGREEMENT,
EXCEPT THAT RPS SHALL HAVE NO LIABILITY WHATSOEVER UNDER SECTION 9
RELATING TO ANY COMPOUND CONCERNING WHICH CTI HAS WAIVED ITS CLAIMS IN
THIS SECTION 4.1(B), AND (II) RELIEVE RPS OF ANY LIABILITY UNDER SECTION 5
RELATING TO ANY COMPOUND CONCERNING WHICH CTI HAS WAIVED ITS CLAIMS IN
THIS SECTION 4.1(B).
4.2 CTI Use and Non-Infringement Warranty and Covenant
CTI represents and warrants that it is entering into this Agreement solely
to obtain Compound for use by CTI in the manufacturing of Drug Products,
and it shall at all times comply with all applicable laws and regulations
relating to its activities under this Agreement, and its transportation,
export, handling, storage, marketing, sale, and distribution, or any other
use of the Compound or any Drug Products. Without limiting the foregoing,
in no event will CTI sell any Compound or Drug Product to any Third Party
for human consumption prior to the completion of the Validation Report, as
contemplated herein. In addition, CTI acknowledges that it has disclosed
the CTI Technology to RPS for use in making the Compound and in otherwise
performing RPS' obligations hereunder and that RPS will use the CTI
Technology for such purpose and CTI further represents and warrants that:
(i) CTI owns the CTI Technology and/or has the unencumbered right to
disclose the CTI Technology to RPS and to authorize use of the CTI
Technology by RPS for such purpose, and (ii) to the best knowledge of CTI
as of the Effective Date use of any CTI Technology by RPS in the
performance of its obligations hereunder, including without limitation
RPS' obligations to manufacture (including manufacture of any required
intermediate compounds) and sell the Compound, will not infringe the
patent rights or any other intellectual property rights of any Third
Party, except the rights of Xxxxxx Laboratories in the Abbott Technology,
as defined below, under which CTI has secured certain licenses from Xxxxxx
Laboratories and has secured the agreement of Xxxxxx Laboratories not to
assert such rights against CTI or third parties acting on behalf of CTI,
as set forth in the letter of January 28, 2005, from Xxxxxx Laboratories
to CTI (the "Abbott Letter"), a copy of which is attached hereto as Annex
14.
EXCEPT FOR THE FOREGOING, CTI MAKES NO WARRANTY OR REPRESENTATION OF ANY
KIND, EITHER EXPRESS OR IMPLIED, AND ALL SUCH WARRANTIES ARE EXPRESSLY
DISCLAIMED.
4.3 Debarment Warranty
RPS warrants that it will not knowingly use in connection with the
services rendered under this Agreement in any capacity the services of any
person debarred under the U.S. Food, Drug & Cosmetic Act or any other
similar law or regulation governing drug manufacturing.
4.4 Supply Chain Introduction Date Records
CTI will maintain, and will cause any of its designated agents to whom
Compound manufactured hereunder is delivered to maintain, accurate written
records evidencing
12
the Supply Chain Manufacturing Date for all Compound delivered by RPS
hereunder, and CTI will provide RPS with copies of such records promptly
upon RPS' request.
5.0 RECALLS AND SEIZURES
(a) Information to CTI and RPS
The Parties shall keep each other fully informed of any notification or
other information, whether received directly or indirectly, which might
affect the marketability, safety or effectiveness of the Compound or which
might result in Recall or Seizure of the Compound or Drug Products. CTI
will notify RPS of any Recall or Seizure that is likely to affect the
manufacture of the Compound as contemplated hereunder as soon CTI learns
of any such information. In the event of any Compound or Drug Product
Recall or Seizure, RPS will co-operate as reasonably required by CTI,
having regard to all applicable laws and regulations
(b) Recall/Seizure
In the event of any Compound or Drug Product Recall or Seizure arising
solely out of RPS' breach of this Agreement, or the negligence or willful
misconduct of RPS or its Affiliates, then RPS shall, at the election of
CTI, either (i) supply Compound, without charge to CTI, in an amount
sufficient to replace (x) the amount of the Compound recalled or seized
and (y) the amount of Compound contained in any recalled or seized Drug
Product, or (ii) refund to CTI, and/or give credit to CTI against
outstanding receivables due from CTI hereunder or receivables to become
due from CTI hereunder for purchases of Compound, in amounts equal to the
price paid by CTI for the volume of Compound affected by such Recall or
Seizure, plus all transportation costs and export and import duties not
recovered by CTI in respect of such recalled or seized Compound or Drug
Product; provided that RPS will have no liability under this Section 5(b)
in the case of any Recall or Seizure relating to Compound concerning which
CTI has waived its claims per Section 4.1(b) above.
(c) Recall/Seizure Costs and Expenses
In the event of any Recall or Seizure arising solely from RPS breach of
this Agreement or the negligence or willful misconduct of RPS or its
Affiliates, then, in addition to its obligations in Section 5(b) above,
RPS shall pay CTI's reasonable out-of-pocket expenses incurred in
connection with such Recall or Seizure. In the event of any Recall or
Seizure where there is comparative fault of the Parties, the cost and
expenses resulting from such Recall or Seizure shall be apportioned
between the Parties by mutual agreement based upon the percentage of
relative fault they bear to one another in respect thereof. All other
Recalls and Seizures involving the Compound and/or Drug Products and,
notwithstanding anything to the contrary contained in this Article 5, any
Recall or Seizure relating to Compound concerning which CTI has waived its
claims per Section 4.1(b) above, shall be the sole responsibility and
liability of CTI, including without limitation any Recalls or Seizures
caused by the fault of Third Parties, and CTI shall pay to RPS any
reasonable out-of-pocket expenses incurred by RPS in connection with such
Recall or Seizure. It is understood and agreed between the Parties that
the costs and expenses concerning which they must reimburse one another
under this Section 5 are deemed to be direct damages of the Party entitled
to such reimbursement.
6.0 INDEPENDENT CONTRACTOR STATUS
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6.1 Each of the Parties in performing this Agreement shall be and be deemed to
be acting as an independent contractor and not as the agent or employee of
the other. Neither RPS nor CTI shall have any authority whatsoever to act
as agent or representative of the other party nor any authority or power
to contract or create any obligation or liability on behalf of the other
party or otherwise bind any other party in any way for any purpose.
7.0 CONFIDENTIALITY
7.1 Each Party shall hold all Confidential Information received from the other
Party in strictest confidence and shall use the same level of care to
prevent any unauthorized use or disclosure of such Confidential
Information as it exercises in protecting its own information of similar
nature. A Party shall not disclose any Confidential Information received
from the other Party to any third party without the prior written consent
of the other Party and shall not use such Confidential Information for any
purposes other than the purposes of this Agreement.
7.2 The Confidential Information shall be supplied to the Parties in written
form and shall be identified as being confidential and disclosed under the
provisions of this Agreement.
7.3 Each Party shall have the right to disclose the Confidential Information
of the other Party only to those officers and employees of such receiving
Party who need to know it for the purposes of this Agreement. Such
disclosure is allowed only on condition that the persons to whom the
Confidential Information will be disclosed shall be, by law, contract or
other binding undertaking, under confidentiality obligations at least as
restrictive as those set out in this Agreement.
7.4 The disclosing Party retains all rights to its Confidential Information.
7.5 The confidentiality obligations of this Agreement shall not apply to:
a) Confidential Information which at the time of the disclosure is in
the public domain; or
b) Confidential Information which, after disclosure, becomes part of
the public domain otherwise than by breach of this Agreement; or
c) Confidential Information which can be established by reasonable and
competent proof to have already been in the receiving Party's
possession prior to disclosure and was not acquired, directly or
indirectly, from the disclosing Party; or
d) Confidential Information which a receiving Party shall receive from
a third party who has the legal right to disclose it and who would
by disclosure not breach, directly or indirectly, any
confidentiality obligation to either Party; or
e) Confidential Information which is released for disclosure by prior
written consent of the disclosing Party; or
f) Confidential Information which has been independently developed by a
Party hereto without the use or benefit of Confidential Information
received from the other Party; or
14
g) Confidential Information which is required to be disclosed by law or
by order of court of competent jurisdiction, provided that due
advance notice is given to the other Party of such a requirement and
also such disclosure is then made only to the minimum extent so
required.
7.6 The burden of proving that any of the above exceptions is applicable to a
Party to relieve it of its liability or obligations hereunder shall be
upon the Party claiming such exception(s).
7.7 Notwithstanding anything to the contrary in this Agreement, each Party
acknowledges and agrees that the other Party may disclose the terms of
this Agreement, and may provide a copy of this Agreement or to include a
copy of this Agreement in its public filings with the U.S. Securities and
Exchange Commission, NASDAQ or any other party, if the disclosing Party,
in its sole discretion, believes such disclosure or filing is required by
applicable law or by any rule, requirement or regulation of any
governmental entity or regulatory authority, any stock exchange or NASDAQ.
8.0 INTELLECTUAL PROPERTY RIGHTS
8.1 (a) As used herein "Intellectual Work Product" means all inventions,
modifications, discoveries, improvements (including, without limitation,
process improvements and improvements in analytical methods), processes,
techniques, analytical methods, documentation, scientific and technical
data, drawings and other information) that is generated as a result of any
of the performance by RPS of its obligations hereunder. RPS reserves all
rights in and to all present and future documentation, scientific and
technical data, processes, test procedures and other information and
techniques that are owned, developed or licensed by RPS other than in the
performance of its obligations hereunder (the "RPS Technology"). Without
limiting the foregoing definition of "RPS Technology", it is expressly
understood and agreed that such term shall include any and all
intellectual property rights owned, developed or licensed by RPS relating
to the [**]. CTI shall not have any rights in any of the RPS Technology,
except to the extent that RPS is required to license such RPS Technology
to CTI in accordance with the terms of Section 10.7 below.
(b) The Parties hereto understand and agree that no rights are being
conveyed to RPS (or any of its Affiliates) to use any CTI Technology (as
hereafter defined) for any purpose other than the sole purpose of
manufacturing the Compound for CTI in accordance with the terms of this
Agreement. As used herein, "CTI Technology" means all present and future
documentation, scientific and technical data, processes, test procedures,
information, techniques, technology, patents, patent rights, inventions
and other intellectual property rights that are owned, developed, or
licensed by CTI, including, without limitation, certain patents and
technology of Xxxxxx Laboratories for manufacturing the Compound and/or
manufacturing any starting or intermediate materials for use in making the
Compound (the "Abbott Technology") licensed by CTI.
8.2 (a) RPS acknowledges that CTI shall be the sole and exclusive owner of all
Intellectual Work Product. In consideration of the covenants contained
herein, and for other good and valuable consideration set forth herewith,
RPS hereby assigns and transfers to CTI and its successors and assigns all
right, title and interest that RPS has or may later acquire in and to such
Intellectual Work Product under copyright, patent, trade secret and
trademark law. Such assignment includes the assignment of the entire
right, title and interest in and to all applications for letters patent
and any and all letters patent or patents in the United States of America
and
15
all foreign countries which may be granted on and in connection with such
Intellectual Work Product.
(b) RPS agrees to cooperate with CTI so that CTI may enjoy to the fullest
extent the entire right, title and interest in and to the Intellectual
Work Product. In connection therewith, RPS agrees to execute, if
necessary, additional papers and documents and to take all actions
requested by CTI in order to (a) further evidence ownership of
Intellectual Work Product by CTI and its successors and assigns and (b)
allow CTI to procure, maintain and enforce all letters patent and
intellectual property rights to the Intellectual Work Product. CTI agrees
to reimburse RPS all reasonable costs in relation to the production of
such additional papers and documents.
8.3 CTI hereby grants to RPS a non-exclusive, royalty-free, license to use any
and all CTI Technology provided by CTI to RPS in connection with this
Agreement and the Proposal Agreement for use by RPS in the performance of
its obligations under this Agreement. Except as specifically described in
this Agreement, no right, title, interest, or license in or to any
trademark, patent, copyright or service xxxx or symbol or any other
intellectual property right of a party is granted to the other party under
this Agreement. CTI hereby covenants and agrees to maintain at its sole
cost and expense the validity of the licenses referred to in the Abbott
Letter (the "Licenses") to the extent necessary for RPS to have valid and
enforceable rights at all times under the license granted by CTI under
this Section 8.3 to use the CTI Technology, including the Abbott
Technology, to manufacture, sell, and deliver Compound to CTI as
contemplated hereunder. In addition, CTI agrees to provide RPS with
written notification as soon as possible of any actual or prospective
termination of the Licenses for any reason.
9.0 INDEMNIFICATION PROVISIONS; FORCE MAJEURE; ARBITRATION
9.1 CTI will indemnify and hold harmless RPS, its affiliates, any present or
future parent or subsidiary of them, and their respective officers,
directors, employees, counsel, agents and affiliates (the "Indemnified RPS
Parties") against any and all losses, liabilities, damages, costs and
expenses incurred in defending against any litigation, commenced or
threatened, or any claim (including, but not limited to, reasonable
attorney fees and any and all reasonable expenses), and all amounts
reasonably paid (with RPS' prior written consent) in settlement of any
claim or litigation, commenced or threatened ("Losses"), to the extent
such Losses arise out of (i) the breach of any of CTI's representations,
warranties, or covenants contained in this Agreement, (ii) any negligent
act or omission or willful misconduct of CTI in relation to this
Agreement, (iii) the storage, handling, transportation of the Compound by
CTI or the use by CTI of the Compound in the manufacture of Drug Products,
(iv) Recalls or Seizures for which CTI is responsible under Article 5
hereof, (v) the promotion, marketing, distribution and sale, whether
directly or through distributors, of the Compound purchased hereunder or
any Drug Product, or (vi) any claim that (a) making, using, importing,
offering for sale, or selling the Compound, or (b) making or using any
starting or intermediate material that is required to be made and/or used
in order to make the Compound in accordance with the CTI Technology, or
(c) using the CTI Technology to make the Compound infringes the
intellectual property rights of any Third Party; PROVIDED, HOWEVER, THAT
IN NO EVENT SHALL CTI HAVE ANY OBLIGATION TO INDEMNIFY OR HOLD HARMLESS
ANY OF THE INDEMNIFIED RPS PARTIES TO THE EXTENT THAT RPS OR ANY
INDEMNIFIED RPS PARTY, IS IN ANY WAY RESPONSIBLE BY NEGLIGENT OR WILLFUL
ACT FOR SUCH LOSSES (EXCLUDING, FOR THE AVOIDANCE OF DOUBT,
16
COMPOUND CONCERNING WHICH CTI HAS WAIVED ITS CLAIMS PER SECTION 4.1(B)
ABOVE).
9.2 RPS will indemnify and hold harmless CTI, its affiliates, any present or
future parent or subsidiary of any of them, and their respective officers,
directors, employees, counsel, agents and affiliates (the "Indemnified CTI
Parties") against any and all losses liabilities, damages, costs and
expenses incurred in defending against any litigation, commenced or
threatened, or any claim (including, but not limited to, reasonable
attorney fees and any and all reasonable expenses), and all amounts
reasonably paid (with CTI' prior written consent) in settlement of any
claim or litigation, commenced or threatened ("Losses"), to the extent
such Losses arise out of (i) the breach of any of RPS' representations,
warranties, or covenants contained in this Agreement, (ii) any negligent
act or omission or willful misconduct of RPS in relation to this
Agreement, (iii) the storage, handling or use of any Raw Materials or
intermediates used in the manufacture of the Compound hereunder or any
storage or handling of the Compound, (iv) Recalls or Seizures for which
RPS is responsible under Article 5 hereof; PROVIDED, HOWEVER, THAT, IN
ADDITION TO THE EXCLUSION OF LIABILITY FOR RPS IN INDEMNITY CONCERNING
COMPOUND FOR WHICH CTI HAS WAIVED ITS CLAIMS PER SECTION 4.1(B) ABOVE, IN
NO EVENT SHALL RPS HAVE ANY OBLIGATION TO INDEMNIFY OR HOLD HARMLESS ANY
OF THE INDEMNIFIED CTI PARTIES TO THE EXTENT THAT CTI OR ANY INDEMNIFIED
CTI PARTY, IS IN ANY WAY RESPONSIBLE BY NEGLIGENT OR WILLFUL ACT FOR SUCH
LOSSES.
9.3 Conditions of Indemnification
With respect to any indemnification obligations of either Party to the
other Party under this Agreement, the following conditions must be met for
such indemnification obligations to become applicable:
a) The indemnified Party shall notify the indemnifying Party promptly in
writing of any claim which may give rise to an obligation on the part of
the indemnifying Party hereunder;
b) The indemnifying party shall be allowed to timely undertake the sole
control of the defense of any such action and claim, including all
negotiations for the settlement, or compromise of such claim or action at
its sole expense; provided that in no event will the indemnifying Party
enter into any settlement or compromise of an indemnified claim without
the indemnified Party's prior written consent;
c) The indemnified Party shall at its sole expense render reasonable
assistance, information, cooperation and authority to permit the
indemnifying Party to defend such action.
9.4 Force Majeure
Neither party shall be liable to the other for damages of any sort arising
from any delay or default in such party's performance hereunder caused by
events or conditions beyond such party's reasonable control and which such
party is unable through the exercise of due diligence to prevent,
including, but not limited to, acts of nature, government action, war,
civil commotion, destruction of public utilities or synthesis or
production facilities or materials by earthquake, explosion, fire, flood
or storm ("Force Majeure"). Each party agrees promptly to notify the other
party of any event of Force Majeure and to employ all reasonable efforts
toward prompt resumption of its performance when possible. If Force
Majeure prevents performance by one party of its obligations hereunder in
whole or in part for more than thirty (30) days, the other party shall
have the right to terminate any remaining
17
Phase or Phases of the Project or the remainder of this Agreement upon
written notice to the non-performing party. In no event shall Force
Majeure affecting RPS obligate RPS to procure supplies of Product for CTI
from alternate suppliers, or to allocate its available manufacturing
resources and product supplies in other than a fair and reasonable manner
giving equal consideration to the internal manufacturing needs of RPS and
its Affiliates and to the needs of CTI and RPS' other regular customers
whether or not they are then under contract. However, if an event of Force
Majeure prevents RPS from providing Compound to CTI, RPS shall provide any
reasonable assistance required by CTI in establishing a new supplier of
the Compound, at CTI's sole cost and expense.
Notwithstanding anything to the contrary in the immediately preceding
paragraph of this Section 9.4, it is understood and agreed that any action
by the British Health and Safety Executive, or other governmental body
having jurisdiction, not brought about due to the negligence or willful
misconduct of RPS and that requires RPS, in its reasonable judgment, to
curtail, delay, suspend or cease the manufacturing of the Compound due to
health, safety or environmental issues associated with the use of CTI
Technology to manufacture Compound at the Manufacturing Site will be
deemed to be an event of Force Majeure within the terms of such preceding
paragraph.
