EXHIBIT 10.21
Production Agreement
Project:
This Production Agreement (hereinafter the "Agreement") is entered into the 7th
day of March, 2000
by and between
ESPERION THERAPEUTICS, INC., a Delaware corporation located at 0000 X. Xxxxx
Xxxxxx, 000 XXX Xxxxx, Xxx Xxxxx, Xxxxxxxx 00000, XXX, hereinafter referred to
as "ESPERION",
and
EUROGENTEC S.A., a Belgian corporation located at Xxxx Xxxxxxxxxxxx xx Xxxx
Xxxxxx, X-0000 Xxxxxxx, Xxxxxxx, hereinafter referred to as "EUROGENTEC",
hereinafter referred to individually as "a Party" or collectively as "the
Parties",
Whereas the Parties wish to set forth in writing the terms and conditions under
which EUROGENTEC will produce and supply to ESPERION, and ESPERION will purchase
from EUROGENTEC, batches intended to be used in research, research
(phamacokinetics, toxicology, stability, scale-up processes, production
consistency, etc.), clinical development, scaling up of process, and production
of consistency of ESPERION's compound Pro-Apolipoprotein A-I, in EUROGENTEC's
production facilities at Seraing. The number of weeks required for of usage of
EUROGENTEC's production facility is defined in Annex 3.
Now it is hereby agreed as follows:
Article 1 : Definitions
1.1 "Cell Bank" shall mean Master Cell Bank or derived Cell Bank including GMP,
GLP and Working Cell Banks.
1.2 "Current Pharmaceutical Guidelines" shall refer to guidelines described in
US 21 Part. 210 and 211 CFR cGMP regulation, US 21 Part. 600 CFR (additional
regulation for Biologicals) and EC Guide to Good Manufacturing Practices.
1.3 "Clinical Batch" shall mean the fermentation of a strain of Escherichia
coli (hereafter referred to as the "Strain") expressing the compound Pro-
Apolipoprotein Al (hereinafter referred to as the "Product") and the
purification of the Product in EUROGENTEC's pharmaceutical Production Unit, as
hereinafter defined, applying Current Pharmaceutical Guidelines, with the
intention to use the Product for research, preclinical research
(phamacokinetics, toxicology, stability, scale-up processes, production
consistency, etc.), and clinical development.
1.4 GMP shall mean the current rules for "Good Manufacturing Practice" as
defined and published by the US Food and Drug Administration and the European
Union equivalent administration for the manufacture of pharmaceutical products.
1.5 "Product" shall mean human recombinant proapoplipoprotein A-I.
1.6 "Specification documents" shall mean the preparation and production
instructions for each Clinical Batch, including batch protocols and records,
identification of raw materials and specific instrumentation, the specifications
for the Product, the identification of critical steps, the quality control
methods and all information necessary to carry out the production and quality
control operations.
Article 2 : The Production of Clinical Batches
2.1 EUROGENTEC shall diligently manufacture in its Production Unit Clinical
Batches of the Product as ordered by ESPERION in accordance with the Current
Pharmaceutical Guidelines and Specification documents (as defined in Annex 1) to
be supplied by ESPERION before each Clinical Batch production.
2.2 The general responsibilities of EUROGENTEC and ESPERION for the preparation
of Clinical Batches and/or Cell Banks are defined in Annex 1, which forms an
integral part of this Agreement.
2.3 The products resulting from Clinical Batches produced by EUROGENTEC are
bulk proapolipoprotein A-I for injection to be used in research, preclinical
research (phamacokinetics, toxicology, stability, scale-up processes, production
consistency, etc.), and clinical development to be conducted on a world-wide
basis under the responsibility of ESPERION.
2.4 The production planning of Clinical Batches will be jointly defined by the
Parties. The Specification documents will be made available to EUROGENTEC by
ESPERION in due time to allow EUROGENTEC to produce in accordance with the
Current Pharmaceutical Guidelines.
2.5 EUROGENTEC shall diligently assure the consistency of manufactured batches.
Article 3 : EUROGENTEC Production Unit, Equipment & Personnel
3.1 The preparation of Clinical Batches or Cell Banks will take place in the
pharmaceutical multipurpose production unit of EUROGENTEC located at Xxxx
Xxxxxxxxxxxx xx Xxxx Xxxxxx, X- 0000 Xxxxxxx, Xxxxxxx (phone 00.0.000.00.00 &
fax 00.0.000.00.00) (the "Production Unit"). The Production Unit will be
maintained, cleaned and operated by EUROGENTEC in compliance with Current
Pharmaceutical Guidelines.
3.2 A currently registered (in Belgium) pharmacist, with knowledge of cGMP
requirements, on EUROGENTEC's payroll will control the production of Clinical
Batches.
3.3 ESPERION reserves the right to use some areas of the Production Unit (as
such use is defined in Annex 3) for the period defined in Annex 3.
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Article 4 :Auditing
4.1 ESPERION, or a party designated by ESPERION, shall be permitted to audit
the Production Unit of EUROGENTEC from time to time upon reasonable prior notice
to EUROGENTEC.
4.2 The responsibilities for Quality Control sampling will be defined in the
Process Document (as defined in Annexes 1 and 2 attached hereto). Samples from
each Clinical Batch shall be kept at EUROGENTEC and shall be transferred to a
location designated by ESPERION within two weeks upon the later of(a) one (1)
year after the concerned Clinical Batch expiry date, or (b) two (2) years after
the end of clinical studies upon ESPERION's request.
Article 5 :Compliance with Legal Requirements
5.1 All activities to be performed by EUROGENTEC under this Agreement and in
the Production Unit shall comply with requirements enacted by the Belgian
Ministry of Health, the U.S. Food and Drug Administration and any other
relevant authority and shall be in compliance with Current Pharmaceuticals
Guidelines and all applicable legal requirements. EUROGENTEC shall obtain and
maintain any required authorization for the performance of this Agreement.
5.2 In particular, EUROGENTEC warrants to ESPERION that the Production Area
dedicated to the performance of this Agreement as defined in Annex 3 will be
independent from any other activity and that all precautions shall be taken by
EUROGENTEC in order to avoid any cross contamination.
5.3 EUROGENTEC and ESPERION shall cooperate and be diligent in responding to
all requests for information from, and in making all required filings with,
regulatory authorities having jurisdiction to make such requests or require such
filings. EUROGENTEC shall obtain and comply with all current licenses,
consents, permits and regulations which may from time to time be required by
appropriate legal and regulatory authorities with respect the performance of its
obligations hereunder.
Article 6 :Price and Payment Conditions
6.1 All prices hereunder are in BEF and are exclusive of VAT. The prices to be
paid by ESPERION for the performance of this Agreement are set forth in Annex 4
attached hereto, which forms an integral part of this Agreement. The total cost
for technology transfer is defined in Annex 4. The total cost for production
is defined in Annex 4.
