AGREEMENT
BETWEEN
LONZA BIOLOGICS PLC
AND
AVANT IMMUNOTHERAPEUTICS INC
Confidential Treatment Requested As To Certain Information Contained In This
Exhibit
THIS AGREEMENT is made the _______ day of _________, 2000 BETWEEN
1. LONZA BIOLOGICS PLC, the registered office of which is at 228 Bath
Road, Slough, Berkshire SL1 4DY, England ("LB"), and
2. AVANT IMMUNOTHERAPEUTICS INC, of 119 Fourth Avenue, Needham MA
024942725, USA, ("the Customer").
WHEREAS
A. Customer is the proprietor of the *** Confidential Treatment Requested
as to this information *** expressing *** Confidential Treatment
Requested as to this information *** protein and owns certain
intellectual property rights in relation thereto, and
B. LB has expertise in the development of processes for and manufacture
of products from similar cell lines, and
C. Customer wishes to contract with LB for Services to develop a Process
for and manufacture Product from its proprietary cell line; and
D. LB is prepared to perform such Services for Customer on the terms and
conditions set out herein.
NOW THEREFORE it is agreed as follows:
1. In this Agreement, its recitals and the schedules hereto, the words
and phrases defined in Schedule 4 hereto and in the Standard Terms for
Contract Services set out in Schedule 5 hereto shall have the meanings
set out therein.
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2. Subject to the Standard Terms for Contract Services set out in
Schedule 5 and any Special Terms; LB agrees to perform the Services
and the Customer agrees to pay the Price together with any additional
costs and expenses that fall due hereunder.
3. 3.1 Any notice or other communication to be given under this
Agreement shall be delivered personally or sent by facsimile
transmission, or if facsimile transmission is not available, by first
class pre-paid post addressed as follows:
3.1.1 if to LB to:
Lonza Biologics plc
228 Bath Road
Slough Berkshire SL14DY
Facsimile: 01753 777001
For the attention of the President
3.1.2 if to the Customer to:
Avant Immunotherapeutics Inc
119 Fourth Avenue
Needham MA 02494-2725
USA
Facsimile: 001 781433 0262
For the attention of the President;
or to such other destination as either party hereto may
hereafter notify to the other in accordance with the provisions
of this clause.
3.2 All such notices or other communications shall be deemed to
have been served as follows:
3.2.1 if delivered personally, at the time of such delivery;
3.2.2 if sent by facsimile, upon receipt of the transmission
confirmation slip showing completion of the
transmission;
3.2.3 if sent by first class pre-paid post, ten (10) business
days (Saturdays, Sundays and Bank or other public
holidays excluded) after being placed in the post.
AS WITNESS the hands of the duly authorised representatives of the parties
hereto the day and year first above written.
Signed for and on behalf of
-------------------------
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LONZA BIOLOGICS PLC
-------------------------
TITLE
Signed for and on behalf of
AVANT IMMUNOTHERAPEUTICS INC
-------------------------
-------------------------
TITLE
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SCHEDULE 1
For the purposes of this document:
"Cell Line" shall mean the *** Confidential Treatment Requested as to this
information *** created by the Customer expressing Product.
"Product" shall mean *** Confidential Treatment Requested as to this
information *** from the Cell Line.
A. DRAFT SPECIFICATION FOR BULK PURIFIED PRODUCT
Lonza Biologics and the Customer will agree a draft Specification for the
Bulk product * to be manufactured in Stage 8. Test parameters to be
included in the Specification could be:
***Confidential Treatment Requested as to this information***
Note: Lonza will release bulk Product against this draft Specification as
outlined above.
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A. DRAFT SPECIFICATION FOR VIALLED PRODUCT
Lonza Biologics and the Customer will agree a draft Specification for the
vialled product. Test parameters to be included in the Specification could
be:
***Confidential Treatment Requested as to this information***
Note: Lonza will release vialled Product against this draft Specification as
outlined above.