9.5 Arbitration
Any controversy or claim arising under this Agreement, or the breach
thereof which cannot be settled amicably within a period of two (2) months
after the date of notification, by registered mail, of the controversy or
claim by one Party to another shall be settled exclusively by arbitration
in Boston, Massachusetts, in accordance with the Rules of Conciliation and
Arbitration of the International Chamber of Commerce ("ICC") then in
effect, such arbitration to occur before a single arbitrator mutually
agreeable to both parties; provided however that, in urgent situations in
which time is of the essence to obtain proper remedies, the rights of the
Parties to bring claims or actions in Courts of law shall remain
unimpaired. The arbitrator shall render his/her decision within thirty
(30) days of the completion of the hearing, and may, in his/her
discretion, award costs and expenses (including attorneys' fees) to the
winning Party. The judgment and award of the arbitrator shall be final and
binding and may be entered in any court having jurisdiction thereof, or
application may be made to such court for judicial acceptance of any award
or an order of enforcement, as the case may be. Under no circumstances
shall the arbitrator be authorized to award punitive or multiple damages,
including but not limited to federal or state statutes permitting multiple
or punitive damage awards, except to the extent that a party entitled to
indemnification under Section 9 above is finally determined to be liable
to a Third Party for such damages and the arbitrator awards recovery of
such damages to the indemnified party under the terms of Section 9. Any
purported award of punitive or multiple damages or of other damages not
permitted under this Agreement shall be beyond the arbitrator's authority,
void, and unenforceable. RPS and CTI shall share equally the fees and
expenses of the arbitrator. It is further understood between the parties
that both the arbitration proceeding and the arbitration award will be
confidential and kept confidential by the arbitrator, the ICC and the
Parties, except for such disclosure as may be required to comply with
legally required corporate disclosure and disclosure to shareholders,
investors, alliance partners, accountants, attorneys and financial
advisors of the disclosing party.
10.0 TERM AND TERMINATION
10.1 This Agreement shall enter into force as of the Effective Date of the
Agreement and, unless earlier terminated, shall continue in full force and
effect through December 31, 2009, and this Agreement shall automatically
renew for successive Contract Years
18
thereafter (collectively the "Term") at the Compound price last in effect
in the immediately preceding Contract Year, unless RPS provides CTI with
not less than eighteen (18) months prior written notice of cancellation of
this Agreement.
10.2 CTI shall have the right to terminate this Agreement for any reason upon
twelve (12) months advance written notice to RPS, provided that CTI may
not terminate this Agreement prior to January 1, 2008 through the exercise
of its termination right under this Section 10.2 for the purpose of
replacing RPS as the exclusive supplier of Compound to CTI and its
Affiliates during the Initial Delivery Period and/or as the supplier of
the Annual Contract Volume to CTI and its Affiliates through December 31,
2007.
10.3 Sections 4, 5, 8, 9, and 13 shall survive any termination of this
Agreement. The obligations under Section 7 of this Agreement shall
terminate five (5) years after the termination of this Agreement.
10.4 Either Party shall have the right, without prejudice to any other rights
or remedies available to it, to terminate this Agreement for cause with
immediate effect by written notice to the other Party in any of the
following events:
a) The other Party defaults in the performance of any of its material
obligations under this Agreement and such default continues
unremedied for thirty (30) days from the date that written notice of
such default is delivered to the defaulting Party, except that such
cure period shall (i) be limited to ten (10) business days from the
date of delivery of such notice in the case of a payment default and
(ii) not be available to CTI in the case of a breach by CTI of any
of its covenant to maintain the Licenses contained in Section 8.3
here above;
b) The other Party intentionally makes (or is discovered to have
intentionally made) any material false representations in connection
with this Agreement;
c) Any of the representatives of the Parties engages in (or is
discovered to have engaged in) fraudulent, criminal or negligent
conduct in connection with this Agreement;
d) The other Party files a petition in bankruptcy, has a petition in
bankruptcy involuntarily filed against it, is adjudicated a
bankrupt, files for reorganization, is placed in liquidation, makes
a general assignment for the benefit of its creditors (other than a
solvent financial reorganization), becomes insolvent or is otherwise
unable to fulfill its payment obligations generally as they become
due.
10.5 CTI may also terminate this Agreement at any time upon six (6) months
prior written notice to RPS in the event that CTI terminates its plans to
commercialize the Compound for all therapeutic indications, whether human
or veterinary.
10.6 Notwithstanding anything to the contrary herein contained, the Parties may
terminate this Agreement if the Parties, together, determine that one or
more of the Validations concerning the Compound as required under
applicable Governmental Approvals, including without limitation the
repeatability of the manufacturing process and other requirements under
applicable cGMP, is not feasible.
10.7 Consequences of Termination
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(a) Promptly after notice of termination from either Party under any
provision of Section 10.5 and 10.6, CTI and RPS shall meet to
discuss and agree in writing upon a manufacturing wind down plan for
this Agreement ("Wind Down Plan"). Such Wind Down Plan shall
include, among other things, a mutually agreeable quantity of
Compound that RPS will continue to manufacture during the
termination period, if any; provided however,that
in the event of a termination by CTI under Section 10.5, at a
minimum, RPS shall be entitled to complete the manufacturing of all
Compound work-in-progress at the time CTI's notice of termination is
received by RPS. In the case of termination by CTI under Section
10.2 or by RPS under Section 10.1 the Parties shall also meet to
agree on a Wind Down Plan, provided, however, that each of the
Parties shall be expected to carry out their
respective Compound manufacturing, sale, and purchase obligations
hereunder through the applicable termination date without any
reduction in the volume of Compound required to be so manufactured,
sold and purchased.
(b) In the event of a termination by CTI under Section 10.5, CTI will
pay to RPS the price applicable hereunder for all Compound
manufactured by RPS hereunder prior to receipt of CTI's termination
notice (including without limitation all validation batches and
[**]), for all additional Compound that has been agreed by the
Parties in the Wind Down Plan to be made during the termination
period, if any, and, if none, then CTI will purchase all Compound
manufactured from work-in-progress at the time CTI's termination
notice is received by RPS at RPS's cost; provided, however, that CTI
shall not be obliged to purchase any minimum additional volume of
Compound to be produced during such termination period as might be
required under the terms of Section 2.1(b) unless CTI wishes to do
so in its sole discretion;
(c) In the event of a termination by CTI under Sections 10.2 or 10.5,
CTI will reimburse RPS for its cost of unused Raw Materials and
intermediates to the extent that RPS is not able to cancel an order
for or resell any of such Raw Materials and intermediates to Third
Parties. Upon the request of CTI, RPS shall deliver all such Raw
Materials and intermediates to a location indicated by CTI, at CTI's
sole cost and expense;
(d) In the event of a termination by CTI under Sections 10.2 or 10.5,
CTI will reimburse RPS for all other out-of-pocket costs and
expenses reasonably incurred by RPS due to the early termination of
this Agreement by CTI, including without limitation any cost
associated with the cancellation of contracts for supplies,
materials and services purchased by RPS in reliance upon this
Agreement running for its full Term and will reimburse RPS for
[**]-percent ([**]%), or such lesser percentage as mutually agreed
at the time (taking into account, among other things, the amount of
Compound purchased by CTI as of the date of the notice of
termination and the extent of the capital work already completed),
of (i) any costs and expenses incurred by RPS in connection with the
work described in the Manufacturing Site Capital Project and (ii)
the reasonable out-of-pocket cost of [**] any such capital
improvements that RPS must undertake; provided, however, that the
combined total of (i) and (ii) shall not exceed US$ [**], and that
CTI will have no liability to RPS for such costs in (i) or (ii) if
CTI purchases no less than [**] metric tons of Compound hereunder at
a price of no less than the Initial Delivery Period price of
US$[**] per kilo;
(e) At CTI's request, RPS shall provide to CTI all Intellectual Work
Product documentation and information that is in RPS' possession,
including, but not limited to, identification of suppliers of Raw
Materials and instructions for the synthesis, processing and
analysis of the Compound and shall provide such reasonable
assistance needed by CTI to transfer the production of the Compound
or any Raw Material to a Third Party ("Technology Transfer");
20
(f) In the event that CTI terminates this Agreement under Sections 10.2
or the Parties terminate this Agreement under Section 10.6, CTI
shall reimburse RPS for any reasonable out-of-pocket costs and
expenses RPS incurs for the Technology Transfer, including without
limitation FTE expenses at RPS at the rates then charged by RPS;
(g) In the event that RPS terminates this agreement under Section 10.1,
CTI shall not be obligated to reimburse RPS for any costs or
expenses, including FTE costs, that RPS expends for any Technology
Transfer;
(h) RPS shall grant a fully paid-up, royalty-free, worldwide, perpetual
non-exclusive license (with the right to sub-license) to any RPS
Technology concerning the manufacturing of the raw material 2ABT;
and
(i) In the event of the termination of this Agreement under Section
10.6, CTI's sole liability shall be for the payment to RPS of (i)
the purchase price for the validation batches of Compound produced
by RPS per Section 2.1(a) above and (ii) the purchase price for any
commercial scale Compound then produced by RPS under Section 2.1(b)
above (including without limitation all validation batches and
[**]).
(j) It is understood and agreed between the Parties that the types of
costs and expenses that CTI must reimburse to RPS as described in
this Section 10.7 are deemed to be direct damages of RPS, and
nothing in this Section 10.7 shall limit RPS' right to recover such
costs and expenses as direct damages from CTI in the event of a
breach of this Agreement by CTI, including without limitation (i)
any costs and expenses incurred by RPS in connection with the work
described in the Manufacturing Site Capital Project and (ii) the
reasonable out-of-pocket cost of [**] any such capital improvements
that RPS must undertake; provided, however, that the combined total
of (i) and (ii) shall not exceed the lesser of [**]-percent ([**]%)
of such costs and expenses or US$ [**], and that CTI will have no
liability to RPS for such costs in (i) or (ii) if CTI purchases no
less than [**] metric tons of Compound hereunder at a price of no
less than the Initial Delivery Period price of US$[**] per kilo.
11.0 CRITICAL INTERFACES AND NOTICES
11.1 All notices referred to herein shall be sent by prepaid registered mail,
by recognized courier service (such as Federal Express), or by facsimile
and shall be deemed delivered if sent to the addresses of the respective
Parties hereinbelow indicated, or such other address as is furnished by
such notice to the other Party.
Notices to RPS shall be made to:
RHODIA PHARMA SOLUTIONS LTD.
Dudley, Xxxxxxxxxxx
Xxxxxxxxxxxxxx XX00 0XX
Xxxxxxx
Attn: Xxxxxxxx Xxxx
Fax: 000 00 000 000 0000
Phone: 000 00 000 000 0000
e-mail: xxxxxxxx.xxxx@xx.xxxxxx.xxx
with a copy to:
RHODIA PHARMA SOLUTIONS INC.
000 Xxxxxxxx Xxxxxx Xxxx
Xxxxxxxx, XX 00000-0000
21
Attn: Xxxx Xxxxxxx
Fax: 919/000-0000
Phone: 919/000-0000
e-mail: xxxx.xxxxxx@xx.xxxxxx.xxx
Notices and invoices to CTI shall be made to:
CRITICAL THERAPEUTICS, INC.
00 Xxxxxxxx Xxxxxx
Xxxxxxxxx, XX 00000
XXX
Attn: Chief Financial Officer
Fax: 000-000-0000
Phone: 000-000-0000
11.2 Status Updates
RPS shall keep CTI regularly informed of the status and progress of all
Phase 1 and 2 work through regular telephone or e-mail updates, [**] and
through written summaries.
11.3 Contact Procedures
The following individuals shall serve as initial points of contact at RPS
and CTI with respect to any questions or occurrences that may arise with
respect to the Agreement and the work conducted hereunder:
RPS CONTACTS:
Technical Matters: Xxx Xxxxxxx
Payment or Financial Matters: Xxxxx Xxxxxx
Business Matters: Xxxx Xxxxxxx/Xxxxxxxx Xxxx
Contract Matters: Xxxxxxx Xxxxxxx, Esq.
CTI CONTACTS:
Technical Matters: Xxxxxx Xxxxxxxxx
Payment or Financial Matters: Xxxxx Xxxxxx
Business Matters: Xxxxx Xxxxxxxxx
Contract Matters: Xxxxxxx X. Xxxxxxxx, Esq.
11.4 Change Management
RPS will promptly notify CTI whenever there is a change in management or
key personnel connected with the work to be conducted by RPS hereunder.
11.5 Complaint Procedures
Procedures to address any complaint related to the manufacturing of the
Compound are contained in the standard operating procedures (SOPs) for the
Manufacturing Site.
22
11.6 Responsibility for Regulatory Communications
(a) CTI will have responsibility for initial regulatory communication with
the FDA and other Governmental Authorities regarding the manufacture of
the Compound.
(b) RPS will have responsibility for providing back-up assistance and
support as requested by CTI in connection with communications with the FDA
and other Governmental Authorities regarding the manufacture of the
Compound.
12.0 ASSIGNMENT
12.1 This Agreement is deemed personal to CTI and RPS. Neither Party shall,
without prior written consent of the other Party, assign this Agreement or
any of its rights nor delegate any of its duties or obligations herein;
provided, however, that either party shall be entitled to assign its
rights under this Agreement to an Affiliate or in connection with the sale
of all or substantially all of its business and assets to which the
subject matter of this Agreement pertains without the prior consent of the
other party so long as the permitted assignee assumes in writing, in form
and substance reasonably satisfactory to the non-assigning party, all
obligations of the assigning party under this Agreement or the obligations
under the specific terms of this Agreement that are the subject of such an
assignment.
13.0 MISCELLANEOUS
13.1 Waivers
Failure of either Party at any time to require strict performance by the
other Party of any of the provisions of the Agreement shall in no way
affect the right thereafter to enforce the same, nor shall the waiver of
any term, provision, covenant or condition hereof be taken or held to be a
waiver of any subsequent breach hereof or as nullifying the effectiveness
of such term, provision, covenant or condition.
13.2 Counterparts
This Agreement may be executed in two or more counterparts, which all
together shall constitute one instrument.
13.3 Entire Agreement
This Agreement embodies the entire understanding of the Parties concerning
the manufacturing of the Compound from and after the Effective Date and
shall supersede all previous communications, representations, or
understandings, either oral or written, between the Parties relating to
that subject matter hereof; provided that it is expressly understood that
this Agreement shall not supersede the Proposal Agreement, and, in respect
of such Proposal Agreement: (a) this Agreement supplements the terms
thereof and, in particular, shall govern the rights and obligations of the
parties to the extent that any validation batches of Compound that are the
subject of such Proposal Agreement become commercial batches of Compound
after the completion of the requisite Validations hereunder, and (b) in
the event of any conflict between the terms of this Agreement and the
terms of such Proposal Agreement, the terms of this Agreement shall
control.
13.4 Amendments
No amendments or modifications of this Agreement will be deemed legally
binding unless made in writing and signed by both Parties hereto.
13.5 Severability
In case one or more of the provisions contained in this Agreement shall,
for any reason, be held invalid, illegal, or unenforceable in any respect,
such invalidity,
23
illegality or unenforceability shall not affect any other provision of
this Agreement, but this Agreement shall be construed by amending or
limiting such invalid, illegal, or unenforceable provision so as to
conform as closely as possible to the intent of the Parties or, if such is
not possible, by deleting such provision from this Agreement.
13.6 Annexes
Should any internal discrepancies or variances occur between this
Agreement and its annexes, this Agreement shall take precedence except to
the extent that any provision in such annexes specifically cites the
provision in this Agreement over which it takes precedence.
13.7 Governing Law
This Agreement is made under and shall be construed in accordance with the
laws of the State of Delaware, without regard to the conflicts of law
principles thereof. The Parties agree that the United Nations Convention
on Contracts for the International Sale of Goods (1980) shall not apply to
this Agreement.
13.8 Headings
The headings in this Agreement may not be used in the interpretation of
any provisions hereof.
13.9 Use of Names & Publicity
Except as expressly required pursuant to law, neither Party or its
Affiliates will without prior written consent of the other:
(a) Use in advertising, publicity, promotional premiums or otherwise,
any trade name, trademark, trade device, service xxxx, symbol, or
any abbreviation, contraction or simulation thereof owned by the
other Party,
(b) Represent, either directly or indirectly, that any product or
service of one Party is a product or service of the other, or
(c) In addition to any public announcements allowed under Section 7.7
above, issue or cause to be issued any press release or other
announcement or public communication with respect to this Agreement
or the transactions contemplated hereby and, in addition to
obtaining the other Party's prior consent, the other Party will be
consulted concerning the timing and content of such press release,
announcement or communication before the same is issued or
published.
24
IN WITNESS WHEREOF, the Parties hereto through their authorized
representatives have executed this Agreement as of the Effective Date.
RHODIA PHARMA SOLUTIONS LTD.
By: /s/ Xxxx Xxxxx
----------------------------------
Title: President
Date: 2/8/05
CRITICAL THERAPEUTICS, INC.
By: /s/ Xxxxxx Xxxxxxxx
----------------------------------
Title: Chief Operating Officer
Date: 2/8/05
25
ANNEX 1
Rhodia Pharma Solutions Authorized: /s/ X. Xxxxxxxx
13-10-2004
[**] (micronised IR) Page 1 of 4
METHOD OF ANALYSIS No: 6000721/S/2
First Issued: GB/SW
Revised & Re-issued LW/TMS
CHANGES SINCE PREVIOUS ISSUE
1. Updated following customer review.
Written by: Checked by: Authorised by: Date of Issue: Review Date:
/s/Xxx Xxxxxxx /s/Xxxx Xxxxx /s/X. Xxxxxxxx 12-10-2004 October 2006
[LOGO] Authorised:
QUALITY DEPARTMENT
[**] MICRONISED (IR) Page: 2 of 4
SPECIFICATION No: [**]
1. Appearance
[**]
2. Identity by Infra Red Spectrum
The sample spectrum should compare to that of an authentic reference
standard.
3. Specific Rotation
[**]
4. Residue on Ignition
[**]
5. Foreign matter 2% solution in methanol
[**]
6. Clarity 2% Methanol
[**]
7. Heavy Metals
[**]
8. Colour 2% in Methanol
[**]
9. Particle Size
[**]
10. Tapped Density
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QUALITY DEPARTMENT
[**] MICRONISED (IR) Page: 3 of 4
SPECIFICATION No: [**]
[**]
11. Water Content
[**]
12. Assay and Impurity (Identity)
[**]
Impurities: [**]
[**]
13. [**]
[**].
14. Residual Solvents
[**]
15. Crystal Form by XRD
[**]
16. Salmonella
[**]
17. E. Coli
[**]
18. Aerobic Microbial Count
[**]
19. Surface Area
[LOGO] Authorised:
QUALITY DEPARTMENT
[**] MICRONISED (IR) Page: 4 of 4
SPECIFICATION No: [**]
[**]
20. Particle Size by laser diffraction
[**]
Rhodia Pharma Solutions Authorized: /s/ X. Xxxxxxxx
13-10-2004
[**] (micronised IR) Page 1 of 25
METHOD OF ANALYSIS No: [**]
Version 3
First Issued: GB/SW
Revised & Re-issued GB/TMS
Revised & Re-issued LW/TMS
CHANGES SINCE PREVIOUS ISSUE
1. Updated following customer review.
Written by: Checked by: Authorised by: Date of Issue: Review Date:
/s/Xxx Xxxxxxx /s/Xxxx Xxxxx /s/X. Xxxxxxxx 12-10-2004 October 2006
[LOGO] Authorized:
[**] (MICRONISED IR) Page 2 of 19
METHOD OF ANALYSIS No: [**]Version 3
NOTE THE REFERENCES TO SOP'S CONTAINED WITHIN THE TEXT IN THIS METHOD OF
ANALYSIS, ARE SPECIFIC TO THE QC LABORATORY RHODIA PHARMA SOLUTIONS XXXXX. OTHER
LABORATORIES USING THIS METHOD SHOULD REFER TO THEIR OWN RELEVANT PROCEDURES
1. APPEARANCE
See relevant SOP "use of the G210 colour matching cabinet"
View the appearance of the sample against a white background noting the
presence of any visible impurities.