6.2 The exchange rate for conversion of BEF to US dollars shall be equal to a
rolling three (3) month average exchange rate, calculated during the period
covered by the services provided and starting with the month in which services
commenced..
6.3 Raw materials, including entry QC and specific consumables, needed for the
production of Clinical Batches or Cell Banks under this Agreement, other than
chemical materials used by EUROGENTEC in quality control activities, are not
included in the price referred to in Article
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6.1. and will be supplied and invoiced separately by EUROGENTEC. The total costs
for raw materials is defined in Annex 4.
6.4 ESPERION shall pay upon signature of this Agreement an advance payment of
30% of the estimated price defined in Annex 4 attached hereto. This advance
payment shall be deducted proportionally from each invoice due to EUROGENTEC
under Article 6.1. In the event that ESPERION terminates or cancels this
Agreement for any reason whatsoever, except for negligence, misconduct or
default of EUROGENTEC, Esperion shall pay only for costs incurred as of the time
of termination. All materials produced as of the time of termination shall be
returned to ESPERION or destroyed at ESPERION's discretion.
6.5 EUROGENTEC shall send monthly invoices to ESPERION together with supporting
documentation, and payment will be made by ESPERION within thirty (30) days from
date of receipt of such invoice.
Article 7 : Liabilities of EUROGENTEC
7.1 EUROGENTEC warrants that the Clinical Batches manufactured and supplied
hereunder to ESPERION shall be manufactured in accordance with Current
Pharmaceutical Guidelines and shall conform to the Specification documents. The
foregoing is the exclusive warranty of ESPERION for defects in the Clinical
Batches manufactured by EUROGENTEC under this Agreement and is in lieu of any
other warranty, express or implied, including but not limited to, implied
warranty of merchantability or fitness for a particular purpose. EUROGENTEC
shall have no liability hereunder for incidental or consequential damages,
including lost profits.
7.2 ESPERION shall have the right to give EUROGENTEC written notice of
rejection of any shipment of Clinical Batch that in whole or in part breaches
EUROGENTEC's warranties, covenants and obligations under this Agreement, which
notice shall be given within thirty (30) days after discovery of such breach
however not later than 90 days after receipt of shipment. If there is
disagreement between the parties as to whether the Clinical Batch meets
Specification documents, the parties shall have such Clinical Batch tested by a
mutually agreed upon third party and such party's determination as to whether
such Clinical Batch meets Specification documents shall be binding on the
parties hereto. The expense for such testing and for any costs associated with
the destruction of such Clinical Batch shall be borne by EUROGENTEC except to
the extent it is determined that EUROGENTEC is not responsible for such failure
or breach. At ESPERION's option, EUROGENTEC shall promptly replace any Clinical
Batch which does not conform with EUROGENTEC's warranties under this Agreement.
ESPERION shall have the right to setoff any refund due ESPERION on account of
any rejected Clinical Batch against invoices otherwise due or which become due
to EUROGENTEC. The provisions of this Article 7.2 shall survive termination of
this Agreement.
7.3 EUROGENTEC shall indemnify, defend and hold ESPERION, each affiliate of
ESPERION and the officers, directors, stockholders and employees thereof (each
an "ESPERION indemnified party") harmless from and against any and all losses,
liabilities, damages, claims, expenses, suits, recoveries, judgments and fines
(including reasonable attorneys' fees and expenses) (collectively "Losses") that
may be incurred by any ESPERION
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indemnified party or any third party arising out of any (a) actual or alleged
damage to property or injury or death occurring to any person arising out of
possession, use or consumption by any person of the Clinical Batches to the
extent that such damage, injury or death was caused by the failure of such
Clinical Batches to meet Specification documents; (b) claim, action or
proceeding brought by any governmental or regulatory authority arising out of or
resulting from any breach of EUROGENTEC under this Agreement; or (c) breach by
EUROGENTEC of any of its obligations, representations or warranties under this
Agreement.
7.4 If the first 300 grams of Product is not delivered by EUROGENTEC in
accordance with the time schedule set forth in Annex 3, EUROGENTEC shall pay to
ESPERION, as liquidated damages for such delay and not as a penalty, an amount
equal to 5% of the aggregate price hereunder for such undelivered quantity for
each week (or part thereof) of delay beyond the scheduled delivery date up to a
maximum of US$350,000. If any quantity of Product after of such first 300
grams is not delivered by EUROGENTEC in accordance with the time schedule set
forth in Annex 3, EUROGENTEC shall pay to ESPERION, as liquidated damages for
such delay and not as a penalty, an amount equal to 10% of the aggregate price
hereunder for such undelivered quantity for each week (or part thereof) of delay
beyond the scheduled delivery date. Such liquidated damages shall be payable by
EUROGENTEC to ESPERION on demand or, at the option of ESPERION, may be offset by
ESPERION against any amount owed by ESPERION to EUROGENTEC under this Agreement.
Such liquidated damages cover only damages resulting from such delay in delivery
and shall not limit or affect any other claims or rights which ESPERION may have
hereunder or under applicable law. For delivery of future batches, EUROGENTEC
shall pay to ESPERION the liquidated damages for delay and not as a penalty, an
amount equal to 5% of the aggregate price hereunder for such undelivered
quantity for each week (or part thereof) of delay beyond the scheduled delivery
date up to a maximum of 35% of the aggregated price not to exceed US$1,000,000.
7.5 EUROGENTEC shall have no liability hereunder for incidental or
consequential damages, including lost profits.
Article 8 : Liability of ESPERION
8.1 ESPERION warrants to EUROGENTEC that the use of the Strain will not involve
a risk for the human beings, the animals and the environment that would require
more than a containment level 2 as defined in directive 98/81/EC. In case of
recombinant microorganisms, ESPERION and EUROGENTEC shall agree upon an
appropriately validated procedure for the inactivation of the Strain.
8.2 ESPERION shall indemnify and hold EUROGENTEC harmless from and against any
and all Losses asserted by any third party arising out of or in connection with
the use of the Strain by EUROGENTEC or its employees if the Strain supplied by
ESPERION does not conform to the specifications described in this Agreement and
its Annexes, in particular in Article 8.1., or with the use of any products
derived from the Clinical Batches delivered by EUROGENTEC to ESPERION in
accordance with this Agreement, except if such damages were caused by
negligence, misconduct or breach of this Agreement on the part of EUROGENTEC or
its employees, subject to the terms and conditions provided for in Article 7.
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8.3 ESPERION shall have no liability hereunder for incidental or consequential
damages, including lost profits.