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B. SPECIFICATION FOR A MASTER AND WORKING CELL BANK
STARTING MATERIAL DEFINITION
Master or Working Cell Bank of a cryopreserved ***Confidential
Treatment Requested as to this information*** prepared from
a pooled culture and stored in individual ampoules in liquid nitrogen
refrigerators.
GENERAL MASTER CELL BANK SPECIFICATION
1. The acceptance criteria for tests performed on ampoules from the cell
bank
***Confidential Treatment Request as to this information***
2. Tests carried out on an ampoule of the cell bank or ort an ampoule of
a cell stock linearly related to the cell bank, for example the
Customer Stock. (The acceptance criteria to release the cells to
Lonza's GMP facility are given in parentheses).
***Confidential Treatment Request as to this information***
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SCHEDULE 2 SERVICES
CONTENTS
1. Supply of Customer Materials and Customer Know-How
2. Activities to be undertaken by Lonza
Stage 1 - Medium Selection, Cloning and Cell Line Selection
Stage 2 - Fermentation Studies
Stage 3 - Master and Working Cell Bank Preparation and Analysis
Stage 4 - Assay Transfer and Validation
Stage 5 - Purification Process Transfer
Stage 6 - Development Pilot Batch, Production of Non-GMP Product
Stage 7 - GMP Documentation
Stage 8 - Production of GMP Product at *** Confidential Treatment
Requested as to this information ***: Creation of a Post Production
Cell Bank
Stage 9 - Regulatory Documentation/Support for *** Confidential
Treatment Requested as to this information ***
Stage 10 - Evaluation of Virus Clearance
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1. SUPPLY OF CUSTOMER MATERIALS AND CUSTOMER KNOW HOW
Customer shall supply to Lonza the following:
i) Sufficient information on the Cell Line and the Product to allow a
risk assessment as required by the `Genetically Modified Organisms
(Contained Use)' Regulations 1992 and a safety assessment by Lonza's
Biological Safety Committee.
ii) At least 10 identical ampoules of viable frozen cells from the Cell
line (Customer's Stock) containing approximately 5 x 106
cells/ampoule.
iii) If available a sample of purified Product as a reference standard.
iv) A formulation for the Product that will be produced by the Cell
Line. The Customer has developed a suitable formulation for the
Product. The formulation will be supplied to Lonza Biologics to
enable completion of the purification of the pilot material
(Stage 6).
v) Detailed information on the purification procedures used to date to
purify Product by the Customer.
vi) Protocols for any product specific assays that the Customer will
transfer to Lonza such that Lonza can test the Product in
Development Laboratories and QC (Stage 4).
vii) Full details including suppliers of up to four commercially
available media prior to commencement of Stage 1.
viii) Documents relating to mycoplasma testing performed on the Cell Line.
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2. ACTIVITIES TO BE UNDERTAKEN BY LONZA BIOLOGICS
1.0 STAGE 1 - MEDIUM SELECTION, CLONING AND CELL LINE SELECTION
1.1 OBJECTIVES
1.1.1 To assess up to four commercially available ***
Confidential Treatment Requested as to this information
*** culture media for suitability for use with the
incoming Cell Line.
1.1.2 To clone the incoming Cell Line, adapt sub clones to serum
free suspension culture and select the most suitable Cell
Line for long term production.
1.1.3 To monitor stability of production and growth
characteristics of selected Cell Line and one back-up Cell
Line.
1.2 ACTIVITIES
SUBSTAGE 1 a - MEDIUM SELECTION
1.2.1 Receive details from the Customer on the cell culture
process conditions used to date to grow the Cell Line.
1.2.2 Receive details including suppliers of up to four
commercially available media. Source media and components
if required from approved suppliers.
1.2.3 Receive documents from Customer detailing Cell Line virus
and mycoplasma testing data. Receive ampoules of the Cell
Line from the tested cell bank.
1.2.4 Review documentation from 1.2.3 and confirm that the Cell
Line is negative for mycoplasma. Revive cells from an
ampoule of the incoming Cell Line and grown in suspension
in up to four different commercially available ***
Confidential Treatment Requested as to this information
*** culture media. Establish criteria for routine
subculture of the Cell Line.