2. IDENTITY BY IR
See relevant SOP " use of the XXXXXX-XXXXX RX II spectrum FTIR" and "Use
of KBr disks"
Prepare a KBr disc of the sample as per the SOP. Scan the spectrum between
4000 cm(-1) and 400 cm(-1). Alternatively scan a neat sample between
4000cm(-1) and 400cm(-1) using a diamond ATR accessory. Compare the
spectrum to that of an authentic reference standard.
3. SPECIFIC ROTATION
See relevant SOP "Use of the Polaar 2001 polarimeter".
3.1 Procedure
NOTE: Procedure must be performed at 25 degrees C.
Weigh 100mg of sample into a 10ml volumetric flask, dissolve and dilute to
volume with methanol, transfer this solution into a 1dm micropolarimeter
tube and determine the angular rotation of the solution. Carry out a blank
determination using methanol and correct the sample readings accordingly.
3.2 Calculation
Specific rotation = (sample rotation degrees - blank rotation degrees) x 100
------------------------------------------------------- x 100
1(dm) x (100 - moisture) x (sample weight g/100ml)
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[**] (MICRONISED IR) Page 3 of 19
METHOD OF ANALYSIS No: [**]Version 3
4. RESIDUE ON IGNITION
See relevant SOP "Use of the muffle furnace".
4.1 Procedure
Pre-treat a clean porcelain crucible with sulphuric acid at 600 degrees C
+ or - 25 degrees C overnight, allow to cool and record the weight.
Accurately weigh 1-2g of sample into the crucible. Heat gently until
thoroughly charred, do not allow the sample to ignite into flames. Moisten
the residue with 1ml of sulphuric acid and heat gently until no white
fumes are produced. Ignite at 600 degrees C + or - 25 degrees C in a
muffle furnace until all of the carbon is consumed. Allow the crucible to
cool for 3 minutes then place into a dessicator and allow to cool to room
temperature, reweigh and record the weight.
Note: the time taken to cool to room temperature should approximate that
of the cooling time prior to analysis (approximately 45 minutes) although
this will increase if more than one crucible has to be cooled at the same
time. Report the result to 1 decimal place.
4.2 Calculation
% residue on ignition = weight of residue (g) x 100
----------------------------
Weight of sample (g)
5. FOREIGN MATTER 2% SOLUTION IN METHANOL
Dissolve 0.2g of sample in 10ml of methanol and observe the solution for
foreign matter.
6. CLARITY 2% METHANOL
6.1 Solution Preparations
6.1.1 Hydrazine Sulphate
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METHOD OF ANALYSIS No: [**]Version 3
Dissolve 1.0g of hydrazine sulphate R in 100ml of water, allow to stand
for 4 to 6 hours.
6.1.2 Hexamethylenetetramine Solution
Dissolve 2.5g of hexamethylenetetramine R in 25.0ml of water in a 100ml
glass stoppered flask.
6.1.3 Primary Opalescent Suspension
To the hexamethylenetetramine solution prepared as per 6.1.2 add 25ml of
the hydrazine sulphate solution prepared as per 6.1.1. Mix and allow to
stand for 24 hours. This has an expiry of 2 months if kept in a glass
container free from surface defects. The suspension must not adhere to the
glass and must be mixed well before use.
6.1.4 Opalescence Standards
Dilute 15ml of primary opalescent suspension prepared as per 6.1.3 to
1000ml with water. This has an expiry of 24 hours. Pipette 5ml and 10ml of
the opalescence standard suspension into two separate 100ml volumetric
flasks and dilute to volume with water. Fill two 50ml colour comparison
tubes with each of the standards. These are reference suspensions 1 and 2
respectively.
6.2 Sample Preparation
Weigh 2g of sample into a 100ml volumetric flask, dissolve and dilute to
volume with methanol. Retain this sample for colour test.
6.3 Blank Preparation
Fill a 50ml colour comparison tube to the xxxx with methanol.
6.4 Procedure
View the tubes in diffused daylight 5 mins after preparation. View
vertically against a black background such that the blank, reference
suspension 1 and reference suspension 2 can be easily distinguished from
one another.
[LOGO] Authorized:
[**] (MICRONISED IR) Page 5 of 19
METHOD OF ANALYSIS No: [**]Version 3
A liquid is considered clear if its clarity is the same as the solvent
used, or if its opalescence is not more pronounced than that of
opalescence reference suspension 1 when examined under the conditions
explained above.
7. HEAVY METALS
7.1 Reagent Preparation
7.1. Lead Nitrate Solution
To 100ml of water add 1ml of nitric acid and 159.8mg of lead nitrate.
Dissolve and dilute with water to 1000ml (prepare and store in glass
containers).
7.1.2 Standard Lead Solution
Dilute 10.0ml of lead nitrate stock solution to 100.0ml with water.
7.1.3 pH 3.5 acetate buffer
Dissolve 25.0g of ammonium acetate in 25ml of water, add 38.0ml of 6M
hydrochloric acid, adjust the pH to 3.5 using 6M hydrochloric acid or 6M
ammonium hydroxide. Dilute with water to 100ml and dissolve.
7.1.4 Thioacetamide TS
Dissolve 4g of thioacetamide in 100ml of deionised water.
7.1.5 1.0M Sodium Hydroxide
Prepare from "convols" or other material Available from chemical
suppliers.
7.1.6 Glycerin base TS
To 200g of glycerol (glycerin) add deionised water and bring the weight to
235g. Add 140ml of 1.0M sodium hydroxide and 50ml of deionised water.
7.1.7 Thioacetamide Glycerin Base TS
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[**] (MICRONISED IR) Page 6 of 19
METHOD OF ANALYSIS No: [**]Version 3
Mix 0.2ml of thioacetamide TS and 1ml of glycerin base TS and heat in a
boiling water bath for 20 seconds. Use the mixture immediately.
7.1.8 1N (1M) acetic acid
Available preprepared from chemical suppliers
7.1.9 6N (6M) Hydrochloric Acid
Dilute 51mls of conc hydrochloric acid to 100mls with deionised water.
7.1.10 6N (6M) ammonium hydroxide
Dilute 33.6mls of "880" (Sp gr 0.88) ammonia to 100ml with deionised
water".
7.2 Standard Preparation
Pipette 2ml of standard lead solution into a 50ml colour comparator tube
and dilute to 25ml with water. Adjust to between pH 3.0 and 4.0 with 1M
acetic acid or 6M ammonium hydroxide and, dilute to 40ml with water and
mix.
7.3 Sample Preparation
Transfer 1g of sample into a crucible, wet sample with sulphuric acid and
ignite at low temperature until thoroughly charred.
Add 2ml of nitric acid and 5 drops of sulphuric acid to the crucible, heat
cautiously until white fumes are no longer produced. Ignite in a muffle
furnace at 600 degrees C +/- 25 degrees C until all the carbon is burned
off.
Cool in a dessicator, add 4ml of 6M hydrochloric acid, cover and digest on
a steam bath for 15 minutes, uncover and evaporate to dryness on a steam
bath.
Moisten with 1 drop of hydrochloric acid and add 10ml of hot water and
digest for 2 minutes.
Add 6M ammonium hydroxide dropwise, until the solution is just alkaline.
Dilute contents to 25ml with water, adjust the pH to between 3.0 and 4.0
with 1M acetic acid.
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[**] (MICRONISED IR) Page 7 of 19
METHOD OF ANALYSIS No: [**]Version 3
If necessary, filter the solution, wash the crucible and the residue
with 10ml of water, pour the filtrate into a graduated 50ml colour
comparator tube, dilute to 40ml and mix well.
7.4 Procedure
To each tube add 2ml of pH 3.5 acetate buffer and 1.2ml of
thioacetamide-glycerin base TS. Dilute each tube to 50mls mix and stand
for 2 minutes. View downwards over a white surface. The colour of the
sample solution should not be darker than that of the standard.
8. COLOUR 2% IN METHANOL
8.1 Solution Preparation
NOTE The reference colour standards B6 and BY6 can be purchased from
chemical suppliers and should be accompanied with certification, or
alternatively they can be made by the method shown below
8.1.1 Yellow Solution
Dissolve 46g of ferric chloride R in about 900ml of a mixture of 25ml of
hydrochloric acid R and 975ml of water (0.3N hydrochloric acid) and dilute
to 1000ml with this mixture.
Place 10ml of solution, 15ml of water, 5ml hydrochloric acid R and 4g of
potassium iodide into a 250ml stoppered conical flask. Allow to stand in
the dark for 15 minutes and add 100ml of water.
Titrate the liberated iodine with standardised 0.1N sodium thiosulphate.
Towards the end of the titration when the solution is a light yellow
colour (about 16ml) add 0.5ml of starch indicator, continue the titration
until the blue colour has gone.
Calculate the concentration of the solution using the following equation:
FeCl(3)6H(2)0(mg/ml) = mls of Na(2)S(2)0(3) x N of Na(2)S(2)0(3) x 27.03mg
Adjust the concentration to within 10% of 45mg/ml by diluting with
0.3N hydrochloric acid using the calculation below.
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[**] (MICRONISED IR) Page 8 of 19
METHOD OF ANALYSIS No: [**]Version 3
ml of 0.3N HCl per 100ml of yellow solution = 100 - 4500
--------------------
FeCl(3)6H(2)0 mg/ml
8.1.2 Red Solution
Dissolve 60g of cobalt chloride R in about 900ml of a mixture of 25ml of
hydrochloric acid R and 975ml of water, dilute to a 1000ml with the same
mixture.
Place 5ml of the solution, 5ml of dilute hydrogen peroxide and 10ml of 30%
w/v sodium hydroxide into a 250ml ground glass stoppered flask.
Boil gently for 10 minutes, allow to cool and add 60ml of dilute sulphuric
acid and 2g of potassium iodide.
Close the flask and dissolve the precipitate by shaking gently.
Titrate the liberated iodine with standardised 0.1N sodium
thiosulphate. Towards the end of the titration (about 12ml) add 0.5ml of
starch indicator, continue the titration until the solution turns pink and
an end point has been reached.
Calculate the concentration of the solution using the following equation.
mg/ml Co(11)Cl(2) = ml of Na(2)S(2)0(3) x N of Na(2)S(2)0(3) x 23.79mg/0.5ml
Adjust the concentration to within 10% of 59.5mg of C0Cl(2)6H(2)0 per ml
by diluting with 0.3N hydrochloric acid using the calculation below:
ml of 0.3N hydrochloric acid per 100ml red solution = 100 - 5950
-----------------
mg/ml Co(11)Cl(2)
8.1.3 Blue Solution
Dissolve 63g of copper sulphate R in about 900ml of a mixture of 25ml
hydrochloric acid and 975ml water, dilute to 1000ml with the mixture.
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METHOD OF ANALYSIS No: [**]Version 3
Place 10ml of solution, 50ml of water, 12ml of dilute acetic acid R and 3g
of potassium iodide into a 250ml ground glass stoppered conical flask.
Titrate the liberated iodine with standardised 0.1N sodium thiosulphate.
Towards the end point (about 24ml) add 0.5ml of starch indicator, continue
titrating until the end point (disappearance of blue to a slight pale
xxxxx).
Calculate the concentration of the solution using the
calculation shown below:
mg/ml CuS0(4)5H(2)0 = mlNa(2)S(2)0(3) x N of Na(2)S(2)O(3) x 24.97mg
Adjust the solution to within 10% of 62.4mg/ml by diluting with 0.3N
hydrochloric acid using the calculation below:
ml/HCl = 100 - 6240
--------------------
mg/ml CuS0(4).5H(2)0
8.1.4 0.3N Hydrochloric Acid
Thoroughly mix together 25ml of hydrochloric acid and 975ml of water.
8.1.5 (0.1M) 0.1N Sodium Thiosulphate
Prepare from convols or other material available from chemical suppliers.
8.1.6 Starch Indicator
0.5% prepared from 1% solution obtainable from chemical suppliers.
8.1.7 Dilute Acetic Acid
Dilute 11.7ml of glacial acetic acid to 100ml with deionised water.
8.1.8 Dilute Hydrogen Peroxide
Dilute 10.0ml of 30% hydrogen peroxide to 100ml with deionised water.
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METHOD OF ANALYSIS No: [**]Version 3
8.1.9 Dilute Sulphuric Acid
Dilute 5.5ml of sulphuric acid to 100mls with deionised water.
8.1.10 30% w/v Sodium Hydroxide Solution
Dissolve 30g of sodium hydroxide in 100ml of deionised water.
8.1.11 1% w/v Hydrochloric Acid
Dilute 1g of hydrochloric acid to 100ml with deionised water.
8.2 Standard Solution B
Into a 200ml volumetric flask pipette 30ml of yellow primary solution,
30ml of red primary solution, 24ml of blue primary solution and 16ml of 1%
w/v hydrochloric acid.
8.2.2 Standard Solution BY
Into a 200ml volumetric flask pipette 24ml of yellow primary solution,
10ml of red primary solution, 4ml of blue primary solution and 62ml of 1%
w/v hydrochloric acid.
8.3 Reference Standard Solution Preparation
Note: Prepare reference standards immediately before use.
8.3.1 Reference Standard B6
Into a 200ml volumetric flask pipette 5ml of standard solution B and 95ml
of 1% w/v hydrochloric acid.
8.3.2 Reference Standard BY6
Into a 200ml volumetric flask pipette 5.0ml of standard solution BY and
mix with 95ml of 1% w/v hydrochloric acid.
8.4 Sample Preparation
See sample preparation for colour test section 6.
8.5 Procedure
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METHOD OF ANALYSIS No: [**]Version 3
Transfer the B6, BY6 reference solutions and the sample solution to
identical xxxxxxx cylinders. The depth of the layer should be 40mm,
compare the solutions in diffused daylight, viewing vertically against a
white background.
The sample solution should not be more intensely coloured than the
reference solutions B6 or BY6.
9. PARTICLE SIZE
See appropriate SOP "Use of Micron Air-jet sieve".
9.1 Operating Conditions
Vacuum: not less than 12 inches of water.
Time: 120 seconds
Sieve: [**]
9.2 Procedure
Weigh 3 x 20g of sample.
Inspect the sieve for defects and cleanliness.
Assemble the sieve rubber gasket and cover and weigh.
Place assembled sieve on top of the vacuum unit and test the vacuum top
ensure it is within the specified limits.
Distribute the sample evenly onto the sieve and sieve for 120 seconds,
record the initial vacuum to the nearest 0.1 inch of water.
After the sieve stops, reweigh.
Using at least one additional sieve repeat the above procedure for the two
remaining samples. Report result to 1 decimal place.
9.3 Calculation
% retained = final weight (g) - tare weight (g)
---------------------------------- x 100%
Sample weight (g)
Where: final weight = weight of sieve assembly after sieving
[LOGO] Authorized:
[**] (MICRONISED IR) Page 12 of 19
METHOD OF ANALYSIS No: [**]Version 3
Tare weight = weight of sieve assembly before adding sample
Sample weight = weight of sample placed on sieve
10. TAPPED DENSITY
See appropriate SOP "Use of bulk density equipment".
10.1 Procedure
Place the empty cylinder on the balance and tare. Add approximately
40g of sample to the cylinder while holding the cylinder at a 30 degrees C
angle. Gradually bring the cylinder upright and level the powder, record
the weight of sample used. Place the cylinder into the bulk density
apparatus and tap 1000 times, record the volume of the sample after
tapping is complete and calculate the density. Report result to 2 decimal
places.
10.2 Calculation
Tapped density = weight of sample (g)
-----------------------
volume of sample (ml)
11. WATER CONTENT
See appropriate SOP "Use of the Xxxxxxx XX00 Xxxx Xxxxxxx titrator"
11.1 Procedure
Following the SOP, use a sample weight of 0.90 - 1.10g and methanol as the
carrier solvent. Determine the water content % w/w in duplicate. Report
the mean result to 1 decimal place
12. ASSAY AND IMPURITY (IDENTITY)
See relevant SOP "Use of HP1100 series HPLC system".
[LOGO] Authorized:
[**] (MICRONISED IR) Page 13 of 19
METHOD OF ANALYSIS No: [**]Version 3
12.1 Conditions
[**]
12.2 Mobile Phase and Diluent Preparation
[**]
12.3 Gradient Program
[**]
12.4 Impurities Reference Solution (stable for [**])
[**]
[LINE GRAPH]
[**]
[LINE GRAPH]
[LOGO] Authorized:
[**] (MICRONISED IR) Page 14 of 19
METHOD OF ANALYSIS No: [**]Version 3
[**]
[LINE GRAPH]
12.10 Integration
ONLY INTEGRATE UP TO 90 MINS. Integrate all impurities greater than 0.01%
of the main [**] peak area. For any impurities that are not weighed out in
the impurity standard calculate the impurity content as per the assay
calculation using the [**] peak area and weight and the relevant RF for
the imp from section 12.9.
12.11 Manual Calculations
%recovery = Area std 2 x weight imp in Std 1 x 100
Mean area std 1 weight imp in Std 2
Assay (%w/w) = Area(sample) x Weight of std (mg) x reference purity x RF
Mean area (std1) weight of sample (mg)
Assay anhydrous = Assay x 100
-----------------------
100 - % water content
Weighed Impurity content (%w/w) = Area(sample) x weight of impurity (mg) x 1 x Reference purity
-------------------------------------------------------------
Mean area (std1) weight of sample (mg) 100
[**]
[LOGO] Authorized:
[**] (MICRONISED IR) Page 15 of 19
METHOD OF ANALYSIS No: [**]Version 3
The identity shall be positive if the retention time of the [**] resembles
that of an authentic reference standard within +/- 0.5 mins.
13. [**] DETERMINATION
[**]
[LINE GRAPH]
[**]
[LINE GRAPH]
[**]
[LOGO] Authorized:
[**] (MICRONISED IR) Page 16 of 19
METHOD OF ANALYSIS No: [**]Version 3
[LINE GRAPH]
13.11 Manual Calculations
% Recovery of STD 2 = area std 2 x weight std 1 x 100
--------------------------------------
Mean area std 1 weight std 2
[**](ppm) = area (sample) x std weight (mg) x 5 x reference purity
-------------------------------------------------------
Mean area (std1) sample weight (mg)
14. RESIDUAL SOLVENTS
See relevant SOP "Use of HP5890 and HP6890 series gas chromatographs".
14.1 GC Conditions
[**]
14.2 Headspace Conditions
[**]
[LOGO] Authorized:
[**] (MICRONISED IR) Page 17 of 19
METHOD OF ANALYSIS No: [**]Version 3
[LINE GRAPH]
[**]
[LINE GRAPH]
14.9 Manual Calculations
% recovery std 2 = R std 2
------------
Mean R std 1
Response ratio (R ) analyte = area analyte
-------------
area ISTD
Solvent content (% w/w) = R sample x weight of std (g) x 1 x 2 x purity
------------------------------------------------
R std weight of sample (g) 100 100
Weight of standard (g) = vlme taken (ml) x specific gravity
[LOGO] Authorized:
[**] (MICRONISED IR) Page 18 of 19
METHOD OF ANALYSIS No: [**]Version 3
[**]
15 XRD
This analysis shall be performed by the Analytical Development Group,
Rhodia Pharma Solutions, Xxxxxx.
See appropriate SOP "Philips X'pert X-Ray Diffractometer
[**]
16. SALMONELLA
Analysis will be performed by an external laboratory.
17. E COLI
Analysis will be performed by an external laboratory.
18. AEROBIC MICROBIAL COUNT
Analysis will be performed by an external laboratory.
19. SURFACE AREA
This will be carried out by an external laboratory.