Article 9 : Intellectual Property Rights
9.1 ESPERION agrees to indemnify and hold EUROGENTEC harmless from and against
any and all claims, demands, causes of action, actions or suits, arising out or
related to any intellectual property rights whatsoever owned by any third
parties on techniques, know-how or materials used by EUROGENTEC in the
performance of EUROGENTEC activities covered by this Agreement, which either are
supplied by ESPERION or are acquired by EUROGENTEC on behalf of ESPERION at
ESPERION's request.
9.2 ESPERION shall grant to EUROGENTEC a non-exclusive license for use of its
necessary proprietary technologies, know-how and materials for the sole purpose
of EUROGENTEC' s performance under this Agreement. EUROGENTEC warrants that any
of its employees having access to such ESPERION's proprietary technologies,
know-how and materials : (i) shall be made aware of the confidentiality of such
technologies, know-how and materials; (ii) shall be bound by confidentiality
agreements in place; (iii) will keep such technologies, know-how and materials
in strict confidence; and (iv) will not disclose same to any third party.
9.3 Any proprietary technologies, information, know-how and materials owned by
ESPERION or provided by ESPERION to EUROGENTEC in connection with this Agreement
shall not be used by EUROGENTEC in the manufacture of any products or batches
(other than the Clinical Batches manufactured for ESPERION) or disclosed or made
available to any customers of EUROGENTEC or other third parties. All such
information shall be deemed confidential information subject to the provisions
of Article 10.
9.4 EUROGENTEC shall not enter into any agreement to manufacture any product
with the same properties as Proapolipoprotein A-I.
9.5 (a) If any improvements or modifications to the Product are developed by
ESPERION or EUROGENTEC, either jointly or severally, such improvements or
modifications shall be the exclusive property of ESPERION and shall be held in
confidence by EUROGENTEC for ESPERION's sole benefit in the development and/or
the operation of manufacturing processes with respect to the Product.
EUROGENTEC shall disclose to ESPERION and receive the approval of ESPERION with
respect to all such improvements or modifications relating to the manufacturing,
and/or packaging process of the Products or use of the Products developed by
EUROGENTEC. Any trademarks, trade names, brand names, patents, slogans, logos,
copyrights, trade dress, know-how and goodwill associated with the Product shall
be the sole and exclusive property of ESPERION. EUROGENTEC shall have no right
or license to use any such rights at any time before, during or after the term
of this Agreement, except as necessary for the manufacture, processing,
packaging and supply of Clinical Batches to ESPERION hereunder.
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(b) It is agreed that ESPERION is the sole owner of any and all
Specification documents supplied or paid for by ESPERION, and EUROGENTEC shall
not use any such Specification documents except in connection with its
performance under this Agreement.
(c) The provisions of this Article 9.4 shall survive the termination or
expiration of this Agreement.
Article 10 : Confidentiality
10.1 Inasmuch as some of the information and data intended to be exchanged
between the parties may be confidential and proprietary to a party hereto, each
of the parties hereto agrees with the other that the party receiving the
confidential information (hereinafter the "Recipient Party") will maintain as
secret and confidential and will not disclose to third parties without written
permission from the Party disclosing the information (hereinafter the
"Disclosing Party") any trade secrets and other confidential information gained
from discussions, or in any other way, including but not limited to, formulae,
descriptions, specifications and the like disclosed by or obtained from the
Disclosing Party. The provisions contained in this Article 10.1 shall survive
the termination or expiration of this Agreement.
10.2 The Recipient Party and its representatives will not practice any of the
trade secrets and other confidential information of the Disclosing Party without
first obtaining a license from the Disclosing Party to do so.
10.3 For purposes of this Agreement, the term "trade secrets and other
confidential information" shall include and be limited to, information disclosed
by the Disclosing Party to the Recipient Party that: (i) was not known to the
Recipient Party at the time of such disclosure; (ii) at the time of disclosure
was not or did not later on become known to or available to the public; or (iii)
was not disclosed to the Recipient Party by any other Party legally entitled to
disclose such information who did not, in turn, require the Recipient Party to
keep the information confidential.
Article 11 : Duration and Termination
11.1 This Agreement shall become effective as of March 7, 2000 and shall remain
in full force and effect until the delivery of all of the Clinical Batches or
--
for a period of 5 years, unless extended or renewed by mutual agreement in
writing.
11.2 Either party may forthwith terminate this Agreement by giving a written
notice to the other if the other party commits any material breach of this
Agreement and, if the breach is capable of remedy, fails to remedy it within 30
days of receipt of a written notice specifying such breach.
11.3 ESPERION may terminate this Agreement at any time upon 30 days prior
written notice to EUROGENTEC.
11.4 The provisions of articles 7, 8, 9 and 10 shall continue in force in
accordance with their terms, notwithstanding expiry or termination of this
Agreement for any reason.
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Article 12 : GMP Requirements
12.1 Documents to be submitted by both parties before and after a Clinical
Batch production and approval procedures of such documents are detailed in Annex
1 attached hereto.
12.2 EUROGENTEC shall issue to ESPERION monthly written reports detailing its
activities for each Clinical Batch.
12.3 EUROGENTEC agrees to have the production facility and records for Product
inspected and/or audited by relevant regulatory agencies of any country and
shall provide a copy of requested documents to authorities.
12.4 EUROGENTEC shall provide for technology transfer to any institutions upon
the request of ESPERION and at ESPERION's expense based on a daily rate.
Article 13 : Miscellaneous
13.1 If any party hereto is delayed or prohibited from fulfilling its
obligation or obligations under this Agreement for any reason beyond its
reasonable control, including without limitation, reason of fire, war,
embargoes, acts of God, unavailability of raw materials, breakdown of or damage
to machinery, or equipment, strike, lock out or other labor dispute, any rule,
order or regulation of any governmental authority, domestic or foreign, or any
other cause or occurrence beyond the reasonable control of such party, and, if
prompt written notice of said delay or prohibition shall be given to the other
party, then performance of said obligation or obligations shall be excused for
the period of time during which the cause of such delay or prohibition shall
continue, provided that the party so impeded shall have made reasonable efforts
to minimize any such delay.
13.2 All notices which are required to be given under this Agreement shall be
deemed to have been sufficiently given if in writing and sent by registered mail
or express courier with the requisite postage affixed, or if by fax, confirmed
by registered mail or expressed courier addressed to the party notified, at the
address set forth in the preamble above, or such other address as may
hereinafter be given by such party to the other for notice purpose. The date of
such delivery, or five (5) days after the date of such mailing, shall be the
date of service of such notice.
13.3 This Agreement, together with all annexes thereto which form an integral
part thereof, supersedes any previous agreements and understandings and
constitutes the entire agreement between the parties hereto relating to the
subject matter hereof. Any amendments, modifications, variations, or waivers,
including amendments and modifications to the various annexes must be in writing
and signed by both parties hereto.
13.4 This Agreement shall not be construed to make either party a legal
representative of the other party or to give either party any right or power to
bind the other party to any contract or the performance of any obligation to or
with any third party.
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13.5 Each party shall conduct its operations as an independent contractor and
no claims for taxes of any kind, nor claims arising out of labor laws, nor any
other claims asserted against one party may be asserted against the other as a
consequence of this Agreement.
13.6 (a) Any dispute, controversy or claim arising out of, relating to, or in
connection with, this Agreement, or the breach, termination or validity thereof,
shall be governed by and construed in accordance with the laws of the State of
New York, without reference to choice of law doctrine, and shall be finally
settled by arbitration.
(b) The arbitration shall be conducted in accordance with the World
Intellectual Property Organization Arbitration Rules in effect at the time of
the arbitration (the "WIPO Rules"), except as they may be modified herein or by
mutual agreement of the parties.
(c) The seat of the arbitration shall be in Geneva, Switzerland, and the
arbitration shall be conducted in the English language, provided, however, that
either party may submit testimony or documentary evidence in French but shall,
on the request of the other party, furnish a translation or interpretation into
English of any such testimony or documentary evidence.
(d) The arbitral tribunal shall consist of a sole arbitrator who shall be
selected as provided for in the WIPO Rules, except that such arbitrator must be
free of any potential for bias or conflict of interest with respect to any of
the parties to the dispute, whether directly or indirectly; be in a position to
hear the dispute immediately and thereafter render a decision within the time
specified, and be a party who is familiar with the biotechnology field.
(e) At the request of a party, the arbitrator may take such interim
measures as he deems necessary in respect of the subject matter of the dispute.
In addition to the authority conferred on the arbitrator by the WIPO Rules
specified above, the arbitrator shall have the authority to order reasonable
discovery and production of documents.
(f) The arbitral award shall be in writing, decided in accordance with
law, state the reasons for the award, and be final and binding on the parties.
The award may include an award of costs, including reasonable attorneys' fees
and disbursements. Judgment upon the award may be entered by any court having
jurisdiction thereof or having jurisdiction over the parties or their assets.
IN WITNESS WHEREOF, the parties hereto have caused this Agreement to be signed
by their duly authorized officers on the date first above written.
EUROGENTEC S.A. ESPERION THERAPEUTICS, INC.
By: /s/ Xx. Xxxxxx Xxxxx By: /s/ Dr. Xxxxx Xxxxxx
------------------------------ ---------------------------------------------
Xx. Xxxxxx Xxxxx Dr. Xxxxx Xxxxxx
Biopharmaceutical B.U. Manager Esperion Therpeutics Inc., President and CEO
By: /s/ Xxxx Xxxxxx Delwart By:
------------------------------ ---------------------------------------------
Xxxx Xxxxxx Delwart
Administrateur-Delegue
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Annex 1
Production of Clinical Batch and Master Cell Bank
ARTICLE 1 : Definitions
1.1 "Product" shall mean the properly packed amount of bulk of human
proapolipoprotein A-I resulting from the Clinical Batch or, in case of
master cell banks, the properly packed amount of viable Strain with its
buffer, bottle caps and labels.
1.2 The "Specification Document" shall include the manufacturing instructions,
including the identification of raw materials ("Xxxx of Material") and
specific instrumentation, the specifications for the Product (including in
case of master cell bank preparations, type and number of vials), the
identification of critical steps and the QC methodologies ("Product Control
Specification").
1.3 The "Process Document" shall include the procedures established by
EUROGENTEC to adapt the manufacturing and QC operations defined in the
Specification Document to a pharmaceutical production into its facilities
applying the Current Pharmaceutical Guidelines. It shall also include
general requirement under the Current Pharmaceutical Guidelines related to
the use of EUROGENTEC' personnel, equipment and Production Unit, and to the
preparation of documentation pertaining to the Clinical Batch operations.
1.4 The "Manufacturing Batch Record" is the collection of all manufacturing and
control documentation regarding each single batch of the Product.
1.5 All other capitalized terms not defined in this Annex I shall have the
meaning as described to such terms in the Production Agreement of which
this Annex 1 forms an integral part.
ARTICLE 2 General responsibilities of ESPERION
2.1 For each Clinical Batch it orders and in due time before the starting of
the production, ESPERION will provide EUROGENTEC with the Specification
Document necessary to carry out the manufacturing and QC operations.
2.2 ESPERION will provide EUROGENTEC with the initial Strain as a glycerol
suspension to be stored at - 70(degrees)C with the GMP certificate joined.
Shipment of the Strain is under ESPERION's responsibility. Identity of the
Strain after shipment is under ESPERION's responsibility, provided
EUROGENTEC properly stores the Strain at - 70(degrees).
2.3 ESPERION will promptly communicate to EUROGENTEC any change related to the
Specification Document.
2.4 ESPERION will promptly approve the Process Document prepared by EUROGENTEC
before implementation of the production by EUROGENTEC. EUROGENTEC shall
ensure that the manufacture of Pro-Apolipoprotein A-I shall take place in
strict
accordance with the Process Document (defined after discussion with
EUROGENTEC and after feasibility study).
2.5 EUROGENTEC does not warrant that modifications to the Specification
Document introduced by ESPERION after approval of the Process Document by
ESPERION will be included in the manufacturing process.
2.6 EUROGENTEC will be responsible for batch numbering of the Product.
ARTICLE 3 : General responsibilities of EUROGENTEC
3.1 EUROGENTEC commits to accomplish its contracting work according to the
Current Pharmaceutical Guidelines.
3.2 EUROGENTEC will be responsible for carrying out validation and control in
the following areas:
. HVAC and room classification,
. Purification water system,
. Calibration of EUROGENTEC equipment,
. Sterilisation and decontamination equipment,
. Cleaning procedures.
3.3 EUROGENTEC will perform environment monitoring (Air, Surfaces) and water
testing.
3.4 EUROGENTEC will prepare the Process Document and will request ESPERION's
approval thereon before implementation.
3.5 EUROGENTEC will make no changes to the Process Document without formal
approval of ESPERION. However, changes referring to the document lay-out or
internal procedures are not subject to formal ESPERION's approval.
3.6 EUROGENTEC will prepare the Manufacturing Batch Record. The original
Manufacturing Batch Record will be kept at EUROGENTEC and will be archived
for a period of 2 years after the clinical trials. A copy will be delivered
to ESPERION with the Product ESPERION.
3.7 EUROGENTEC will not subcontract any work without the prior written consent
of ESPERION.
ARTICLE 4 Raw material
4.1 All raw materials will be QC controlled wider the responsibility of
EUROGENTEC and released by EUROGENTEC in due time before production of each
Clinical Batch.
ARTICLE 5 : Manufacturing
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5.1 Division of responsibilities between the parties concerning the
manufacturing operations is specified in Annex 2 which is considered to be
part of the Agreement.