20. PARTICLE SIZE (BY LASER DIFFRACTION)
When required this analysis will be carried out by an external laboratory
[LOGO] Authorized:
[**] (MICRONISED IR) Page 19 of 19
METHOD OF ANALYSIS No: [**]Version 3
21. HANDLING INFORMATION
CHEMICAL RISK CATEGORY HANDLING CATEGORY
---------------------- ------------- -----------------
Zileuton ([**]) 12 C
Methanol 1,2,12 B
Sulphuric acid 2,12 D1
Hydrazine sulphate 2,5,6,12 D1
Hexamethylenetetramine 2,4,5,12 D1
Nitric acid 1,2,12,13 D1
Lead nitrate 1,2,6,9,12 C
Ammonium acetate 2,12 B
Hydrochloric acid 1,2,1,2,13 D1
Acetic acid 1,2,12,13 D1
Thioacetamide 2,4,11,12 D1
1.0M sodium hydroxide 1,2,12,13 C
Glycerol 2,12 B
Ammonia 2,12,13 D2
Ferric chloride 2,12,13 C
Potassium iodide 2,6,12 C
Sodium thiosulphate 1,2 D1
Starch indicator 3 B
Cobalt chloride 2,3,4,5,6,12 D1
Hydrogen peroxide 2,12,13 B
Copper sulphate
Hydranal composite 5 2,12 D1
Triethylamine 2,12,13 D1
THF 2,11,12 C
Acetonitrile 1,5,6,12 D1
Acetohydroxamic acid
IPA 1,2,12 B
Ethanol 2,12 B
Ethyl acetate 2,12 B
DMA 2,12 C
Toluene 2,6,9,11,12 D1
D.SOP014A/018 REV 3 ANNEX 2
PPQP NO. 04.23
PAGE 1 OF 33
[RHODIA LOGO]
PHARMA SOLUTIONS
PROCESS PERFORMANCE QUALIFICATION PROTOCOL
PROJECT NAME: [**] PROJECT NO. N/A
PPQP NO. PPQ.04.23 PPQP.04.23 ISSUE NO. 1
PREPARED BY: /s/ X. Xxxxxxxx DATE: 7TH OCTOBER 2004
REVIEWED BY:
Validation: /s/ Xxxxx Xxxxx DATE: 07 Oct 2004
APPROVED BY:
R & D Chemist (if applicable): /s/ X. Xxxx DATE: 7-10-04
Quality Services /s/ X. Xxxxxx DATE: 8th October 2004
Manufacturing /s/ X. Xxxxxxx DATE:7.10.04
OQ Manager: /s/ Xxxxx Xxxxxxx DATE: ................
ADDENDUM
UPDATE DATE ATTACHED REASON FOR UPDATE
------ --------- -------- -----------------
REVISION DATE REASON FOR REVISION
-------- -------- -------------------
DISTRIBUTION LIST
ORIGINAL- VALIDATION FILE D SOWERBY S TREVENEN A XXXXXX CTI
S XXXXXXX K THOMSON R XXXXXX
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PPQP No. 04.23 PAGE 2 OF 33
CONTENTS
1. SUMMARY
2. INTRODUCTION
3. OBJECTIVES
4. VALIDATION METHODOLOGY
4.1 OVERALL PHILOSOPHY
4.2 PREREQUISITES
4.3 PROCESS SUMMARY
4.4 CRITICAL PROCESSING PARAMETER
4.5. YIELD
4.6 EQUIPMENT
4.7 SAMPLING & ANALYSIS
4.8. ACCEPTANCE CRITERIA
4.9. SPECIFICATION
5. REFERENCE DOCUMENTS
6. REPORTING AND ARCHIVAL
7. PREREQUISITES TO PPQ
8. PROCESSING PARAMETERS
9. RAW MATERIAL / INPUT MATERIAL SUMMARY
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1. SUMMARY
The process for the manufacture of [**] is to undergo validation in the
Pilot Plant production building, Rhodia Pharma Solutions (RPS) (Dudley),
Cramlington, Northumberland.
This protocol has been written in accordance with D.SOP014A/018 and
D.SOP014A/008.
In accordance with D.SOP014A/008, the customer has requested that the
validation batches be released on a batch-by-batch basis prior to the
completion of the validation study.
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2. INTRODUCTION
[**] is an API manufactured for CTI and is used in the treatment of
asthma.
[**] is manufactured in the Xxxxxx Pilot Plant production building. The
material is then sent to [**] for milling, then returned to RPS for for
full analytical testing and release.
The purpose of this protocol is to demonstrate how the PPQ exercise
relating to the manufacture at Xxxxxx will be conducted, controlled and
documented.
The milling exercise at [**] will be validated separately.
The PPQ will be carried out in accordance with this protocol.
D.SOP014A/008 states that:
`a pre-validation review is conducted following the manufacture of the
commissioning / demonstration batches.'
This review shall not occur during the current campaign prior to the
validation exercise and after the commissioning batches, as the validation
campaign is proposed to commence with the first batch of the campaign. The
pre-validation review will therefore be conducted by reviewing the second
campaign report as per D.SOP014A/008.
The review will be conducted in this fashion as a [**] batch
pre-validation manufacturing campaign using the identical process and
equipment during July 2004. No changes have been made to the process or
the equipment since this campaign. Therefore, the material produced during
July 2004 will be considered as the commissioning batches and on this
basis, the validation campaign will commence with the first batch of the
current manufacturing campaign.
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3. OBJECTIVES
- [**] API (excluding milling) process will operate consistently
according to the approved PRS.
- [**] API (excluding milling) process will consistently produce
material that meets the current analytical specification.
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PPQP NO.04.23
4. VALIDATION METHODOLOGY
4.1 OVERALL PHILOSOPHY
4.1.1 The process to be validated will be that specified in the Rhodia
Pharma Solutions.
4.1.2 [**] pre-nominated consecutive batches must meet validation
criteria.
4.1.3 Validation of the [**] manufacture will be considered complete upon
compliance with this protocol.
4.1.4 Once the PPQ has been completed, a PPQ Report will be issued
summarising the validation activity and the achievement against the
requirements of the protocol.
4.1.5 Data will be compiled in a copy of the table in Section 8 as part of
the PPQ Report.
4.1.6 Raw materials must comply with the applicable specifications and be
released by QC prior to use.
4.2 PREREQUISITES
Before commencement of the Process Performance Qualification (PPQ)
exercise the following conditions must be satisfied:
4.2.1 All instruments or equipment used to monitor process parameters must
be calibrated and calibration must cover the range of use and be
within the current calibration period.
4.2.2 Satisfactory completion of process [**]. [Ref. No. 04.23]
4.2.3 Satisfactory completion of any relevant analytical methodology
validation.
4.2.4 Satisfactory completion of any relevant software validation.
4.2.5 Completion of the pre-validation review of any commissioning /
demonstration batches.
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4.2.6 Pre-nomination of the validation batches by the production
representative. The pre-nominated batches are recorded in the table
in Section 7.
4.2.7 The table in Section 7 will be completed prior to commencement of
the PPQ to document that all the pre-requisites are in place prior
to start up.
4.3 PROCESS SUMMARY
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THERE ARE [**] REACTIONS INVOLVED IN THE SYNTHESIS OF [**].
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[**]
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PPQP NO.04.23
4.4 CRITICAL PROCESSING PARAMETERS
Critical processing parameters have been identified for the [**]
process, illustrated below and are included in Section 8. These
parameters have been established by Xxxxxx Laboratories and are
listed and justified in a report provided by Abbott.
CRITICAL TARGET CONSEQUENCE OF
OPERATION RANGE RANGE DEVIATION
--------- -------- ------ --------------
[**]
[**] [**] [**] [**]
[**] [**] [**] [**]
[**] [**] [**] [**]
[**] [**] [**] [**]
[**] [**] [**] [**]
[**] [**] [**] [**]
[**]
[**] [**] [**] [**]
[**] [**] [**] [**]
[**] [**] [**] [**]
[**] [**] [**] [**]
[**] [**] [**] [**]
[**] [**] [**] [**]
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PPQP NO.04.23
[**]
[**] [**] [**] [**]
[**] [**] [**] [**]
[**] [**] [**] [**]
[**] [**] [**]
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PPQP NO.04.23
[**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**] [**]
(1.) With respect to the [**]
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PPQP NO.04.23
2. With respect to the [**]
All L/KG refer to litres per kilogram of [**]
4.5. YIELD
Expected yield: [**]
Acceptable yield range: [**]
[**]
4.6 EQUIPMENT
The equipment used in the [**] manufacturing process is located in the
Pilot Plant facility. The main items utilised are:
[**]
4.7 SAMPLING & ANALYSIS
The [**] pre-nominated batches will be dried and discharged. In order to
illustrate that a) the batch is uniform following drying, and b) the
composite sample taken for final batch analysis is representative of the
batch, the following samples will be taken.
- A sample from a composite sample taken as per the normal sampling
procedure detailed in the PRS.
- Validation samples will be sampled as specified in the following table and
in accordance with written and approved instructions
Analysis will comprise of that specified in the following table.
SAMPLE ANALYSIS MONOGRAPH
--------- -------- ---------
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
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PPQP NO.04.23
* [**] will be performed but are not applicable to this validation
exercise because compliance is controlled by the [**] not the [**].
4.8 ACCEPTANCE CRITERIA
4.8.1 All prerequisites will be completed prior to the start of
manufacture.
4.8.2 The [**] consecutive batches are manufactured according to the
approved PRS. This will be demonstrated by OQ review and approval of
the completed PRS.
4.8.3 The batches will be produced following the approved PRS except where
a deviation from the PRS has been evaluated by OQ and found to be
acceptable with regards to process control and quality attributes.
4.8.4 The [**] batches comply with the specifications in Section 4.9.
4.8.5 Validation samples (specified in Section 4.7) meet all the criteria
listed in this section required to show that the process is
operating consistently / under control.
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4.9. SPECIFICATION
In-process analysis will be conducted in accordance with
[**] [**] [**]
---- -------- --------
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
The [**] (pre milling) will be analysed according to monograph [**]
[**] [**]
---- ------------------
[**] [**]
[**] [**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
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PPQP NO.04.23
[**] [**]
---- ------------------
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**] [**]
[**] [**]
[**] [**]
The [**] (post milling) will be analysed according to monograph 6000721
[**] [**]
---- ---------------
[**] [**]
[**] [**]
[**] [**]
[**] [**]Not less
than -0.5 degrees and
not more than +0.5
degrees calculated on
the anhydrous basis
at 25 degrees C
[**] [**]
[**] [**] [**]
[**] [**]
[**] [**]
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[**] [**]
---- ----------------
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] The mean percent
retained on a [**]
sieve is not more
than 7.0%
[**] [**]
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[**] [**]
---- -----------------------------
[**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
[**] [**]
NOTE
[**] have been excluded.
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5. REFERENCE DOCUMENTS
Process Record Sheet [**]
Validation Master Plan ([**]
[**]
Process Validation Protocol Report number [**] (Dated 23rd February 1998)
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6. REPORTING AND ARCHIVAL
A PPQ Report will be generated upon completion of the validation batches
in accordance with [**].
All data generated by the protocol will be stored on data record sheets,
which will be stored with the relevant batch record filed in OQ.
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7. PREREQUISITES TO PROCESS VALIDATION
ITEM RESULT INITIALS DATE
--------- -------- -------- ----------
[**] Y/N SP 08 Oct 04
[**] Y/N SP 08 Oct 04
[**] Y/N SP 08 Oct 04
[**] Y/N SP 08 Oct 04
[**] Y/N SP 08 Oct 04
[**] Y/N SP 08 Oct 04
[**] Y/N SP 08 Oct 04
/*NB: LABORATORY WORK COMPLETED. FINAL REPORT TO BE SIGNED. SP 08OCT04/
PRS REFERENCE AND REVISION [**]
[**] [**]
---- ----
[**]
[**]
[**]
[**]
START UP APPROVAL:
Approved By: /s/ Xxxxx Xxxxxxx Date: 8.10.04
-----------------
Process Manager
/ Project Leader /s/ Xxxxx Xxxxxxx 08 Oct 04
-----------------
Approved By: _____________________ Date: _________
OQ Manager
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PPQP NO. 04.23
8. PROCESSING PARAMETERS
The parameters listed in the following table examine the reproducibility of
processing and subsequent batch quality. A copy of this table will be completed
in the PPQ Report
[**] [**] [**] [**] [**] [**] [**] [**] [**]
---- ---- ---- ---- ---- ---- ---- ---- ----
[**] [**] [**] [**] [**]
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Prepared by:............................................. Date:
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Checked by: ............................................. Date:
.....................................
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[**] [**] [**] [**] [**] [**]
----------- ---- ---- ---- ---- ----
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[**] [**] [**] [**]
[**] [**] [**] [**]
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Prepared by:............................................. Date:
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Checked by: ............................................. Date:
.....................................
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[**] [**] [**] [**] [**] [**]
----------- ---- ---- ---- ---- ----
[**] [**] [**] [**]
[**] [**] [**] [**]
[**] [**] [**] [**]
Prepared by:............................................... Date:
.....................................
Checked by: ............................................... Date:
.....................................
D.SOP014A/018 REV 3 PAGE 25 OF 33
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[**] [**] [**] [**]
---- ---- ---- ----
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Prepared by:................................................. Date:
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Checked by:.................................................. Date:
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[**] [**] [**] [**]
---- ---- ---- ----
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[**] [**] [**]
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Prepared by:................................................. Date:
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Checked by:................................................. Date:
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D.SOP014A/018 REV 3 PAGE 27 OF 33
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[**] [**] [**] [**]
---- ---- ---- ----
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Prepared by:................................................. Date:
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Checked by:.................................................
Date.............................................
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ANALYTICAL SUMMARY
[**] [**] [**] [**] [**] [**]
---- ---- ---- ---- ---- ----
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
Not less than -0.5 degrees
and not more than +0.5
degrees calculated on
the anhydrous basis at 25
degrees C
[**] [**] [**]
Prepared by:................................................. Date:
..............................................
Checked by:................................................. Date:
..............................................
D.SOP014A/018 REV 3 PAGE 29 OF 33
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[**] [**] [**] [**] [**] [**]
---- ---- ------------ ---- ---- ----
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Prepared by:................................................. Date:
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Checked by:................................................. Date:
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[**] [**] [**] [**] [**] [**]
---- ---- ------------ ---- ---- ----
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Prepared by:................................................. Date:
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Checked by:................................................. Date:
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[**] [**] [**] [**] [**] [**]
---- --------- ------------- -------- -------- --------
[**] [**] [**] [**]
[**] [**]
[**] [**]
[**] [**] [**]
[**] [**] [**]
Prepared by:................................................. Date:
..............................................
Checked by:................................................. Date:
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[**] [**] [**] [**] [**] [**]
---- ---- ---- ---- ---- ----
[**] [**] [**]
[**] [**] [**]
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[**] [**] [**]
[**] [**] [**]
[**] [**] [**]
D.SOP014A/018 REV 3 PAGE 32 OF 33
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Prepared by:................................................. Date:
..............................................
Checked by:................................................. Date:
..............................................
D.SOP014A/018 REV 3 PAGE 33 OF 33
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9. RAW MATERIAL / INPUT MATERIAL SUMMARY
[**]
[**] RAW MATERIAL / INPUT MATERIAL
---- -----------------------------
Annex 3-Validation Schedule
[**]
ANNEX 4
OBSERVATION SHEET
PRODUCT: [**](ZILEUTON) SHEET NO: 1
REFERENCE NO: 6000550.7X1.04 PROCESS ORDER NO:_________
PRS.982
Date: 15th September 2004 SHEET NO: 1
Replaces: [**] PROCESS ORDER NO:_____________
Valid until: 2 years after date of approval (unless superseded)
Plant: [**]
Product: [**](ZILEUTON)
Procedure: FINAL PRODUCT
Equipment: [**]
Ref. No: [**]
Process written by: X.X.XXXXXXX....................................Date: 23.9.04.....................
Process checked by R & D: /s/ illegible..................................Date: 23.9.04.....................
Process authorised by Plant Manager: /s/ illegible..................................Date: 23.9.04.....................
Process approved by Operational Quality: /s/ illegible..................................Date: 07 Oct 04...................
C O N F I D E N T I A L
NOT TO BE RELEASED TO UNAUTHORISED PERSONNEL
OBSERVATION SHEET
PRODUCT: [**](ZILEUTON) SHEET NO: 2
REFERENCE NO: 6000550.7X1.04 PROCESS ORDER NO:_________
HAZARDS
THE PERSONAL PROTECTIVE EQUIPMENT STIPULATED IN THIS PROCESS IS THE MINIMUM
REQUIRED AND HAS BEEN DETERMINED ON THE BASIS THAT (WHERE AVAILABLE) THE LOCAL
EXTRACTION SYSTEM IS OPERATING SATISFACTORILY. IF THE LOCAL SYSTEM IS NOT
OPERATING THE SUPERVISOR MUST BE CONSULTED WHO WILL ENSURE THAT CORRECTIVE
ACTION IS TAKEN TO RESTORE THE LEV SYSTEM. OPERATIONS MUST NOT PROCEED UNTIL LEV
SYSTEMS ARE WORKING.
SODIUM HYDROXIDE: CORROSIVE SOLID. Causes severe xxxxx. Risk of serious damage to eyes.
NON-COMBUSTIBLE SOLID. DO NOT ALLOW SKIN/EYE CONTACT OR BREATHE DUST.
HAZARD CATEGORY: R2S3
50% AND 32% SODIUM HYDROXIDE SOLUTION: CORROSIVE LIQUID. CAUSES SEVERE XXXXX. RISK OF SERIOUS DAMAGE TO THE EYES.
NON COMBUSTIBLE LIQUID
HAZARD CATEGORY: R1S3 DO NOT ALLOW ANY CONTACT OR EXPOSURE
2-ACETYLBENZOTHIOPHENE: IRRITANT SOLID. Irritating to eyes. WILL BURN IN A FIRE. AVOID SKIN AND
EYE CONTACT. AVOID BREATHING DUST.
HAZARD CATEGORY: R2S2
SODIUM BOROHYDRIDE: TOXIC SOLID. Toxic by inhalation, ingestion and in contact with the skin.
WILL BURN IN A FIRE
HAZARD CATEGORY: R3S3 DO NOT ALLOW ANY CONTACT OR EXPOSURE.
ETHYL ACETATE: IRRITANT LIQUID. Irritating to the eyes. Repeated exposure may cause skin
dryness or cracking. Vapours may cause drowsiness and dizziness. HIGHLY
FLAMMABLE. AVOID SKIN AND EYE CONTACT.
HAZARD CATEGORY: R2S2 AVOID BREATHING VAPOUR.
OBSERVATION SHEET
PRODUCT: [**](ZILEUTON) SHEET NO: 3
REFERENCE NO: 6000550.7X1.04 PROCESS ORDER NO:_________
HAZARDS
THE PERSONAL PROTECTIVE EQUIPMENT STIPULATED IN THIS PROCESS IS THE MINIMUM
REQUIRED AND HAS BEEN DETERMINED ON THE BASIS THAT (WHERE AVAILABLE) THE LOCAL
EXTRACTION SYSTEM IS OPERATING SATISFACTORILY. IF THE LOCAL SYSTEM IS NOT
OPERATING THE SUPERVISOR MUST BE CONSULTED WHO WILL ENSURE THAT CORRECTIVE
ACTION IS TAKEN TO RESTORE THE LEV SYSTEM. OPERATIONS MUST NOT PROCEED UNTIL LEV
SYSTEMS ARE WORKING.
METHANOL: TOXIC LIQUID. Toxic by inhalation, ingestion and in contact with the
skin. Danger of very serious irreversible effects through inhalation, ingestion
and in contact with skin. HIGHLY FLAMMABLE LIQUID.