5.2 Modification to the Process Document may be required if a conflict between
a specific process contained in the Process Document and the spirit of the
Current Pharmaceutical Guidelines is observed during the manufacturing
operations. Such modification will be subject to approval by ESPERION
before EUROGENTEC can continue the manufacturing process. ESPERION's
failure to approve or reject the modification in due time will free the
responsibility of EUROGENTEC concerning the failure to manufacture the
Product.
ARTICLE 6 Release of Product
6.1 The Qualified Person of EUROGENTEC will review each single Manufacturing
Batch Record for compliance with the Process Document. EUROGENTEC will
release each single batch for shipment to ESPERION only after full
compliance of the batch documentation with the Process Document. He will
notify ESPERION of any significant deviation prior to release and shipment.
6.2 The Qualified Person of EUROGENTEC will notify the release of each single
batch to ESPERION by means of a product specific release certificate
limited to the manufacturing specifications and the specifications of the
controls being performed by EUROGENTEC or by an external contractor under
its responsibility.
6.3 An appropriate number of samples of Product or amount of intermediate
active ingredient, as specified in the Specification Document, will be
conserved by EUROGENTEC for retesting in case of disagreement between
EUROGENTEC and ESPERION about EUROGENTEC' responsibility in Product failure
to conform to the product specifications.
ARTICLE 7 Storage and transport
7.1 The transport of the Product will be organized by ESPERION and will be done
under its own responsibility and at its own expenses.
7.2 If physically possible, EUROGENTEC may store the Product for a short period
of time upon ESPERION's prior agreement.
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Annex 2
Clinical Batch: Responsibilities for Manufacturing
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Responsibilities
Area Activity or event ----------------------- Comment
EUROGENTEC Contracting
Partner
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Initiate Obtain batch order X
Inspect and release facilities and equipment for use X
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Raw Materials
Purchase of raw materials X
Release of raw materials X
Manufacture Manufacture X
Fermentation, downstream & Establishing sample procedures X
harvesting Perform sampling X -----------------------------
Perform in-process testing X
Perform release testing on intermediaries
Decide rework on intermediates X If acceptable
according to GMP
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Manufacture Manufacture X
(purification) Establish sampling procedures X
Perform Sampling X
Perform in-process testing (IPC) X
Perform release testing on intermediates X
Decide work on intermediates X If acceptable
according to GMP
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Quality assurance Perform environmental testing X Copies of all records shall
Maintain test records X be provided to Esperion
File batch record X
Audit bulk operations X X
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Release/Reject/Rework Review and release batch record X ------------------------------------
Release/reject batch X Contacting Partner may
reject a batch released by
EUROGENTEC
Resolved and document any manufacturing problems X
not implying rework
Dispose of rejected material X
Maintain reject records X
4
-----------------------------------------------------------------------------------------------------------------------------------
Responsibilities
Area Activity or event ----------------------- Comment
EUROGENTEC Contracting
Partner
----------------------------------------------------------------------------------------------------------------------------------
Store release bulk X
Reconcile material usage X
QC Take and store retention samples X
Take and store stability samples X
Operate bioburden program for facilities and X
equipment
Perform release testing on purified bulk X X
Provide process analytical guide X
-----------------------------------------------------------------------------------------------------------------------------------
Cleaning Dispose of unused materials X
Clean facilities and equipment X
Establish and update cleaning procedures X
-----------------------------------------------------------------------------------------------------------------------------------
5
Annex 3
The Project
ARTICLE 1 : Definitions
(A listing of the various steps required to achieve the project)
ARTICLE 2 : Schedule
(A precise table of succession of the various steps and their duration)
ARTICLE 3 : Resources implications
-------------------------------------------------------------------------------
ACTIVITIES % of implication for the DURATION
project
-------------------------------------------------------------------------------
FERMENTATION Production Team
-------------------------------------------------------------------------------
DOWN-STREAM Production Team
-------------------------------------------------------------------------------
FERMENTATION Development Team
-------------------------------------------------------------------------------
DOWN-STREAM Development Team
-------------------------------------------------------------------------------
QC Team
-------------------------------------------------------------------------------
AQ Team
-------------------------------------------------------------------------------
Management, maintenance &
logistics
-------------------------------------------------------------------------------
Annex 4
The Price
ARTICLE 1 : Definitions
All prices are in BEF and are exclusive of VAT.
ARTICLE 2 Article 2 : Price list
------------------------------------------------------------------------------
ACTIVITIES PRICE PER WEEK (MONTH)
------------------------------------------------------------------------------
FERMENTATION Production Team
------------------------------------------------------------------------------
DOWN-STREAM Production Team
------------------------------------------------------------------------------
FERMENTATION Development Team
------------------------------------------------------------------------------
DOWN-STREAM Development Team
------------------------------------------------------------------------------
QC Team
------------------------------------------------------------------------------
AQ Team
------------------------------------------------------------------------------
Management, maintenance & Logistics
------------------------------------------------------------------------------
ARTICLE 3 : Price estimation for the Project
ACTIVITIES % of implication for DURATION PRICE
the project ESTIMATION
--------------------------------------------------------------------------------
FERMENTATION Production Team
--------------------------------------------------------------------------------
DOWN-STREAM Production Team
--------------------------------------------------------------------------------
FERMENTATION Development Team
--------------------------------------------------------------------------------
DOWN-STREAM Development Team
--------------------------------------------------------------------------------
QC Team
--------------------------------------------------------------------------------
AQ Team
--------------------------------------------------------------------------------
Management, maintenance &
Logistics
--------------------------------------------------------------------------------
TOTAL:
--------------------------------------------------------------------------------
Annex 3
The Project
ARTICLE 1 : Definitions
The work programme is defined in the attached document
-----------------------------------------------------------
Pro-APO Al Project -- Work Programme -3
-----------------------------------------------------------
The allocation of the rooms in the GMP production facility of Eurogentec is
described in the attached document
-----------------------------------------------------------
(Room allocation - Proapolipoprotein Al (ApoAl project)
-----------------------------------------------------------
ARTICLE 2 : Schedule
The schedule is defined by the xxxxx charts
-----------------------------------------------------------
Pro-ApoAl total 06 March 2000
-----------------------------------------------------------
and
-----------------------------------------------------------
Pro-ApoAl DSP
-----------------------------------------------------------
---------------------------------------------------------------
[Pro-APO A1 Project - Work Programme - 3
---------------------------------------------------------------
Final work programme revised as March 6, 2000.
1 Introduction
Following the visit of 19 January 2000 of Xxx Xxx and Dasseux who presented the
pro-APO Al project, there have been two technical meetings with Xxx Xxxxx to
study in depth the production process.
The objective of this analysis was to answer two questions. First can
Eurogentec perform the production process and his largest scale (300 litres),
and second, is it possible to deliver 300 g of pro-APO Al for end of June.
It came to the conclusion that providing some moderate scaling up, Eurogentec
should be capable of performing the production up to the delivery of purified
pro-APO A1 ready for fomulation. To say, down to point V of the pro-APO A1Rec
flow sheet provided by Xx Xxxxx in the February 3 meeting. Providing the very
tight timing and the necessity to provide 300 g of product, it is impossible to
accommodate the formulation of the pro-APO Al. Moreover, Eurogentec has no
experience in such formulation, hence it is probably more efficient that
Esperion takes care of the formulation or outsource it to a specialised
contractor.
Regarding the delivery of 300 g of purified pro-APO Al this target can be
achieved providing that the announced yield of 200 mg of purified protein per
litre of culture broth is observed and that the purification process can be
performed at the 3001 scale.
2 Technology transfer
A technology transfer phase has been designed. It has been much compressed to
meet the June dead line.
2.1 Fermentation
The fermentation in the R&D laboratory will be performed at the 20 litres scale
that is directly scalable to 300 litres owing to our extensive experience of E.
coli processes. The purpose of the fermentation will be (1) to master the
process developed by Xx. Xxxxx and (ii) to provide material for the down stream
processing (DSP).
Two fermentations have been programmed with the process of Xx Xxxxx. The
protocol will be superstitiously reproduced in every details. A third one will
be done if the parameterisation of the fed batch flow is more difficult than
expected.
As soon as the DSP has reproduced the process and the QC as established the
necessary assays to qualify the protein, a fermentation will be performed
according to our standard fermentation formula. It has been improved for years
and has always been superior to what our sponsors have provided. During our
meetings, we have expressed some concerns on the fermentation protocol used so
far which appears to us to be outdated and not usefully complex, hence with some
consistency issue. If our standard formula yields similar amount of best
quality protein, we will propose to you to change for our simpler and more
efficient protocol. If not, we will continue with the current method.
As soon as the fermentation protocol is implemented in the laboratory, it will
be transferred to the production unit. Two fermentations are planned to first
confirm the scalability of the process second, to set the harvest parameters.
So far the bacterial cells were harvested as a solid paste, this is impossible
with our equipment at the 300 litres scale. The continuous centrifuge yields
highly enriched cell suspension in buffer. Will this buffer exchange in the
centrifuge be sufficient to go on with the process and how many cycles will be
necessary to achieve sufficient medium removal. The cells harvested at this
stage will be directly transferred to the R&D DSP laboratory for further
processing and assessment of quality.
The first step of full-scale liquid-liquid extraction and filtrabiity of the
pro-APO Al fraction will be tested at this stage. The purchase of two large
volume centrifuge will be necessary to run the process at the 300 litres scale.
Two more 300 litres fermentations are planned for further consistency and to
provide adequate material for the first full-scale purification, see annexed
Xxxxx chart (Esperion total).
At the completion of these assays, the fermentation process, harvest and
extraction will be ready for true GMP operations.
2.2 Downstream processing
Starting from the cells harvested from the first fermentation, the exact process
described will be repeated at the 1 litre scale. The columns will be scaled for
a 1 litre process as a 100 x scale down from the described process. The flows
will be reduced accordingly.
In order to optimise the flows, a second purification will be performed at the 1
litre scale. The flow will be increased to the usual value for the said'
chromatographic resin. This step is crucial to be able to perform the complete
DSP within one working week.
A third purification will be performed on the same columns, possibly with the
increased flows, but at the 3 litres scale. Xx Xxxxx told us that the capacity
of the columns was largely superior to what was needed for his scale of
operation. The aim of this step is to investigate the possibility of running
the GMP process at the 300 litres scale instead of 100 litres. The final size
of the column will be set according to the result obtained at this stage. Of
course in process control will be implemented in order to document possible
overloading of the columns.
The most delicate step of the current process is the final SP chromatography
with a pH gradient. We could obtain only fragmentary data on that part of the
process. So two kinds of gradient durations will be tested, 4 or 16 hours. The
impact of the result on the duration of the DSP is pivotal.
If necessary any of these experiments will be repeated in order to obtain
consistent results. Eurogentec can provide the material obtained during these
early development stages.. It will be appreciate that Esperion can run some
testing on the purified protein and confirms our QC results.
At this stage, the fermentation team will be growing the strain in the 300
litres fermentor and will investigate the harvest procedure. The complete DSP
will be performed at small scale on the material fermented and harvested at
large scale in order to verify that the full scale harvest and liquid-liquid
extraction perform according to the expectation.
The sterile filtration of the PEG fraction following the liquid-liquid
extraction will be developed at this stage in close collaboration between the
fermentation and DSP teams.
Finally, two full-scale purifications will be performed in the GMP production
unit in order to validate the flow rates and column load before entering true
GMP operations. At this stage it will be possible to give a forecast of the
production yield.
The product obtained can be used for formulation or animal studies.
A second industrial chromatograph will be purchased to achieve the highest
consistency level.
2.3 Quality Control
The QC and IPC tests will be developed concomitantly with the development of
femientation and DSP. The GMP QC team will be in charge of this development.
One supplementary technician will be engaged. There is a trained person on the
waiting list so that this hiring should cause no hurdle.
2.3.1 QC on raw materials
The listing of the raw material currently used in the process shows that 13
compounds are not yet in our warehouse. The testing of those for which
pharmacopoeia monographs are available will be outsourced to a licensed
laboratory. These controls will be outsourced in order to allow the QC team to
properly adapt or develop the pro-APO Al specific controls.
We will set the specifications and QC procedures for then 5 compounds that don't
have monographs (Dextran T500, Hepes, Mops, ammonium sulfate & IPTG). The
controls will be performed in house.
2.3.2 Fermentation IPC
These tests such as purity, identification, plasmid retention, dry weight are
adaptation of the current tests and should not cause any hurdles.
However, we would appreciate to have an end of femientation test that measures
the level of expression of the pro-APO Al. This test will be transferred from
the laboratoiy of Xx Xxxxx.
2.3.3 Purification IPC
Specific procedures need to be adapted for the protein assay, SDS-PAGE and IEF.
2.3.4 Quality Control on purified bulk
The following test has been planned and will be adapted or transferred from
laboratory of Xx Xxxxx.
1. Protein quantification
2. Purity by SDS-PAGE
3. Identity of pro-APO Al by Western blot / ELISA
4. Activity of pro-APO Al by RIA (availability of reagent is still
questionable)
5. IEF
6. Endotoxins (gel clot following pre-treatment of the sample)
7. Residual DNA (quantitative PCR) possibly outsourced
8. Sterility
9. Purity of bulk by measurement of E. coli contaminant (ELISA/WB)
Since the final bulk and most of the chromatographic process is performed in
urea, a specific urea removal method has to be defined. Gel filtration on
disposable columns or dialysis will be evaluated.