HAZARD CATEGORY: R3S3 DO NOT ALLOW ANY CONTACT OR EXPOSURE
METHYL CARBAMATE: IRRITANT SOLID. LIMITED EVIDENCE OF CARCINOGENIC EFFECT (CARC CAT 3).
WILL BURN IN A FIRE.
HAZARD CATEGORY: R3S3 DO NOT ALLOW ANY CONTACT OR EXPOSURE
50% HYDROXYLAMINE SOLUTION: HARMFUL, IRRITANT LIQUID. Harmful if swallowed. Irritating to the respiratory
system and skin. Limited evidence of carcinogenic effect (CARC CAT 3). Risk
of serious damage to eyes. May cause sensitisation by skin contact.
NON-COMBUSTIBLE/HEATING MAY CAUSE EXPLOSION.
HAZARD CATEGORY: R3S3 DO NOT ALLOW ANY CONTACT OR EXPOSURE
HYDROCHLORIC ACID 36% AR: CORROSIVE LIQUID. CAUSES XXXXX. Irritating to the respiratory system.
NOT CLASSIFIED AS FLAMMABLE.
HAZARD CATEGORY: R3S3 DO NOT ALLOW ANY CONTACT OR EXPOSURE.
TETRAHYDROFURAN: IRRITANT LIQUID. Irritating to eyes and respiratory system. HIGHLY
FLAMMABLE LIQUID, MAY FORM EXPLOSIVE PEROXIDES. AVOID CONTACT WITH SKIN/
EYES. AVOID INHALATION AND
OBSERVATION SHEET
PRODUCT: [**](ZILEUTON) SHEET NO: 4
REFERENCE NO: 6000550.7X1.04 PROCESS ORDER NO:_________
HAZARD CATEGORY: R2S3 INGESTION
HAZARDS
THE PERSONAL PROTECTIVE EQUIPMENT STIPULATED IN THIS PROCESS IS THE MINIMUM
REQUIRED AND HAS BEEN DETERMINED ON THE BASIS THAT (WHERE AVAILABLE) THE LOCAL
EXTRACTION SYSTEM IS OPERATING SATISFACTORILY. IF THE LOCAL SYSTEM IS NOT
OPERATING THE SUPERVISOR MUST BE CONSULTED WHO WILL ENSURE THAT CORRECTIVE
ACTION IS TAKEN TO RESTORE THE LEV SYSTEM. OPERATIONS MUST NOT PROCEED UNTIL LEV
SYSTEMS ARE WORKING.
TOLUENE: HARMFUL LIQUID. Harmful by inhalation and ingestion. Irritant to eyes
and skin. HIGHLY FLAMMABLE. AVOID CONTACT WITH SKIN/EYES. AVOID INHALATION
AND INGESTION
HAZARD CATEGORY: R2S1
[**] (ZILEUTON): CRYSTALLINE POWDER, ACCORDING TO EXPERIENCE HARMLESS TO HEALTH. WILL BURN
IN A FIRE. AVOID CONTACT WITH SKIN/EYES. AVOID INHALATION AND INGESTION.
HAZARD CATEGORY: R2S2
OBSERVATION SHEET
PRODUCT: [**](ZILEUTON) SHEET NO: 5
REFERENCE NO: 6000550.7X1.04 PROCESS ORDER NO:_________
PROCEDURES FOR THE EMERGENCY SHUTDOWN OF PROCESS PLANT EQUIPMENT
In the event of evacuation from the process areas due to the sounding of Fire or
Hazard alarms, the following action must be taken:
STIRRERS: If running, do not switch off, leave running.
STEAM / HOT WATER HEATING: Turn off steam or steam / water supply to jacket and allow to drift with agitation.
AT REFLUX: Leave lines set for reflux with agitation. Heating set point reduced.
DISTILLATION (ATMOSPHERIC): Leave lines set for distillation with agitation. Heating set point reduced.
DISTILLATION (VACUUM): Leave lines set for distillation. Maintain vacuum with agitation. Heating set point reduced.
GAS OR LIQUID ADDITION: Stop addition. Shut off gassing operations by cylinder valve.
CIRCULATING SCRUBBERS: Leave vessels vented to circulating Scrubbers with Scrubber pumps left running.
TRANSFER OPERATIONS Stop transfer operations, either venting Nitrogen from pressurised vessel and closing line valve,
(INCLUDING VIA IN-LINE FILTERS): or circulate via pump back to charcoalation or initial reaction vessel.
COOLING: Continue cooling the vessel. Maintain agitation.
PRODUCT FILTRATION: Stop slurry feed to filter or centrifuge. Either maintain vacuum on filter or allow centrifuge
to spin dry.
SOLID TRANSFERS: e.g. Charging Vessel, collecting wet cake, charging drier etc. Close all containers, chargehole
covers, oven doors etc and suspend operations.
LIQUID TRANSFERS: Suspend operations - close valves, vent Nitrogen pressurised vessel or receiver, vent dispenser
or vessel under vacuum. Cap drum.
OBSERVATION SHEET
PRODUCT: [**](ZILEUTON) SHEET NO: 6
REFERENCE NO: 6000550.7X1.04 PROCESS ORDER NO:_________
The above procedures will apply for all Steps apart from between Steps 42 to 44
when the quench and dump operations will be carried out in the event of the
sounding of the fire alarm. If the hazard alarm sounds during Steps 42 to 44,
the reaction vessel will be monitored from the assembly point.
OBSERVATION SHEET
PRODUCT: [**](ZILEUTON) SHEET NO: 7
REFERENCE NO: 6000550.7X1.04 PROCESS ORDER NO:_________
NOTES
1. Throughout the process SUPERVISOR refers to Team Leader, Shift Manager,
Process Manager, R&D Chemist, Pilot Plant Technician, Shift Chemist or
Product Manager or those acting in an authorised supervisory capacity.
2. At the start of manufacturing, i.e. equipment checks the
Technician/Supervisor must sign his full name at the top of the page, along
with his shift details, the time and date.
3. When a new page is started the Technician is to record the date at the top
of the page in the space provided.
4. Technician to initial and enter the time in the record columns and include
the date if it is different from the date at the top of the page.
5. Any unusual occurrences or events that occur during the process must be
recorded on the observation sheet attached to the back of the PRS. If any
additional instructions are required as a result of an observation,
procedure "Control of Changes or PRSs (both planned and unplanned)" is to
be followed. The Development Chemist will complete the technical assessment
and judge whether an observation should be upgraded to a Process Deviation
Report (PDR).
6. "Checked by: ............................." in the records column means
that a second person must check the operation in question as it happens
(typically the description and quantity of the material to be charged), and
initial the records entry.
7. * means delete as appropriate.
8. Before commencing a step ensure all the instructions for that step have
been read and understood.
9. Ensure a Process Control Analytical Report (PCAR) or an inspection report
is available for every piece of in-process analysis performed -- enclose
the original PCAR if analysis was performed by Plant personnel or the fax
copy of the inspection report if the analysis was performed by Analytical
Services.
10. When a charge needs to be calculated and/or entered, the person who
calculates and/or enters the charge must sign at the relevant step
instructions.
OBSERVATION SHEET
PRODUCT: [**](ZILEUTON) SHEET NO: 8
REFERENCE NO: 6000550.7X1.04 PROCESS ORDER NO:_________
XXXX OF MATERIALS
11. The `TIME / DATE' and `TECHNICIAN INITIALS' columns contain dotted line
entries (..........) for filling in against records when requested. The
continuous line ( _____ ) indicates the completion of a step. On many
occasions the last record filled in is also the end of a step, in which
case only the continuous line ( _____ ) is shown.
12. At the shift handover the off going and on coming Technicians review the
documentation then the oncoming Technician completes the handover record on
the last sheet of this PRS.
13 Xxxx of Materials for a typical batch of [**]:
RAW MATERIAL MATERIAL NO. QUANTITY
----------------------------------- ------------ --------
[**] 5001390 [**]
[**] 1000203 [**] [**]
[**] 1000246 [**]
[**] 1001337 [**]
[**] 1000997 [**]
[**] 1000082 [**]
[**] 1000145 [**]
[**] 1001338 [**]
[**] 5005130 [**]
[**] 1000817 [**]
[**] 1000105 [**]
[**] 1000227 [**]
[**] 1000223 [**]
[**] 1000226 [**]
[**] 2000058 [**] [**]
[**] 2000024 [**]
[**] 2000028 [**]
[**] 2000052 [**]
OBSERVATION SHEET
PRODUCT: [**](ZILEUTON) SHEET NO: 9
REFERENCE NO: 6000550.7X1.04 PROCESS ORDER NO:_________
14. CERTAIN EQUIPMENT AND OPERATIONS IN THIS PROCESS ARE CRITICAL TO THE
PROTECTION OF THE ENVIRONMENT. WHERE THIS IS THE CASE A PROMPT WILL BE
GIVEN IN THE KEY POINTS COLUMN. SATISFACTORY ABATEMENT OF RELEASES FROM THE
PROCESS IS ESSENTIAL FOR COMPLIANCE WITH THE ENVIRONMENT PROTECTION ACT.
PLEASE PLAY YOUR PART.
15. CERTAIN EQUIPMENT AND OPERATIONS IN THIS PROCESS ARE CRITICAL FOR THE
PROTECTION OF HEALTH. ENSURE ALL PPE IS IN A SUITABLE CONDITION FOR USE.
WHEN LEV CHECKS ARE INDICATED WITHIN THE PRS ENSURE THAT THEY ARE CARRIED
OUT AND SUPERVISOR IS INFORMED OF ANY DEFECTS. OPERATIONS MUST NOT BE
CARRIED OUT UNTIL LEV SYSTEMS ARE RESTORED TO FULL WORKING ORDER.
SATISFACTORY PROTECTION FROM EXPOSURE TO CHEMICALS IS ESSENTIAL TO
PROTECTING HEALTH AND TO COMPLY WITH THE COSHH REGULATIONS.
ANNEX 5
Critical Therapeutics Inc Delivery No
00 Xxxx Xxxx Xxxxxx Customer Order No
Lexington, MA UA 02421 Rhodia Pharma Solutions Order
USA
CERTIFICATE OF ANALYSIS
MATERIAL [**] (MICRONISED IR)
BATCH [**]
DATE OF RETEST 04/25/2005
DATE OF MANUFACTURE 09/20/2004
DATE OF ANALYSIS 10/26/2004
SPECIFICATION
-----------------
TEST UNIT RESULT LOWER UPPER
----------------------------------- ----- ------ ----- -----
Appearance [**] [**]
Identity: Infra Red Spectrum [**] [**]
Specific rotation (deg mL g-1 dm-1) [**] [**] [**]
Residue on ignition % w/w [**] [**]
Foreign matter (2% soln in methanol) [**] [**]
Clarity (2% soln in methanol) [**] [**]
Heavy Metals (ppm) [**] [**]
Colour ("B") (2% soln in methanol) [**] [**]
Colour ("BY") (2% soln in methanol) [**] [**]
Percent retained on [**] sieve % [**] [**]
Tapped density gfml [**] [**]
Identity: HPLC Retention time [**] [**]
Assay on dry basis % w/w [**] [**] [**]
[**] % w/w [**] [**]
[**] % w/w [**] [**]
[**] % w/w [**] [**]
[**] % w/w [**] [**]
[**] % w/w [**] [**]
[**] % w/w [**] [**]
[**] % w/w [**] [**]
Page 1 of 2
CERTIFICATE OF ANALYSIS
MATERIAL [**] (MILLED)
BATCH 8001362005
SPECIFICATION
--------------------
TEST UNIT RESULT LOWER UPPER
-------------------------------- ------ ------ ------ -----
[**] % w/w [**] [**]
[**] % w/w [**] [**]
[**] % w/w [**] [**]
[**] % w/w [**] [**]
[**] % w/w [**] [**]
[**] % w/w [**] [**]
[**] % w/w [**] [**]
[**] ppm [**] [**]
[**] % w/w [**] [**]
[**] % w/w [**] [**]
[**] % w/w [**] [**]
[**] % w/w [**] [**]
[**] % w/w [**] [**]
[**] % w/w [**] [**]
GLC: Total Solvents % w/w [**] [**]
Crystal form [**] [**]
Water Content % w/w [**] [**]
Assay on wet basis (% w/w) % w/w [**] [**]
Salmonella [**] [**]
E.Coli [**] [**]
Aerobic microbial count (target) CF(mu)/g [**] [**]
Surface area M(2)/g [**] [**] [**]
Particle size um (laser): d90 [**] [**]
Particle size um (laser): d50 [**] [**]
Particle size um (laser): d10 [**] [**]
Manufactured in accordance with ICH Q7A
Customers name: Zileuton ([**])
Date of Manufacture of Unmilled: 7/11/2004
/s/Xxx Xxxxx
------------------------------
Authorised Person
Nov. 03, 2004
Page 2 of 2
RHODIA PHARMA SOLUTIONS
Ref: [**]
Rhodia Pharma Solutions
Xxxxxx
Xxxxxxxxxxx
Xxxxxxxxxxxxxx
XX00 0XX
XX
28 October 2004
LETTER OF DECLARATION OF MANUFACTURE ACCORDING TO GMP RULES
We, Rhodia Pharma Solutions, hereby declare that we manufacture [**] to the
following GMP rules:
GMP as defined by ICH Q7a ("Good Manufacturing Practice Guide for Active
Pharmaceutical Ingredients").
/s/ X. Xxxxxxx
X. Xxxxxxx
Operational Quality Manager
[RHODIA LOGO] ANNEX 6
PHARMA SOLUTIONS
STANDARD OPERATING PROCEDURE
Page 1 of 6
OPERATIONAL QUALITY PROCEDURE FOR DESPATCH OF
FINAL PRODUCT MATERIAL FROM SITE
REFERENCE NO: [**] REV 1
REVISED: FEBRUARY 2003
REPLACES: [**] VERSION 7
REVIEW PERIOD: 2 YEARS (UNLESS SUPERSEDED)
Prepared by: /s/ E Xxxxxx Date 10/2/03
-----------------------------
Operational Quality Manager
Reviewed by: /s/ G McCoull Date 11/2/03
Warehouse -----------------------------
Approved by: /s/ I B Low Date 11/2/03
Plant Manager -----------------------------
Approved by: /s/ R P G Xxxxxx Date 12 Feb 023
Quality Manager -----------------------------
RPGH 12/2/03
CONFIDENTIAL
NOT TO BE RELEASED TO UNAUTHORISED PERSONNEL
VALID FOR 7 DAYS FROM DATE OF PRINTING - DATE PRINTED:
[RHODIA LOGO] APPENDIX 1 TO [**] REV 1
PHARMA SOLUTIONS
CONTENTS
1.0 INTRODUCTION............................................. 3
2.0 DEFINITIONS.............................................. 3
3.0 RESPONSIBILITIES......................................... 3
4.0 PROCEDURE................................................ 3
4.1 RECEIPT OF FINAL PRODUCT BY S12 PROCESS STORES... 3
4.2 PRODUCT SENTENCING BY OPERATIONAL QUALITY........ 3
4.3 RECEIPT AND ALLOCATION OF ORDERS................. 4
4.4 LABELLING AND CHECKING OF CONTAINERS............. 4
4.5 CERTIFICATES OF ANALYSIS......................... 5
5.0 DOCUMENT REVISION HISTORY................................ 5
6.0 DISTRIBUTION LOCATION.................................... 6
CONFIDENTIAL
NOT TO BE RELEASED TO UNAUTHORISED PERSONNEL
VALID FOR 7 DAYS FROM DATE OF PRINTING - DATE PRINTED:
[RHODIA LOGO] APPENDIX 1 TO [**] REV 1
PHARMA SOLUTIONS
1.0 INTRODUCTION
It is the responsibility of the Operational Quality Department to ensure that
all material to be despatched off-site has been manufactured, packaged, tested,
examined and labelled in accordance with current Good Manufacturing Practices.
This procedure covers the progress of final product from the time of its
transfer from Manufacturing to Process Stores through to its despatch from site.
2.0 DEFINITIONS
None
3.0 RESPONSIBILITIES
Warehouse Personnel - responsible for ensuring final products for despatch are
selected, labelled and packaged in accordance with the relevant Process Stores
Procedure.
Operational Quality - responsible for ensuring that the material to be
despatched has been manufactured, packaged, tested, and labelled in accordance
with the relevant Site Procedure and in compliance with cGMP.
4.0 PROCEDURE
4.1 RECEIPT OF FINAL PRODUCT BY S12 PROCESS STORES
A batch of final product will be transferred from Manufacturing to Stores
Department. The batch number and container details of the material being
transferred is available on SAP.
The Stores personnel will then check the conditions of the containers and the
nett weights shown on SAP correspond to those on the containers. The Stores
person will arrange for the material to be stored in the area of the warehouse
designed for final product, in accordance with GMP guidelines.
4.2 PRODUCT SENTENCING BY OPERATIONAL QUALITY
The Operational Quality Unit will check the batch documentation and analytical
data and sentence the material in accordance with the relevant SOP. The expiry
date of the batch will be noted from SAP which will have generated this
automatically.
CONFIDENTIAL
NOT TO BE RELEASED TO UNAUTHORISED PERSONNEL
VALID FOR 7 DAYS FROM DATE OF PRINTING - DATE PRINTED:
[RHODIA LOGO] APPENDIX 1 TO [**] REV 1
PHARMA SOLUTIONS
4.3 RECEIPT AND ALLOCATION OF ORDERS
Following receipt of an order from the customer and within the agreed lead time,
material will be allocated by Customer Services, Xxxxxx via SAP. Batches will be
selected in strict rotation, where possible.
The OQ department will be advised by Customer Services, Xxxxxx of the order and
sent an "Acknowledgement of Order" via fax detailing the material allocation.
The OQ Department will raise a OQ Despatch Checklist (Appendix I) and ensure the
material selected is suitable before authorising the allocation.
4.4 LABELLING AND CHECKING OF CONTAINERS
After OQ have authorised allocation of the order, the Stores personnel may print
off the product labels from SAP.
If labels do not print correctly then a label re-print can be made, all extra
labels generated or destroyed should be documented on the "SAP SHIPPING LABELS
RECONCILIATION SHEET" (Logsheet CL011, page 1).
The old production labels are fixed to log sheet number CL011 against the
corresponding SAP label number for each keg. Hence the original keg number can
be traced to a specific keg in the order. A check will be made to ensure that
the details on the SAP product labels, i.e. batch number, container, number,
gross and nett weights correspond to those on Manufacturing labels. The security
seals are checked, where applicable and any damaged seals replaced.
When product labelling is complete, a check will be undertaken by a second
person to ensure:
- The containers are in good condition and free from product contamination.
- The SAP product label details correspond to those on the displaced
Manufacturing labels and product identity is correct.
- The SAP product label details correspond to those listed in the
"Acknowledgement of Order" and with the master Despatch label.
- Security seals are secure and undamaged.
- Where a numbered security seal is replaced this will be recorded in the
Stores seal register and OQ informed of the new seal number and the
batch/container to which it was affixed.
CONFIDENTIAL
NOT TO BE RELEASED TO UNAUTHORISED PERSONNEL
VALID FOR 7 DAYS FROM DATE OF PRINTING - DATE PRINTED:
[RHODIA LOGO] APPENDIX 1 TO [**] REV 1
PHARMA SOLUTIONS
- All documentation will be returned to the OQ Department for checking
before "final release".
- The OQ Department will check the order prior to signing the "final
release". When satisfied all details are correct, the paperwork will be
signed and returned to Stores for archiving. A copy of a label for each
batch will be retained with the OQ checklist.