3 Seeds
Due to the heavy workload caused by the transfer and adaptation of the process,
Eurogentec will probably not be capable of constructing the Master Cell Bank and
Working Cell Bank of the strain. It is suggested that Esperion outsources these
tasks to a specialised company such as Q-one Biotech in England.
4 GMP manufacturing
The GMP manufacturing will be performed according to rules described in the
provisional "quality package" that has been given to Esperion during our first
meeting.
The annexed Xxxxx chart (Esperion DSP) shows the detail of the operation for one
week. Two distinct series of operation are presented, first, the fermentation
and DSP operation performed in the fermentation hail down to the freezing of the
disrupted cells and second, the DSP operations starting from the liquid-liquid
extraction down to the sterile filtration of the bulk. In the example shown,
the DSP operation would use material produced on the week before.
On the Monday there will be two distinct operations in the fermentation hall,
the conditioning of the fermentor for the next run and the extraction-maturation
procedure on the broken cells produced in a previous run.
To reduce the risks of fermentor breakdown, both fennentors will undergo
complete service before the campaign. The downstream processing equipment
should be trouble free.
The buffers and media will be prepared daily and used immediately. One
additional staff will be engaged for buffer preparation and environmental
control.
The additional staff engagement was planned a few weeks later to service the
second production unit. The construction of this unit is planned to start by
June, but at this period only external embankment works are scheduled, they
should not impact on the GMP operations.
Each batch will undergo full QC testing and will be released for use in human by
our QA officer. The main criteria for release will be purity, endotoxins,
residual DNA and sterility. The batches will be stored on site or forwarded to
you or to the company performing the formulation and freeze drying as you will
instruct us.
To produce 300 g of purified proApo Al protein with an announced yield of 200 mg
per litre of culture broth, 1500 litres are necessary. Thus 5 runs should be
sufficient. 2 more runs have been planned as back up. If all the runs perform
according to the' specifications, more protein, possibly 420 g will be
delivered.
The product will be released as discrete batches of expectedly 60 g. A full
batch record will accompany each batch.
The batches will be sterile filtered and stored at --20(degrees)C until
delivery. We will agree on the type of containers. The shipment will be
organised in dry ice with temperature record if you wish.
5 Project Management
Xx Xxxxx Xxxxxxxx, director of the production unit, will be the project manager.
Upon reception of your order and signature of the contract, he will organise a
Product Development Committee (PDC) in charge of the coordination of the
project. The team leaders from R&D fermentation, R&D DSP, GMP fermentation, GMP
DSP, QC and QA are statutory members of the PDC. At the beginning of the
project they will meet on a weekly basis. Additional technical meetings can be
organised to address specific issues. Xx Xxxxx might be invited to these
meetings.
Eurogentec will appreciate that Esperion also nominates a project manager to
whom it will refer on a regular basis. This person will be welcome to assist to
the PDC's and to stay in our facility for any period of time. Phone conferences
can also be organised.
Due to the very compact development scheme, the division of the project into
phases and milestone might be detrimental to a fast execution. We would rather
propose to establish immediately the closest relationship with your project
manager so that we can together adapt the course of the programme to the reality
of the experimental facts.
Nevertheless, two important milestones can be identified, one at the end of the
small scale DSP operation with 300 litres fermentor material, the other at the
end of the full scale feasibility. At this stage the expected production rate
will be ascertained.
6 Budget
6.1 Technology transfer
The cost of the technology transfer as displayed in the Esperion total Xxxxx
chart will be BEF 7,765,000. This price is all-inclusive.
6.2 GMP operation
The cost of the GMP operation as described here above and in the Esperion total
and Esperion GMP Xxxxx chart will be BEF 29,250,000. This price excludes the
raw materials and chromatographic media costs, those cost will not exceed USD
40,000. Those will be invoiced separately.
Xxxxxx Xxxxx
6 March 2000
Xxxxxxxxxxxxxxxxx X0 (XxxX0 project)
Esperion Therapeutics
---------------------
Step Equipment
Preculture Conical flask
Fermentation (350L) : E coli Fermentor IF-500 (New Brunswick
Cell concentration Continue centrifuge (Westfalia
CSA119
Cell storage (-20(degrees)C) Freezer - 20(degrees)C
Cell breakage DynoMil D20 (glass bead xxxxxx)
Liquid/liquid extraction Nalgene tank
Centrifugation Centrifuge (Xxxxxxx Avanti-J20)
Filtration, 0,22 um
------------------------------------------------------------------------------------------------
1/st/ chromatographic step: Q Sepharose FF BioProcess (Pharmacia) nr1
(ion exchange) Column : Modulne 180 (degrees) 250
2/nd/ chromatographic step: Q Sepharose FF BioProcess (Pharmacia) nr2
(ion exchange) Column : Vantage 250 (degrees) 500
3/rd/ chromatographic step: Sepharose Xxxxxx XX0X BioProcess (Pharmacia) nr1
(hydrophobic) Column : Modulne 350 (degrees) 500
4/th/ chromatographic step: Q Sepharose FF BioProcess (Pharmacia) nr2
(ion exchange) Column : Vantage 90 (degrees) 500
5/th/ chromatographic step: Chelating Sepharose FF BioProcess (Pharmacia) nr1
(affinity) Column : Modulne 90 (degrees) 500
6/th/ chromatographic step: SP Sepharose FF BioProcess (Pharmacia) nr2
(ion exchange) Column : Vantage 90 (degrees) 500
------------------------------------------------------------------------------------------------
Sterile filtration
Purified bulk aliquoting
------------------------------------------------------------------------------------------------
Purified bulk storage (-20(degrees)C) Freezer -20(degrees)C
Step Operations Class Room
Preculture 10000 A01-D-05
Fermentation (350L) : E coli Culture: Fed-batch mode 10000 A01-D-04
(ApoA1 soluble expression
Cell concentration Buffer exchange 10000 A01-D-04
Cell storage (-20(degrees)C) 10000 A01-D-04
Cell breakage 10000 A01-D-04
Liquid/liquid extraction PEG / Dextran extraction (16 hours at 4(degrees)C, stirring 10000 A01-D-04
Centrifugation
Centrifugation: 8000 rpm, 15 minutes -->supernatant Supernatant 10000 A01-D-04
recovery
Filtration, 0,22 um Supernatant clarification between chromatography 10000 A01-D-04
------------------------------------------------------------------------------------------------------------------------------------
1/st/ chromatographic step: Q Sepharose FF Negative mode (flowthrough collection) 10000 A02-C-05
(ion exchange) Protease removal
2/nd/ chromatographic step: Q Sepharose FF Positive mode 10000 A02-C-05
(ion exchange)
3/rd/ chromatographic step: Sepharose Xxxxxx XX0X Elution : urea 6M 10000 A02-C-05
(hydrophobic)
4/th/ chromatographic step: Q Sepharose FF Positive Mode 10000 A02-C-05
(ion exchange)
5/th/ chromatographic step: Chelating Sepharose FF Metal : Cu 10000 A02-C-05
(affinity) Two columns used in series
The second one is not saturated with metal
(Cu removal during elution)
6/th/ chromatographic step: SP Sepharose FF Deamidated forms removal 10000 A02-C-05
(ion exchange) Gradient elution
IEF analysis of eluted fractions - fractions pooling
----------------------------------------------------
------------------------------------------------------------------------------------------------------------------------------------
Sterile filtration 100 A03-B-5
Purified bulk aliquoting 100 A03-B-5
------------------------------------------------------------------------------------------------------------------------------------
Purified bulk storage (-20(degrees)C)
Nom de la tache Duree