- The Stores person will then progress the order through SAP to the
appropriate status for despatch.
4.5 CERTIFICATES OF ANALYSIS
A Certificate of Analysis will be provided, and accompany, all material leaving
site. This Certificate of Analysis is either generated using SAP or manually.
A suitably authorised person in Quality will sign the Certificate of Analysis.
Copies of Certificates of Analysis will be held in the OQ unit for at least one
calendar year.
NB - When material is to be despatched to Mexico the Certificate of Analysis
may only be signed by a notarised signature.
5.0 DOCUMENT REVISION HISTORY
ALTERATIONS, ADDITIONS,
DATE SEQUENTIAL CODE OMISSIONS
------------- --------------- ------------------------------
FEBRUARY 2003 [**] REV 1 FIRST ISSUE - REPLACES AGMP 18
CONFIDENTIAL
NOT TO BE RELEASED TO UNAUTHORISED PERSONNEL
VALID FOR 7 DAYS FROM DATE OF PRINTING - DATE PRINTED:
[RHODIA LOGO] APPENDIX 1 TO [**] REV 1
PHARMA SOLUTIONS
6.0 DISTRIBUTION LOCATION
FILE LOCATIONS (XXXXXX)
A Operational Quality (Masters of all documents)
B Analytical Services (shift lab)
C Pilot Plant
X Xxxxxx 1 (Manufacturing/Engineering)
E Xxxxxx 2 (Manufacturing/Engineering)
F ADG
G R&D
H Main office (to hold documents for Safety/Engineering/Finance/
Accounts/ Human Resources/Purchasing/Planning/Commercial/Customer
Services
I Central Engineering
J Warehouse
K PPG
K 1. Point of Use [specify]
2. Point of Use [specify]
3. Point of Use [specify]
FILE LOCATIONS (XXXXX)
A Operational Quality File
B Shift Managers Office
C General Admin Building (Master)
D S12 Stores
E Engineering Records Office
F 1. Point of Use [specify]
2. Point of Use [specify]
3. Point of Use [specify]
FILE LOCATIONS (XXXXXX CHAPEL)
A Quality Assurance (copy from Xxxxxx)
B Engineering
C GPP
D Orion
E Building 44
F Lyra
G 1. Point of Use [specify]
2. Point of Use [specify]
3. Point of Use [specify]
FILE LOCATIONS (MALVERN)
A Quality Assurance (copy from Xxxxxx)
B 4. Point of Use [specify]
5. Point of Use [specify]
6. Point of Use [specify]
OPERATIONAL QUALITY DESPATCH CHECKLIST
CONFIDENTIAL
NOT TO BE RELEASED TO UNAUTHORISED PERSONNEL
VALID FOR 7 DAYS FROM DATE OF PRINTING - DATE PRINTED:
[RHODIA LOGO] APPENDIX 1 TO [**] REV 1
PHARMA SOLUTIONS
Order No: _____________________ Reference No:____________________
Country of Customer Material
Destination: ____________________ No:____________________
Product Name:_________________________________________________
Product Code:_________________________________________________
Batch No's/No of Kegs
allocated: ____________ ______________
____________ ______________
____________ ______________
____________ ______________
Is material suitable for despatch and allocated YES/NO
to appropriate market?
Allocation Authorised Date:
by: ________________________ _________________
Product identity/containers/labelling/security seals
Checked By: ________________________
Certificates of Analysis Date:
Produced by: ________________________ __________________
Certificates of Analysis Date:
Checked by: ________________________ __________________
Final Check by OQ: ________________ (Sign) Date:__________________
Comments:
Material Despatched: _______________________
Operational Quality Date:__________________
Signature: _______________________
CONFIDENTIAL
NOT TO BE RELEASED TO UNAUTHORISED PERSONNEL
VALID FOR 7 DAYS FROM DATE OF PRINTING - DATE PRINTED:
ANNEX 7
ANNEX 7 - WIRE TRANSFER INFORMATION
HSBC Bank
Newcastle Upon Tyne City Branch
Swift Code : XXXXXX00
IBAN : XX00 XXXX 0000 0000 0000 00
Account : [**]
ANNEX 8 Client#: 1872 CRITICAL
DATE(mm/dd/yyy)
XXXXX(TM) CERTIFICATE OF LIABILITY INSURANCE 11/03/04
------------------------------------------------------------------------------------------------------------------------------------
PRODUCER THIS CERTIFICATE IS ISSUED AS A MATTER OF INFORMATION ONLY AND
Xxxxxxx Xxxxxxxxx Associates CONFERS NO RIGHTS UPON THE CERTIFICATE HOLDER. THIS CERTIFICATE
Insurance Brokers, Inc. DOES NOT AMEND, EXTEND OR ALTER THE COVERAGE AFFORD BY THE
000 Xxxxxxxx Xxxxxx POLICIES BELOW.
Xxxxxx, XX 00000
--------------------------------------------------------------------
INSURERS AFFORDING COVERAGE NAIC #
------------------------------------------------------------------------------------------------------------------------------------
INSURED INSURER A: American Casualty Co. of Reading, PA
--------------------------------------------------------------------
Critical Therapeutics, Inc. INSURER B: Continental Casualty Company
00 Xxxxxxxx Xxxxxx --------------------------------------------------------------------
Xxxxxxxxx, XX 00000 INSURER C: Columbia Casualty
--------------------------------------------------------------------
INSURER D:
--------------------------------------------------------------------
INSURER E:
------------------------------------------------------------------------------------------------------------------------------------
COVERAGES
THE POLICIES OF INSURANCE LISTED BELOW HAVE BEEN ISSUED TO THE INSURED NAMED
ABOVE FOR THE POLICY PERIOD INDICATED. NOTWITHSTANDING ANY REQUIREMENT, TERM OR
CONDITION OF ANY CONTRACT OR OTHER DOCUMENT WITH RESPECT TO WHICH THIS
CERTIFICATE MAY BE ISSUED OR MAY PERTAIN, THE INSURANCE AFFORDED BY THE POLICIES
DESCRIBED HEREIN IS SUBJECT TO ALL THE TERMS, EXCLUSIONS AND CONDITIONS OF SUCH
POLICIES. AGGREGATE LIMITS SHOWN MAY HAVE BEEN REDUCED BY PAID CLAIMS.
POLICY POLICY
1NSR ADD'L EFFECTIVE EXPIRATION
LTR INSRD TYPE OF INSURANCE POLICY NUMBER DATE (MM/DD/YY) DATE (MM/DD/YY) LIMITS
------------------------------------------------------------------------------------------------------------------------------------
A GENERAL LIABILITY A0000000000 10/29/04 10/29/05 EACH OCCURRENCE $1,000,000
---------------------------------------
[X]COMMERCIAL GENERAL LIABILITY DAMAGE TO RENTED
[ ] [ ] CLAIMS MADE [X] OCCUR PREMISES (Ea occurrence) $ 300,000
[ ] ---------------------------------------
-------------------------- MED EXP (Any one person) $ 15,000
[ ] ---------------------------------------
-------------------------- PERSONAL & ADV INJURY $1,000,000
GEN'L AGGREGATE LIMIT APPLIES PER: ---------------------------------------
[ ] POLICY [ ] PROJECT [ ] LOC GENERAL AGGREGATE $ 2,000,00
---------------------------------------
PRODUCTS-COMP/OP AGG $
------------------------------------------------------------------------------------------------------------------------------------
AUTOMOBILE LIABILITY COMBINED SINGLE LIMIT
[ ] ANY AUTO (Ea Accident) $
[ ] ALL OWNED AUTOS ---------------------------------------
[ ] SCHEDULED AUTOS BODILY INJURY (Per Person) $
[ ] HIRED AUTOS ---------------------------------------
[ ] NON-OWNED AUTOS BODILY INJURY (Per accident) $
[ ] ---------------------------------------
-------------------------- PROPERTY DAMAGE
[ ] (Per accident) $
------------------------------------------------------------------------------------------------------------------------------------
GARAGE LIABILITY AUTO ONLY-Ea Accident $
[ ] ANY AUTO ---------------------------------------
[ ] OTHER THAN EA ACC $
---------------------------------------
AUTO ONLY: AGG $
------------------------------------------------------------------------------------------------------------------------------------
B EXCESS/UMBRELLA LIABILITY A2050029007 10/29/04 10/29/05 EACH OCCURRENCE $4,000,000
[X] OCCUR [ ] CLAIMS MADE ---------------------------------------
AGGREGATE $4,000,000
---------------------------------------
$
---------------------------------------
[ ] DEDUCTIBLE $
[X] RETENTION $10000 ---------------------------------------
$
------------------------------------------------------------------------------------------------------------------------------------
WORKERS COMPENSATION AND WC STATU- OTH-
EMPLOYERS' LIABILITY TORY LIMITS ER
---------------------------------------
ANY PROPRIETOR/PARTNER/EXECUTIVE E.L. EACH ACCIDENT $
OFFICER/MEMBER EXCLUDED? ---------------------------------------
E.L. DISEASE - EA
EMPLOYEE $
---------------------------------------
If yes, describe under E.L. DISEASE - POLICY
SPECIAL PROVISIONS below LIMIT $
------------------------------------------------------------------------------------------------------------------------------------
C Other Products Lia ADT10643750030 10/29/04 10/29/05 7,500,000 per occ.
Clinical Trials 7,500,000 aggregate
Claims Made Retro Date: 05/20/01
------------------------------------------------------------------------------------------------------------------------------------
DESCRIPTION OF OPERATIONS/LOCATIONS/VEHICLES/EXCLUSIONS ADDED BY ENDORSEMENT/SPECIAL PROVISIONS
------------------------------------------------------------------------------------------------------------------------------------
CERTIFICATE HOLDER CANCELLATION
------------------------------------------------------------------------------------------------------------------------------------
SHOULD ANY OF THE ABOVE DESCRIBED POLICIES BE CANCELLED BEFORE THE
EXPIRATION DATE THEREOF, THE ISSUING INSURER WILL ENDEAVOR TO MAIL 30 DAYS
WRITTEN NOTICE TO THE CERTIFICATE HOLDER NAMED TO THE LEFT, BUT FAILURE TO
DO SO SHALL IMPOSE NO OBLIGATION OR LIABILITY OF ANY KIND UPON THE INSURER,
Evidence of Coverage IT AGENTS OR REPRESENTATIVES.
/s/ illegible
----------------------------------------------------------------------------
AUTHORIZED REPRESENTATIVE
------------------------------------------------------------------------------------------------------------------------------------
XXXXX 25 (2001/08) 1 of 2 #S60802/M60785 AMS ACCORD CORPORATION 1988
IMPORTANT
If the certificate holder is an ADDITIONAL INSURED, the policy(ies) must be
endorsed. A statement on this certificate does not confer rights to the
certificate holder in lieu of such endorsement(s).
If SUBROGATION IS WAIVED, subject to the terms and conditions of the policy,
certain policies may require an endorsement. A statement on this certificate
does not confer rights to the certificate holder in lieu of such endorsement(s).
DISCLAIMER
The Certificate of Insurance on the reverse side of this form does not
constitute a contract between the issuing insurer(s), authorized representative
or producer, and the certificate holder, nor does it affirmatively or negatively
amend, extend or alter the coverage afforded by the policies listed thereon.
19th July, 2004
To Whom It May Concern
Dear Sirs,
RHODIA U K LIMITED
We act as Insurance Brokers for Rhodia U K Limited and have been asked to
confirm details of the insurance pertaining to Public Liability and Employers
Liability. Details are as follows:
PUBLIC/PRODUCTS LIABILITY
Insurer: AIG
Policy No: 7 109 123
Renewal Date: 1st January, 2005
Cover EUR 7,500,000 any one loss, any one year
EMPLOYERS LIABILITY
Insurer: Zurich Commercial
Policy No: 60006909
Renewal Date: 31st March, 2005
Cover 25,000,000 (British Sterling) per claim or
series of claims arising from any occurrence
inclusive of legal costs
The policies are subject to insurers' standard terms, conditions and exceptions.
This letter is issued for information purposes only and confers no rights to the
holder and imposes no liability on the insurers.
The insurers assume no responsibility to the holder of this letter to provide
any notice of any material change or cancellation of the policy.
Yours faithfully
/s/ X. Xxxxxxxx
X. XXXXXXXX (MISS)
CLIENT SERVICE EXECUTIVE
ANNEX 9
QUALITY ASSURANCE/COMPLIANCE AGREEMENT FOR THE MANUFACTURE OF
ZILEUTON BY RHODIA PHARMA SOLUTIONS ON BEHALF OF CRITICAL
THERAPEUTICS
Version No: October 2004
CIRCULATION:
RPS Operational Quality, Xxxxxx (Original)
RPS Operational Quality, Annan
CTI (C Xxxxxxxxx)
VALID FROM DATE:
Date of last signature on page 2
REVIEW DATE:
Periodically but not more than 3 years from date of last signature
Page 1 of 19
Written by: /s/ X. Xxxxxxx Date: 28th October 04
--------------
K Thomson (Product Manager, RPS)
Approved by: /s/ X. Xxxxx Date: 28th October 2004
------------
I Lisle (Head of Quality, RPS)
Approved by: /s/ Xxxxxx Xxxxxxxxx Date: 29 October 2004
--------------------
C Xxxxxxxxx (Sr. Director QA, CTI)
Page 2 of 19
CONTENTS
1. INTRODUCTION AND SCOPE P(4)
2. DEFINITIONS P(6)
3. GENERAL COMMITMENTS P(7)
4. AUDIT PROGRAMME P(8)
5. ANALYTICAL AND BATCH RELEASE ACTIVITIES P(9)
6. DOCUMENT PROVISION AND REVIEW REQUIREMENTS P(11)
7. CHANGE CONTROL REQUIREMENTS P(12)
8. DEVIATIONS AND OUT-OF-SPECIFICATION INVESTIGATIONS P(13)
9. COMPLAINTS AND RECALLS P(14)
10. STABILITY PROGRAMME P(14)
11. REGULATORY ISSUES P(15)
12. ANNUAL PRODUCT QUALITY REVIEW P(16)
ANNEX A - SPECIFICATIONS P(17)
ANNEX B - RESPONSIBLE PERSONS / CONTACTS P(26)
Page 3 of 19
1. Introduction and Scope
Zileuton is an API manufactured by Rhodia Pharma Solutions Ltd (RPS) at the
following UK sites:
Rhodia Pharma Solutions, Xxxxx
Xxxxx Xxxxx Xxxx
Xxxxxx
Xxxxx
Xxxxxxxxxxxxx
XX00 0XX
Rhodia Pharma Solutions, Xxxxxx
Xxxxxx
Xxxxxxxxxxx
Xxxxxxxxxxxxxx
XX00 0XX
These sites are hereinafter referred to as RPS, Annan and RPS, Dudley
respectively.
Zileuton API is made exclusively on behalf of Critical Therapeutics Inc.
(hereinafter referred to as CTI) who are based at the following US address:
00 Xxxxxxxx Xxxxxx
Xxxxxxxxx, XX 00000
Zileuton API is manufactured at RPS from [**], with all downstream manufacturing
being to full cGMP standards. The API can be milled by RPS, Annan or RPS, Xxxxxx
or externally, by RPS's subcontractors [**]
[**] also conduct the following activities:
[**]
After [**] packages the API, [**]
The material is despatched to SkyePharma (hereinafter SP) or Patheon for onward
formulation at the following addresses:
SkyePharma Production SAS
ZA xx Xxxxxxx Ouest
00 xxx xx Xxxxxxxxxx
XX00
Page 4 of 19
38291 St-Xxxxxxx-Fallavier cedex
Patheon Pharmaceuticals Inc.
0000 Xxxx Xxxxxxxxx Xxxx
Xxxxxxxxxx
XX 00000
XXX
[**]
This Quality Assurance Agreement is between Rhodia Pharma Solutions and Critical
Therapeutics. It defines the quality assurance and quality compliance
obligations and responsibilities of RPS and CTI that relate to the manufacture
and supply of Zileuton API for clinical and/or commercial use. The agreement is
structured to ensure that all pertinent quality issues are clearly identified
and that responsibilities for the management of these issues are unequivocally
defined. It should be noted that commercial issues (including supply, liability
and confidentiality) are governed separately. The agreement does not apply to
the manufacture of material for non-clinical development purposes. Specific
quality assurance / compliance requirements relating to such material will be
agreed separately as necessary.
This agreement will come into effect on the "Valid From Date" (see pages 1 and
2) and will be subject to review periodically or after a maximum of 3 years from
this date. Amendments may be made at any time with the agreement of all
signatories but, with the exception of the API specification (see Annex A),
require the reapproval of this document.
2. Definitions
2.1 "cGMP" - current good manufacturing practice and standards as interpreted
by ICH Harmonised Tripartite Guideline, Good Manufacturing Practice Guide
for Active Pharmaceutical Ingredients (ICH Q7A) and relevant FDA and EMEA
guidance documents that relate directly to API manufacture.
2.2 "API" - active pharmaceutical ingredient as defined by ICH Q7a.
2.3 "CR" - controlled release
2.4 "IR" - immediate release
2.5 "Key raw data" - with respect to analytical data, this term means sample
chromatograms, spectra, x-ray diffractograms and particle size
distribution graphs.
Page 5 of 19
2.6 "Reworking" - upgrading of API that does not conform to standards or
specifications using a process which is not part of the established
manufacturing process.
2.7 "Reprocessing" - upgrading of API that does not conform to standards or
specifications using a process which is part of the established
manufacturing process (e.g. by repeating a crystallisation step).
2.8 "USP" - the United States Pharmacopeia
3. General Commitments
3.1 It is the responsibility of RPS to ensure that the manufacture, analysis,
packaging, labelling, storage and despatch of Zileuton API that falls
within its scope (see Section 1 and separate commercial contract) is fully
in compliance with cGMP as defined in Section 2. This responsibility
extends to all activities at RPS Annan and Xxxxxx and also to its chosen
subcontractors. It should be noted that the approach to compliance for
clinical trial material may reflect section 19 of ICH Q7a.
3.2 RPS commit to ensuring ongoing compliance with API specifications agreed
between CTI and RPS (including packaging, labelling and release
specifications). RPS will inform CTI of any significant non-compliance or
intended changes as per Sections 7 and 8. Note that different
specifications may apply to the API depending on the formulation (e.g.
immediate release and controlled release formulations). Current
specifications are set out in Annex A. Annex A may be updated (with
modified or additional specifications) following approval of the changes
by CTI and RPS, without the need for updating the main body of this
agreement.
3.3 RPS commit to ensuring ongoing compliance with the agreed specifications
for critical in-process testing and for critical raw materials. RPS will
inform CTI of any significant non-compliance or intended changes as per
Sections 7 and 8.
3.4 RPS will manufacture Zileuton API only at those premises agreed by RPS and
CTI (as specified in Section 1). RPS will not outsource / subcontract any
GMP activities that are related to Zileuton API (other than those already
specified in this document) without the prior written agreement of CTI.
RPS shall also ensure that its own subcontractors meet the appropriate
standards of cGMP. To this end RPS will periodically audit its
subcontractors and will implement specific formal quality
Page 6 of 19
agreements to define these responsibilities (as required by ICH Q7a part
16). RPS will provide copies of (or copies of the relevant sections of)
these agreements and any subcontrator audits that specifically relate to
Zileuton.
3.5 RPS shall not use facilities to manufacture Zileuton API that have
previously been used for hazardous or sensitising material without the
prior agreement of CTI. Such materials shall include but are not limited
to penicillins, cephalosporins, pesticides, herbicides, rodenticides and
material of high pharmacological activity or toxicity such as steroids or
cytotoxic anti-cancer agents.
3.6 RPS shall not use any person debarred, disqualified or restricted by the
US FDA for any activity associated with the manufacture or supply of [**].
3.7 CTI and RPS will all comply with the content of this quality agreement.
4. Audit Programme
4.1 CTI has responsibility to evaluate RPS to ensure compliance with the
general commitments set out in Section 3.1. RPS will support CTI in any
reasonable requests for such evaluation and will endeavour to implement
any reasonable changes to the extent that it is not in compliance with
such requirements. To this end, CTI shall have the right to perform a
formal audit of processes and procedures that relate to Zileuton API
(including having access to relevant personnel and facilities) on a yearly
frequency with an additional right to attend upon prior notice if there
has been a serious problem with quality. The audit may include a review of
regulatory compliance, GMP compliance (as defined in ICH Q7a and
appropriate guidelines) and compliance with this Agreement. These rights
are entirely separate from both parties' commitment to regular project and
technical meetings. In addition, CTI may, with prior agreement, attend
relevant RPS sites for the purpose of reviewing Zileuton-specific
documents.
4.2 In the event of serious quality issues relating to zileuton and one (or
more) of RPS's subcontractors, CTI may
Page 7 of 19
request that RPS audit the subcontractor. RPS will support any reasonable
requests from CTI for such an audit and will also support CTI being
present during an audit of this nature.
5. Analytical, Batch Release and Despatch Activities
5.1 RPS is responsible for testing and release of all raw materials.
5.2 RPS are responsible for in-process testing.
5.3 RPS are responsible for testing and releasing the API (Zileuton) following
full review of the batch record (see also Section 5.5 for CTI's
involvement with batch release). The batch record review will cover the
batch production records for RPS [**], review of analytical data and
review of any changes, deviations and out-of-specification investigations.
RPS shall ensure that any API that is released for onward formulation
conforms to the principles of cGMP and to the approved specifications.
However, RPS must also abide by the requirements for document provision
and review, change control and deviation notification as specified below
(see Sections 6, 7 and 8). In addition, RPS must supply CTI with the
following certification for each batch of API that it releases:
- A certificate of analysis (CoA) complying with ICH Q7a section 11.4
that provides all analytical data for which RPS are responsible.
This certificate will specifically reflect either the full set of
tests/specifications for the IR material or the full set of
tests/specifications for the CR material (see Annex A) (unless both
sets of results are required). CTI will inform RPS in advance of the
intended formulation (IR or CR) to ensure correct testing and Cof A
are provided (see Annex A).
- A certificate of conformity that confirms that the batch in question
was manufactured to cGMP standards and that the batch record has
been reviewed and the batch released by RPS quality department. In
addition, this certificate shall specify any deviations, changes or
out-of-specification investigations relating to the batch that
required
Page 8 of 19
prior notification to CTI (see Sections 7 and 8 below).
- A record of the tamper-evident seal numbers (see also section 5.7).
5.4 RPS will provide a copy of the batch record to CTI for each of the NDA
batches made at RPS, for the first [**] commercial lots and thereafter as
requested. These batch records will include (1) RPS's official raw
material release reports including, [**], RPS's key raw data (2) key raw
data for all in-process and release testing (3) batch record from [**]
including key analytical raw data and (4) all major and minor deviations
and investigations. CTI will review these executed batch records and send
any comments to Rhodia prior to the release of the NDA batches, the first
[**] commercial batches from each manufacturing site and thereafter as
requested by CTI. In addition, Rhodia will provide CTI with an example
Certificate of Analysis for each raw material from each of RPS's vendors.
These will be from actual lots used for zileuton manufacture. New
certificates will be sent whenever Rhodia use a different supplier (see
also under 7.1).
5.5 RPS are responsible for ensuring that all of the API release methods are
qualified / validated to an appropriate level as required by cGMP. Some of
the methods are compendial and hence do not require full validation. RPS
are also responsible for conducting a formal transfer of these methods to
SP and Patheon(or to their chosen subcontractor(s)). It should be noted
that those methods carried out by [**] (i.e. particle size/surface area
and microbiological testing respectively) remain the responsibility of RPS
and, to this end, RPS will review and approve the [**] validation
protocols and reports for these methods and will oversee the method
transfers to SP and Patheon. RPS will provide SP, Patheon and CTI with
copies of the method validation protocols and reports for review / comment
and will also provide CTI with the key raw data from the validation and
transfer programmes.
5.6 RPS are responsible for characterising and providing the primary API
reference standard(s) for method validation purposes (except where these
are sourced from the USP).
Page 9 of 19
5.7 RPS will ensure that each keg is sealed with a uniquely-numbered
tamper-evident seal.
6. Document Provision and Review Requirements (including Process Validation)
6.1 CTI and RPS are jointly responsible for approving the specifications of
the API (see Annex 1 for the current versions) and the packaging and
labelling specifications.
6.2 RPS will generate detailed process documentation covering the process at
both Xxxxxx and Annan. These "baseline" documents will define the process,
plant, in-process specifications, critical parameters, the API
specification and methods, packaging specification, sampling requirements
and storage conditions. RPS shall also ensure that corresponding baseline
documents covering [**] activities are prepared by [**] respectively. RPS
will formally review and approve the [**] documents prior to the first
milling of API for human use. RPS shall provide to CTI a copy of both sets
of baseline documents for review and approval and to faciliate compilation
of regulatory dossiers. This will be done prior to manufacture of any API
for human use so that the documents reflect the intent for ongoing
commerical supply (i.e. prior to the initial NDA batches). Updated copies
of the relevant baseline documents will be sent to CTI (as appropriate)
for review in the following circumstances:
- whenever a change is made to the basic synthetic route, to the site
of manufacture (e.g. prior to manufacture and validation on moving
from Xxxxxx to Annan) or to the API specification
- whenever an API analytical method is replaced Thereafter CTI will
review and approve changes as detailed in Section 7. RPS will
provide copies of other master documents relating to the manufacture
and testing of the API to CTI at CTI's request.
6.3 RPS will provide copies of all process validation protocols and reports to
CTI. CTI will approve the initial protocols and reports associated with
each facility (Xxxxxx and Annan) and thereafter will approve any protocols
and reports associated with major changes.
Page 10 of 19
7. Change Control Requirements
7.1 RPS shall notify CTI of all major changes to the process, equipment,
facilities, analytical methods, specifications or materials that affect
Zileuton API. These changes will then be approved by CTI prior to
implementation by RPS. For the purposes of this document, a major change
is defined as any change that has a substantial potential to have an
adverse effect on the identity, strength, quality, purity or potency of
the product or which necessitates revalidation work or which affects any
regulatory submissions in such a way as to require prior notification to
the regulatory body (e.g. requires a minimum of a CBE in the US). The
following categories of change require prior notification to and
authorisation by CTI:
- Any change to the basic synthetic route (e.g. use of different
reagents)
- Any change to a critical process parameter outside the previously
accepted critical range
- Any change from one facility to another (even if on the same site)
- Major equipment changes affecting the API process from the final
solution onwards
- Major equipment changes affecting registration prior to the final
API solution
- Use of recycled solvents
- Changes to the specifications of the API
- Changes to the specifications associated with critical in-process
tests or critical raw materials
- Changes to API analytical methods that require some revalidation or
requalification of the method and/or which affect either
registrations or SP analytical methodology
- Changes to in-process and critical raw material analytical methods
that require some revalidation or requalification of the method and
which affect registrations
- Proposed use of out-of-specification raw materials.
- Changes to suppliers of critical raw materials
- Change of packaging or labelling
- Intent to outsource a GMP activity related to manufacture of
Zileuton API that was previously performed in-house (or vice versa)
Page 11 of 19
- Change of company name
- Change in the use of the Zileuton API facilities to include
hazardous or sensitising materials (see Section 3.6)
- Reprocessing or reworking of a batch of Zileuton API (see Section
8.2)
- Change to the retest date of the API (see Section 10.1)
- Change of contractors for following tests : Surface Area - Particle
Size Distribution -Microbio
7.2 RPS shall provide CTI at the time of implementation with a copy of any
minor changes that impact on the regulatory submission(s). RPS shall also
provide CTI with a summary of all changes affecting the Zileuton
regulatory documentation once per annum one month prior to the annual
report date (see Section 12).
7.3 Minor changes to the manufacturing documentation (i.e. those changes which
have no impact on quality or regulatory submissions) will not be notified
to CTI but will be available for audit.
8. Deviations and Out-of-Specification Investigations
8.1 RPS shall notify CTI of any major deviations that occur during the
manufacture, sampling, analysis, packaging, labelling, storage or despatch
of Zileuton API (including its registered intermediate stages) that are
the responsibility of RPS or any of its agreed subcontractors. This
notification shall occur prior to batch release. CTI will review and
approve the deviations and agree with RPS their impact on the release of
the API. Major deviations are those that could directly have a deleterious
impact on the quality (e.g. deviation from a critical parameter range or
critical in-process control) or are a significant breach of a regulatory
dossier commitment or represent a significant loss of control or breach of
GMP principles. All such deviations will also be recorded on the
certificate of compliance (see Section 5.3).
8.2 RPS shall notify CTI within three working days of any batches of API that
fail to comply with the agreed specifications. Any such batches will not
be despatched.
Page 12 of 19
RPS are responsible for investigating the out-of-specification result
unless the investigation shows that the cause is directly related to
either the data provided by or requests made by CTI. CTI will approve the
disposition of all batches that are impacted by confirmed out-
of-specification results. RPS shall ensure that no reworking or
reprocessing is carried out without the prior agreement of CTI. Any
batches that have been reworked or reprocessed will be notified prior to,
or at the time of, despatch.
9. Complaints and Recalls
9.1 RPS commit to resolving all reasonable complaints made by CTI that relate
to the manufacture of Zileuton API. RPS shall endeavour, wherever
practicable, to resolve the complaint and issue a final response within 28
working days.
9.2 RPS shall inform CTI within one working day of any quality issues that it
finds that have the potential to lead to a recall of any Zileuton.
Notification in writing shall occur within two working days. RPS shall
also provide reasonable and prompt assistance to investigate any recall
relating to Zileuton manufactured by RPS. The co-ordination and management
of any such recall will be the responsibility of CTI.
10. Stability Programme
10.1 The formal API stability programme is the responsibility of RPS. RPS will
provide CTI with the key raw data from this programme as it applies to the
NDA batches and first [**] commercial/validation batches and therafter as
required to enable compilation of ongoing regulatory submissions (see also
Section 12). RPS will also provide CTI with other raw data as required and
requested from the stability programmes. CTI will approve the initial
stability protocols covering the NDA batches and [**] commercial batches.
RPS will thereafter place [**] on stability each year (unless either no
batches are manufactured or more are required and agreed as a result of,
for example, process changes). RPS will inform CTI of any proposed changes
to this intent and of any proposed changes to the testing regime. CTI will
review
Page 13 of 19
and approve any such changes. Any changes to the approved retest date of
the API that may be justified as a result of the stability programme will
not be implemented without the prior approval of RPS and CTI.
11. Regulatory Issues
11.1 RPS commit to ensuring ongoing compliance with relevant regulatory
submissions and to informing CTI of any significant non-compliance (see
also the Sections 7 and 8). CTI commit to providing up-to-date copies of
all sections of regulatory documents with which Rhodia must comply. CTI
also commits to ensuring that compliance with regulatory documents is
facilitated as far as is possible by, for example, ensuring that they are
not contradictory, that they allow for reasonable batch by batch
variability and that they are consistent with the baseline documentation
supplied by Rhodia to CTI prior to submission (see also Section 6).
11.2 RPS shall inform CTI of any cGMP-based inspection (or intended inspection)
by a Regulatory Agency which may directly impact on the manufacture of
Zileuton API. Appropriate CTI employees or representatives will be able to
attend any inspection that is specific to Zileuton. RPS shall also provide
a copy of those parts of the inspection reports that directly impact
Zileuton.
11.3 CTI is responsible for maintaining the regulatory dossiers in compliance
with changes handled in accordance with Section 7.
12. Annual Product Quality Review
12.1 RPS is responsible for conducting a product quality review on an annual
basis. This review shall comply with section 2.50 of ICH Q7a and a copy
shall be provided to CTI one month prior to the annual report due date.
This review shall list all of the changes made during the year that impact
on regulatory submissions and also summarise the stability data generated
during the year in question. Additional review(s) will be undertaken if
necessary to comply with cGMP.
Page 14 of 19
ANNEX A - API SPECIFICATIONS
1. API specification relevant for use in the immediate release (IR)
formulation - version 1
2. API specification relevant for use in the controlled release (CR)
formulation - version 1
Note
This page (and associated specifications) may be updated if the API
specifications are changed and reapproved
Page 15 of 19
1. API SPECIFICATION RELEVANT FOR USE IN THE IMMEDIATE RELEASE (IR) FORMULATION
- VERSION 1
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Page 16 of 19
Approved by: _____________________________
Date: ___________________
(Rhodia Pharma Solutions)
Approved by: _____________________________
Date: ___________________
(Critical Therapeutics)
Specification Revision History
ALTERATIONS, ADDITIONS,
DATE VERSION NUMBER OMISSIONS
--------- -------------- ----------------------
JUNE 2004 VERSION 1 FIRST ISSUE
Page 17 of 19
2. API SPECIFICATION RELEVANT FOR USE IN THE CONTROLLED RELEASE (CR) FORMULATION
- VERSION 1
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Approved by: _____________________________
Date:___________________
(Rhodia Pharma Solutions)
Approved by: _____________________________
Date:___________________
(Critical Therapeutics)
Specification Revision History
ALTERATIONS, ADDITIONS,
DATE VERSION NUMBER OMISSIONS
--------- -------------- ----------------------
JUNE 2004 VERSION 1 FIRST ISSUE
Page 18 of 19
ANNEX B - RESPONSIBLE PERSONS / CONTACTS
CRITICAL THERAPEUTICS
PERSON / RESPONSIBILITY TELEPHONE NUMBER FAX NUMBER
----------------------- ---------------- ------------
QA
Xxxxxx Xxxxxxxxx 000-000-0000 000-000-0000
Xxxxxx Xxxxxx 000-000-0000 000-000-0000
QC
Xxxxxx Xxxxxx 000-000-0000 000-000-0000
Xxxxxx Xxxxx 000-000-0000 000-000-0000
Technical
Xxxxxx Xxxxxxxxx 000-000-0000 000-000-0000
Xxxxxx Xxxxxx 000-000-0000 000-000-0000
Commercial
Xxxxx Xxxxxxxxx 000-000-0000 000-000-0000
RHODIA PHARMA SOLUTIONS
PERSON / RESPONSIBILITY TELEPHONE NUMBER FAX NUMBER
----------------------- ---------------- ---------------
QA
Xxx Xxxxx x00 000 0000000 x00 000 0000000
QC
Xxx Xxxxxxx x00 0000 000000 x00 0000 000000
Xxxx Xxxxxx x00 000 0000000 x00 000 0000000
Technical
Xxxxxxxxxx Xxxxxx x00 0000 000000 x00 0000 000000
Commercial
Xxx Xxxxxxx x00 000 0000000 x00 000 0000000
Page 19 of 19
Annex 10
Validation Report
[document to follow]
35
ANNEX 11
[RHODIA LOGO]
PHARMA SOLUTIONS
CONFIDENTIAL
PROPOSAL
VALIDATION OF ZILEUTON
Proposal ANNSEN22032004A
(Supercedes Proposal ANNMTH25112003)
PREPARED FOR:
XXXX X. XXXXX, M.D.
CHIEF EXECUTIVE OFFICER & PRESIDENT
CRITICAL THERAPEUTICS
000 XXXXXXXXXXXXX XXX. 00XX XXXXX
XXXXXXXXX, XX 00000
23/03/04
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
CONTENTS
1. EXECUTIVE SUMMARY....................................................... 3
2. PROPOSAL................................................................ 4
3. ESTIMATED PRICE/KEY ASSUMPTIONS......................................... 8
4. SCOPE OF WORK/DELIVERABLES.............................................. 13
5. TIMELINE................................................................ 14
6. COMMUNICATION........................................................... 14
7. TERMINATION............................................................. 14
8. CONTACT................................................................. 15
9. ACCEPTANCE.............................................................. 15
Proposal Page 2 of 24
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
1. EXECUTIVE SUMMARY
Critical Therapeutics has agreed to purchase Zileuton CR and Zileuton IR from
Xxxxxx Pharmaceuticals. Zileuton is on the market for the treatment of Asthma.
Critical Therapeutics has asked Rhodia Pharma Solutions to review Xxxxxx'x
process and provide a proposal through validation and commercial manufacture of
Zileuton.
Rhodia Pharma Solutions has considered the above requests and is pleased to
offer the following proposal based on the technical data provided by both
Critical Therapeutics and Xxxxxx Pharmaceuticals. A timeline for the activities
described is provided for discussions between Rhodia Pharma Solutions and
Critical Therapeutics.
Based on the processing details provided, Rhodia Pharma Solutions feels we can
reach Critical's target at the [**] tonne scale of approximately $[**]/kilogram.
The price is estimated to be $[**] to provide material for formulation
development and to register Xxxxx as the site of manufacture and validate the
process in A1. This price would be on a time and materials basis.
PHASE 1
Technical Transfer / Familiarisation Phase $ [**]
Manufacture of [**] batches Dudley Pilot Plant $ [**]
Dudley Validation $ [**]
PHASE 2
Cost for Analytical Validation and TT $ [**]
PHASE 3
Xxxxx Validation $ [**]
Stability Studies $ [**]
------
TOTAL $ [**]
------
Proposal Page 3 of 24
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
2. PROPOSAL
The process used to prepare Zileuton is shown below:
[**]
FIG. 1 PROPOSED PILOT PLANT SYNTHESIS OF ZILEUTON
Phase 1: Familiarisation Phase & Manufacture at Dudley
a) Familiarisation
Abbott developed and scaled up this process in-house before licensing the
process to Critical. As part of transferring the process, Rhodia Pharma
Solutions would carry out laboratory and analytical familiarization.
Rhodia Pharma Solutions has identified raw material suppliers. Currently, a
Japanese supplier is holding enough 2ABT for the manufacture of [**]kg of
Zileuton. Further material is on a [**] lead-time. Methyl carbamate is on a [**]
lead-time.
b) Manufacture of up to [**] kg non-GMP
The initial hazard evaluation work carried out by Rhodia Pharma Solutions has
uncovered a significant safety hazard with the Abbott process. The formation of
hydroxuyurea has been found to be unstable at the reaction temperature. In light
of this there are some additional safety precautions required to fit the 300
gallon stream located at Rhodia Pharma Solution's Dudley, England, facility.
This site is not the long-term home for Zileuton but provides comparatively
rapid entry. The hazard evaluation study has provided the basis for the
engineering design to support both the Dudley pilot plant and the A1 commercial
long-term home at Xxxxx.
Some pilot plant refit work will be required in order to safely handle the
hydroxylamine. (This is related to ensuring that no metal components have the
potential to come into contact with hydroxylamine).
After completion of the lab familiarisation, up to [**] batches will be run to
yield approx [**]kg of Zileuton. This material will support the formulation
development work required on either CR or IR formulation. The material will be
milled by Micron Technologies to an agreed particle size specification.
Details of the initial campaign are summarized below.
Proposal Page 4 of 24
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
TABLE 1. DETAILS FOR [**]KG NON-GMP CAMPAIGN.