-------------------------------------------------------------------------------------------------------------------------------
Fermentation 38 jours
----------------------------------------------------
Fermentation 20 | 1 2 jours
----------------------------------------------------
Fermentation 20 | 2 2 jours
----------------------------------------------------
Fermentation20 | 3 2 jours
----------------------------------------------------
Fermentation300 | 1 3 jours
----------------------------------------------------
Fermentation300 | 2 3 jours GRAPHICS OMITTED
----------------------------------------------------
Fermentation300 | 3 3 jour
----------------------------------------------------
Fermentation 300 | 4 3 jours
----------------------------------------------------
Down stream processing 44 jours
----------------------------------------------------
repeatability 1| 2,8 sms
----------------------------------------------------
optimisation 1| 1 sm
----------------------------------------------------
process 3| + gradient (1/100) 1 sm
----------------------------------------------------
process 31 with 300 | material I sm
----------------------------------------------------
Decision point 0 jour
----------------------------------------------------
full scale feasibility 14 jours
----------------------------------------------------
Decision point 0 jour
----------------------------------------------------
GMP production 45 jours
----------------------------------------------------
run 1 2 sms
----------------------------------------------------
run 2 2 sms
----------------------------------------------------
run 3 2 sms
----------------------------------------------------
run 4 2 sms
----------------------------------------------------
run 5 2 sms
----------------------------------------------------
backup run 1 2 sms
----------------------------------------------------
release of the last batch jour
----------------------------------------------------
Outsourced Cell Banking 4 sms
----------------------------------------------------
QC operations 89jours
----------------------------------------------------
Raw materials controls 40 jours
----------------------------------------------------
Development of IPC 40 jours
----------------------------------------------------
Development of QC on bulk 45 jours
----------------------------------------------------
Environmental controls (GMP) jours
----------------------------------------------------
QC on bulks 59 jours
----------------------------------------------------
QA operations 112 jours
----------------------------------------------------
Raw material specifications 29jours
----------------------------------------------------
-------------------------------------------------------------------------------------------------------------------------------
Nom de la tache Duree
----------------------------------------------------
Review RM SOP 17 jours
----------------------------------------------------
Review of QC & IPC SOP 27jours
----------------------------------------------------
Set product specifications 7 jours
----------------------------------------------------
Review process document 8 jours
----------------------------------------------------
Notification to MH 0 jour
----------------------------------------------------
Obtain clearance from MH 0 jour
----------------------------------------------------
Review batch records 39 jours
----------------------------------------------------
Releases of bulks 36 jours
-------------------------------------------------------------------------------------------------------------------------------
-------------------------------------------------------------------------------------------------------------------------------
A1 project Fermentation steps
----------------------------------------
Fermentation
----------------------------------------
Fermentator set-up
----------------------------------------
Preculture inoculation
----------------------------------------
SIP Filter skid
----------------------------------------
Fermentator aviation
----------------------------------------
Fermentation (cell growth)
----------------------------------------
Induction GRAPHICS OMITTED
----------------------------------------
Cellular concentration
----------------------------------------
Cell breakage
----------------------------------------
Cell freezing
----------------------------------------
CIP fermentor
----------------------------------------
SIP fermentor
----------------------------------------
CIP CU1
----------------------------------------
SIP CU1
----------------------------------------
CIP centrifuge Westfalia
----------------------------------------
SIP centrifuge Wesfalia
----------------------------------------
CIP CU2
----------------------------------------
SIP CU2
----------------------------------------
Al project: purification steps
----------------------------------------
Downstream 100.000
----------------------------------------
Cell thawing
----------------------------------------
Liquid: Liquid extraction
----------------------------------------
1/st/ Centrifugation
----------------------------------------
Maturation
----------------------------------------
2/nd/ Centrifugation
----------------------------------------
Sterile filtration
----------------------------------------
Downstream 10.000
----------------------------------------
First column (QAE (-))
----------------------------------------
QAE (-) equilibration.
----------------------------------------
QAE (-) load
----------------------------------------
----------------------------------------
QAE (-) elution
----------------------------------------
QAE (-) regeneration
----------------------------------------
Second column (QAE (+)
----------------------------------------
QAE (+) equilibration.
----------------------------------------
QAE (+) load
----------------------------------------
QAE (+) elution
----------------------------------------
QAE (+) regeneration
----------------------------------------
Third column (HIC
----------------------------------------
HIC Phenyl equilibration
----------------------------------------
HIC Phenyl load
----------------------------------------
HIC Phenyl elution
----------------------------------------
HIC Phenyl regeneration
----------------------------------------
Fourth column (QAE (+))
----------------------------------------
QAE (+) equilibration.
----------------------------------------
QAE (+) load
----------------------------------------
QAE (+) washing
----------------------------------------
QAE (+) elution
----------------------------------------
QAE (+) regeneration
----------------------------------------
Fifth column (Chelate FF)
----------------------------------------
Chelate FF equilibration.
----------------------------------------
Chelate FF load
----------------------------------------
Chelate FF elution
----------------------------------------
Chelate FF regeneration
----------------------------------------
Sixth column (SP Sepharose)
----------------------------------------
SPFF equilibration.
----------------------------------------
SPFF load
----------------------------------------
SPFF washing
----------------------------------------
SPFF elution
----------------------------------------
SPFF regeneration
----------------------------------------
Fraction pooling
----------------------------------------
Sterile filtration
----------------------------------------
Class 100 operations
----------------------------------------
----------------------------------------
Quality Control
----------------------------------------
IPC analysis (IEF)
-------------------------------------------------------------------------------------------------------------------------------
Annex 4
The Price
ARTICLE 1: Definitions
All prices are in BEF or in USD as specified and are exclusive of VAT.
ARTICLE 2: Prices
The price of the technology transfer phase is BEF 7,765,000.
The price of the GMP manufacturing phase is BEF 29,250,000.
The cost of the raw materials shall not exceed USD 40,000.