TOTAL
EQUIPMENT SIZE NUMBER OF PROCESSING
STAGE (UK GALLONS) BATCHES DAYS
----- ------------ -------------- ----------
1 [**] [**] [**]
TOTAL [**]
Skye Pharma would use the material for tabletting development work for both IR
and CR programmes.
c) Validation
In order to support the IR programme timelines, it is proposed that a validation
campaign be carried out at Dudley. This will also provide Critical Therapeutics
with security of supply, as Zileuton will in due course be manufactured at
either RPS UK facility.
A [**]-batch campaign is planned including [**] validation batches. The [**]
validation lots would be put on stability (6 months at 40 degrees C/75%RH, 24
months at 25 degrees C/60%RH).
The material would be used for sNDA stability for the IR submission and for
tabletting by Skye Pharma for IND bioequivalence work, as well as by Skye Pharma
for scale-up work in Lyon.
TABLE 2. DETAILS FOR [**]KG VALIDATION CAMPAIGN.
TOTAL
EQUIPMENT SIZE NUMBER OF PROCESSING
STAGE (UK GALLONS) BATCHES DAYS
----- ------------ -------------- ----------
1 [**] [**] [**]
TOTAL [**]
Proposal Page 5 of 24
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
Phase 2: Analytical Validation
In order to support the IR programme, the timeline for analytical method
validation has been compressed. In addition full analytical method validation is
now planned to satisfy FDA requirements. Hence the methods for raw materials,
IPC and API will be formally validated prior to the validation campaign in A1 at
Xxxxx and the stability programme being initiated. The API methods would be
transferred to Skye Pharma under the same protocol.
Overall, validation of the methods will require the synthesis and
characterisation of approximately sixteen reference standards. It is assumed
that the remaining will be purchased from USP or suppliers. The characterization
of these impurities is also required in order to develop new analytical methods
where necessary.
Phase 3: Validation batches
The Xxxxx site is especially equipped to handle API manufacture at scale. The
process presents a good fit for the A1 plant which is suitable for the
manufacture of up to [**] Mt of Zileuton.
After completion of Phase 1 & Phase 2, [**] batches, including [**] validation
batches, will be run to target a yield [**] kg of Zileuton. A [**]kg batch size
will be targeted. The [**] validation lots would be put on stability (6 months
at 40 degrees C/75%RH, 24 months at 25 degrees C/60%RH). The data from the Xxxxx
validation campaign will be included in both the IR and CR submissions.
Some plant refit work will be required in order to safely handle the
hydroxylamine and the subsequent hydroxyurea reaction. This will provide a
purpose made facility for the long-term manufacture of Zileuton.
Details of the validation campaign are summarized below.
TABLE 1. DETAILS FOR VALIDATION CAMPAIGN.
TOTAL
EQUIPMENT SIZE NUMBER OF PROCESSING
STAGE (UK GALLONS) BATCHES DAYS
----- ------------ -------------- ----------
1 [**] [**] [**]
TOTAL [**]
Proposal Page 6 of 24
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
The material would be used for NDA stability for both the IR and CR programmes,
as well as providing commercial IR material.
Proposal Page 7 of 24
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
3. ESTIMATED PRICE/KEY ASSUMPTIONS
PHASE 1: FAMILIARISATION PHASE
CALENDAR RESOURCE ESTIMATED
ACTIVITY TIME DAYS RESOURCE PRICE ($)
-------- -------- -------- -------- ----------
Lab Familiarisation [**] [**] [**] [**]
Analytical Support [**] [**] [**] [**]
Hazards Evaluation [**] [**] [**] [**]
Materials and Columns [**]
ESTIMATED TOTAL [**] $[**]
Proposal Page 8 of 24
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
PHASE 1: [**]KG NON-GMP CAMPAIGN
CALENDAR RESOURCE ESTIMATED
ACTIVITY TIME DAYS RESOURCE PRICE ($)
-------- -------- -------- -------- ----------
Pilot Plant Processing
(Including cleaning) [**] [**] [**] [**]
Pilot Plant Safety
Trials [**] [**] [**]
Safety Studies [**] [**] [**] [**]
Chemist Support on
Pilot Plant [**] [**] [**] [**]
Analytical / QA
Support on Pilot Plant [**] [**] [**] [**]
Documentation [**] [**] [**] [**]
Materials and
Supplies [**]
Hydroxylamine Refit [**] [**]
Milling [**] Micron [**]
Xxxxx
ESTIMATED TOTAL $[**]
Proposal Page 9 of 24
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
PHASE 1B: [**] KG VALIDATION CAMPAIGN
CALENDAR RESOURCE ESTIMATED
ACTIVITY TIME DAYS RESOURCE PRICE ($)
-------- -------- -------- -------- ----------
Pilot Plant Processing
(Including cleaning) [**] [**] [**] [**]
Chemist Support on
Pilot Plant [**] [**] [**] [**]
Analytical/QA
Support on Pilot Plant [**] [**] [**] [**]
Materials and
Supplies [**]
Milling [**] Micron [**]
Xxxxx
ESTIMATED TOTAL $[**]
PHASE 2: ANALYTICAL VALIDATION
CALENDAR RESOURCE ESTIMATED
ACTIVITY TIME DAYS RESOURCE PRICE ($)
-------- -------- -------- -------- ----------
Analytical method
validation & tech
transfer [**] [**] [**] [**]
Synthesis of 16
reference substances [**] [**] [**] [**]
Analytical
characterization of 16
reference substances [**] [**] [**] [**]
Purchased of 14
reference substances [**]
Estimated total $ [**]
Proposal Page 10 of 24
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
PHASE 3: VALIDATION CAMPAIGN A1 XXXXX
CALENDER RESOURCE ESTIMATED
ACTIVITY TIME DAYS RESOURCE PRICE ($)
-------- -------- -------- -------- ----------
Processing
(Including cleaning) [**] [**] [**] [**]
Chemist Support on
Pilot Plant [**] [**] [**] [**]
Analytical / QA
Support on Pilot Plant [**] [**] [**] [**]
cGMP Documentation [**] [**] [**] [**]
Materials and
Supplies [**] [**]
Plant Modifications [**] [**]
ESTIMATED TOTAL $[**]
PHASE 3: STABILITY STUDIES
PROTOCOL PULLS IN MONTHS TOTAL DAYS TOTAL PRICE $
-------- --------------- ---------- -------------
[**] batches accelerated [**] [**] [**]
[**] batches long term [**] [**] [**]
Program set-up [**] [**]
ESTIMATED TOTAL [**] $[**]
Proposal Page 11 of 24
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
KEY ASSUMPTIONS
- Analytical methods have been supplied during the technical transfer; the
price includes the formal validation of the methods.
Assumed as:
6 off HPLC methods
3 off GC for residual solvents
1 off XRD ( methodology undefined at present )
Not included:
Microbiological testing, to be defined and outsourced. Surface area
and particle size will be subcontracted to Micron.
- Stability indicating analytical methods are the same as the API release
methods.
- Stability methods are applied to [**] qualification batches out of Dudley
and [**] validation batches out of Xxxxx. Both accelerated and real time
programs will be run in parallel up to [**].
- Milling has been included for the initial Dudley campaign and will be
subcontracted to Micron Technologies. Prices for milling latter campaigns
and validation costs are yet to be defined. The milling will be taken
in-house at suitable volume.
- An estimate of price is given assuming suitable reference standards
(fourteen) can be purchased commercially. Rhodia Pharma Solutions will
manufacture the remaining sixteen standards.
- The 2ABT is on a [**] lead-time.
Chemist, analyst and QA time will be billed at the rate of $[**] per day.
Chemicals, services and supplies will be billed at cost plus [**]%. Pilot Plant
time will be billed at $[**] per day.
The actual charges for Critical Therapeutics account will be invoiced monthly,
with payment due net 30 days from invoice date.
Proposal Page 12 of 24
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
4.SCOPE OF WORK/DELIVERABLES
RHODIA PHARMA SOLUTIONS WILL:
- Perform tech transfer, laboratory evaluation and familiarisation
experiments on the process.
- Synthesise and characterise sixteen reference standards targeting 1-10
grams of each with a minimum purity of 95%. Analyse the standards by HPLC,
IR, NMR and MS.
- Validate the analytical methods and for the API, carry out technology
transfer to Skye Pharma.
- Prepare approximately [**] kg of Zileuton non-cGMP conditions in the Pilot
Plant at its Dudley, England facility.
- Validate the Zileuton process during a [**]kg campaign in the Pilot Plant
at its Dudley, England facility.
- Validate the Zileuton process during the same [**]kg campaign in the A1
Plant at its Xxxxx, Scotland facility
- Provide written status reports on a monthly basis with teleconferences
and/or meetings to be organised as agreed appropriate.
- Provide copies of master batch records used in the pilot plant.
- Provide written reports summarising all phases of the work undertaken on
the project.
- After completion of the registration campaign, carry out stability
programmes and provide a report.
- Provide a hazard evaluation report.
CRITICAL THERAPEUTICS WILL:
- Agree to a final product release specification prior to scale-up
activities.
- Provide any relevant health, safety, and environmental information.
- Provide any hazard information pertaining to the process.
- Provide any samples that are available to assist Rhodia Pharma Solutions
in polymorph determinations and analytical support.
- Provide batch records / development reports for the process and arrange
for technical discussion / transfer with Abbott / SkyePharma.
Proposal Page 13 of 24
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
5.TIMELINE
Upon acceptance by Critical Therapeutics of this proposal, work could begin
immediately at Rhodia Pharma Solutions. The initial Dudley non-GMP material
would be delivered in parts, the first part delivered to Skye by [**]. The
Dudley validation campaign will be complete by [**] and the Xxxxx validation
complete by [**].
6. COMMUNICATION
A Rhodia Pharma Solutions technical project manager will be appointed to handle
technology transfer and technical interface issues for the project. The Rhodia
Pharma Solutions product manager will coordinate all timeline and financial
aspects of the project with Critical Therapeutics and will be available for
discussions as required.
7. TERMINATION
Either party shall be entitled to terminate this agreement before the project
has been completed by giving to the other party 90 days prior written notice of
termination.
Termination shall be effective on the expiration of the applicable notice period
(the Effective Termination Date).
All work performed by RPS prior to the Effective Termination Date of the project
shall be paid for by Critical Therapeutics at the estimated cost provided herein
prorated for the work performed to the Effective Termination Date. Any raw
material/capital expenses incurred and/ or committed by RPS prior to the
Effective Termination Date, or any expenditure required by RPS to return the
unit to its original condition prior to commencement of the capital project
shall be paid by Critical Therapeutics. RPS will seek to minimize all costs
associated with the reason for termination and will provide justification of the
expenditure to Critical Therapeutics.
Proposal Page 14 of 24
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
0.XXXXXXX
For additional information or questions, please contact:
Xxx Xxxxxxx
Product Manager
Rhodia Pharma Solutions
Dudley
Northumberland
England
Phone: 00-00-000-000-0000
Email: xxx.xxxxxxx@xx.xxxxxx.xxx
9. ACCEPTANCE
Please indicate Critical Therapeutics acceptance of this proposal by returning a
signed copy or a purchase order, referencing Proposal. This proposal is valid
for 30 days.
CRITICAL THERAPEUTICS
By: /s/ Xxxx Xxxxx Date: March 23, 2004
-----------------------------------
Name: Xxxx Xxxxx, CEO
Proposal Page 15 of 24
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
APPENDIX
ABBOTT NUMBER CHEMICAL NAME STRUCTURE CAS NUMBER
------------- ------------- --------- ----------
1. [**] [**] [**] [**]
2. [**] [**] [**] [**]
3. [**] [**] [**] [**]
4. [**] [**] [**] [**]
5. [**] [**] [**] [**]
6. [**] [**] [**] [**]
7. [**] [**] [**] [**]
8. [**] [**] [**] [**]
9. [**] [**] [**] [**]
10. [**] [**] [**] [**]
11. [**] [**] [**] [**]
12. [**] [**] [**] [**]
13. [**] [**] [**] [**]
14. [**] [**] [**] [**]
15. [**] [**] [**] [**]
16. [**] [**] [**] [**]
Proposal Page 16 of 24
[RHODIA LOGO]
PHARMA SOLUTIONS
TIMELINE
[**]
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
SCOPE CHANGE NOTIFICATION
RHODIA PHARMA SOLUTIONS, DUDLEY PROPOSAL #
Cramlington, Northumberland, Prepared for:
3 0XX, Xxxxxx Xxxxxxx Xxxxxx Xxxxxxx
Tel: x00 (0)000 000 0000 CTI
Fax: x00 (0) 000 000 0000 Tel:
Fax:
PRODUCT MANAGER: XXX XXXXXXX
NATURE OF CHANGE: Increased Number of Batches
PREVIOUSLY AGREED DELIVERABLE: [**] to [**] batches
IMPACT ON DELIVERY DATE Split Campaigns to [**]
REQUEST MADE BY: Xxx Xxxxxxx DATE: 24th June 04
SCOPE CHANGE ASSESSED BY: Xxxxxx Xxxxxxxx
XXXXX SUMMARY
CALENDAR RESOURCE RESOURCE ESTIMATED
TIME DAYS PRICE ($)
Additional materials $ [**]
Additional Pilot Plant Days [**] $ [**] $ [**]
Additional Chemist Support [**] $ [**] $ [**]
Additional Analytical Support [**] $ [**] $ [**]
TOTAL $ [**]
Note that price excludes milling. A separate scope change will be raised to
cover additional milling requests.
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
AGREEMENT:
CUSTOMER RHODIA PHARMA SOLUTIONS
Signature: /s/ Xxxxxx Xxxxxxx Signature: /s/ Xxx Xxxxxxx
---------------------- ---------------
Name: Xxxxxx Xxxxxxx Name: Xxx Xxxxxxx
Proposal Page 20 of 24
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
SCOPE CHANGE NOTIFICATION
RHODIA PHARMA SOLUTIONS, DUDLEY PROPOSAL #
Cramlington, Northumberland, Prepared for:
XX00 0XX, Xxxxxx Xxxxxxx Xxxxxx Xxxxxxx
Tel: x00 (0)000 000 0000 CTI
Fax: x00 (0) 000 000 0000 Tel:
Fax:
PRODUCT MANAGER: XXX XXXXXXX
NATURE OF CHANGE: Additional Stability Testing
PREVIOUSLY AGREED DELIVERABLE: [**] Xxxxx batches
NEW DELIVERABLE Now plus [**] Dudley batches
REQUEST MADE BY: Xxx Xxxxxxx DATE: 12th August 04
SCOPE CHANGE ASSESSED BY: Xxxxxx Xxxxxxxx
XXXXX SUMMARY
ACTIVITY CALENDAR TIME ESTIMATED PRICE ($)
-------- ------------- -------------------
Dudley validation ([**]) - accelerated [**] [**]
Dudley validation ([**]) - long term [**] [**]
ESTIMATED TOTAL $ [**]
AGREEMENT:
CUSTOMER RHODIA PHARMA SOLUTIONS
Signature: /s/ Xxxxx Xxxxxxxxx Signature: /s/ Xxx Xxxxxxx
-------------------------- ---------------------
Name: Xxxxx Xxxxxxxxx Name: Xxx Xxxxxxx
This negates Scope Change of July 21, 2004 (/s/ SB, 8/12/04)
s Proposal Page 21 of 24
[RHODIA LOGO] CONFIDENTIAL
PHARMA SOLUTIONS
SCOPE CHANGE NOTIFICATION
RHODIA PHARMA SOLUTIONS, XXXXXX PROPOSAL #
Cramlington, Northumberland, Prepared for:
XX00 0XX, Xxxxxx Xxxxxxx Xxxxx Xxxxxxxxx
Tel: x00 (0)000 000 0000 CTI
Fax: x00 (0)000 000 0000 Tel:
Fax:
PRODUCT MANAGER: XXX XXXXXXX
NATURE OF CHANGE: Additional milling requests
PREVIOUSLY AGREED DELIVERABLE: Not applicable
IMPACT ON DELIVERY DATE Not applicable
REQUEST MADE BY: Xxx Xxxxxxx DATE: 28th Sept. 04
SCOPE CHANGE ASSESSED BY: Xxxxxx Xxxxxxxx
XXXXX SUMMARY
CALENDAR RESOURCE ESTIMATED
TIME DAYS RESOURCE PRICE ($)
-------- -------- -------- ---------
Analytical Support $ [**]
Validation & Transfers $ [**]
Milling $ [**]
TOTAL $ [**]
AGREEMENT:
CUSTOMER RHODIA PHARMA SOLUTIONS
Signature: /s/ Xxxxxx Xxxxxxx Signature: /s/ Xxx Xxxxxxx
------------------------- ---------------
Name: Xxxxxx Xxxxxxx Name: Xxx Xxxxxxx
Proposal Page 22 of 24
ANNEX 12 - CAPITAL DESCRIPTION
In order to manufacture [**]/annum on an ongoing basis RPS estimate the
following costs
[**]
ANNEX 13 - POST DELIVERY PERIOD PRICING
Equal to or less than [**]
$[**]/kg
Greater than [**], up to less than [**]
$[**]/kg
Equal to or greater than [**], up to less than [**]
$[**]/kg
Equal to or greater than [**], up to less than [**]
$[**]/kg
Equal to or greater than [**]
$[**]/kg
Target
$[**]/kg
ANNEX 14
ABBOTT
Global Pharmaceutical Licensing and New Business Development
Xxxxxx Laboratories
000 Xxxxxx Xxxx Xxxx
Xxxxxx Xxxx, Xxxxxxxx 00000-0000
January 28, 2005
Xxxxxxx X. Xxxxxxxx
Chief Patent Counsel
Critical Therapeutics, Inc.
00 Xxxxxxxx Xxxxxx
Xxxxxxxxx, XX 00000
Dear Xx. Xxxxxxxx:
Xxxxxx Laboratories, a corporation organized under the laws of the State of
Illinois, USA, with its principal office at 000 Xxxxxx Xxxx Xxxx, Xxxxxx Xxxx,
Xxxxxxxx 00000 ("Abbott") has granted Critical Therapeutics, Inc., a corporation
organized under the laws of the State of Delaware, USA, with its principal
office at 000 Xxxxxxxxxxxxx Xxxxxx, 00xx Xxxxx, Xxxxxxxxx, Xxxxxxxxxxxxx 00000
("CTI") two licenses dated 18 December 2003 and 19 March 2004 related to the
active pharmaceutical compound zileuton. Both of the license agreements included
a "Covenant Not to Xxx" clause which was a promise by Abbott not to assert any
of its patent rights against certain defined activities of CTI.
CTI has now indicated a desire to contract with certain third parties for
production of the zileuton compound and has indicated that said third parties
have expressed a concern about being free to pursue such production free from
liability under any Abbott patents.
Abbott, in order to facilitate CTI's operation under these two licenses and
hasten the day when CTI can reach the market with products contemplated under
these licenses, hereby covenants not to bring any suit for patent infringement
based upon the activities involved in manufacturing the zileuton compound by any
such third party for CTI in support of CTI activities under these licenses. This
promise shall run concurrently with these licenses and shall expire upon the
expiration or termination of the later of these two license to end. It is
intended that any such third party manufacturer be a third party beneficiary of
this promise. CTI is free to provide a copy of this promise to any third party
manufacturer who has expressed or expresses a concern in this regard.
With kind regards,
/s/ Xxxxxxx Xxxxxx
Xxxxxxx X. Xxxxxx, Ph.D.
Divisional Vice President
Scientific Assessment and Technology Licensing
Global Pharmaceutical Licensing
D-R50A, AP34; 000 Xxxxxx Xxxx Xxxx
Xxxxxx Xxxx, XX 00000-0000
Cc: X. Xxxxxxxxx, X. Xxxxxx
39