Note: 5uM methotrexate will be included in all cell
culture media used for culture expansion. Methotrexate
will not be included in media used in cell cultures which
are allowed to overgrow (until cell viability decreases).
1.2.5 Estimate cloning efficiency (by limiting dilution) of the
Cell Line in the four different commercially available
serum free media used in 1.2.4 supplemented with
appropriate concentrations of serum.
1.2.6 For those media that support good cell growth allow shake
flask cultures to overgrow (until cell viability
decreases) and measure Product accumulation by assays
established under Stage 4.
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Note: These shake flask cultures will be fed with glucose.
Deliver samples of cell culture supernatant (approximately
10ml) from the cultures taken at intervals during 1.2.6 to
the Customer to enable the Customer to confirm Product
concentrations and Product quality.
Note: If there is a delay in completion of these analyses
by the Customer at this point, there may be a delay in
completion of the Services
EVALUATION POINT
Evaluate and report the performance of the cell line in the
commercially available *** Confidential Treatment Requested as to
this information *** culture medium.
Agree with the Customer which medium is selected to progress with
for the remaining Stages.
Discuss and agree with the Customer a series of laboratory scale
fermentations to be performed in Stage 2.
SUBSTAGE 1b - CLONING AND CELL LINE SELECTION
1.2.7 Revive cells from an ampoule of the incoming Cell Line and
perform a single round of cloning using the capillary
aided cell cloning technique. The Cell Line will be
cultured and plated in the selected medium supplemented
with an appropriate concentration of serum.
The capillary aided cell cloning technique involves the
use of a capillary which delivers a droplet of a cell
suspension to each well of a 48 or 96 well plate. The
droplet is then examined under a microscope to confirm the
presence of a single cell before medium is added and the
confirmed clones grown on.
1.2.8 Adapt up to 15 clones to serum free culture medium.
Perform an assessment of the productivity of the Cell
Lines in shake flask cultures by allowing the cultures to
grow to maximum cell concentration at high viability and
measure Product accumulation by assays established under
Stage 4.
Deliver samples of cell culture supernatant (approximately
10ml) from the cultures to the Customer to enable the
Customer to confirm Product concentrations and Product
quality.
Note: If there is a delay in completion of these analyses
by the Customer at this point, there may be a delay in
completion of the Services.
Select 3 candidate cloned Cell Lines for further
development.
At this point the Customer and Lonza will agreed on the
Lead Cell Line.
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1.2.9 Cryopreserve pre-seed stocks (PSS) of 12 ampoules of cells
from each of the 3 candidate Cell Lines selected in 1.2.8.
Cryopreserve 2 ampoules of all other serum free adapted
Cell Lines.
1.2.10 Establish criteria for routine subculture of the Cell
Line. Assess the stability of production of the selected
Cell Line and one back-up Cell Line in suspension culture
for 60 generations beyond the PSS in cell culture media
with and without methotrexate.
Deliver samples of cell culture supernatant (approximately
10ml) taken from the culture at appropriate intervals to
the Customer to enable the Customer to confirm Product
concentrations and Product quality.
1.2.11 Issue a report of activities to Customer. This report
shall include the following:
- Details of the key experimental data generated in
Stage 1.
- An assessment of the performance of the Cell Line
at laboratory scale.
Note: In all reports to the Customer any techniques or
reagents used . which are proprietary to Lonza will be
described in outline only.
1.3 TIMESCALE
Stage 1 shall be complete with the issue of the report of
activities and it is estimated that this report will be issued ***
Confidential Treatment Requested as to this information *** from
the start of Stage 1.
Stage 2 (Cell Banking) can commence at the Customer's request any
time after activity 1.2.9 is complete.
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2.1 STAGE 2 - FERMENTATION STUDIES
2.2 OBJECTIVES
2.2.1 To assess the key fermentation parameters for the
Customer's Cell Line.
2.2.2 To determine production kinetics in laboratory scale
fermenters *** Confidential Treatment Requested as to this
information ***
2.2.3 To test if Lonza's generic fermentation Process is
appropriate for production of the Product in the selected
medium.
SUBSTAGE 2a - FERMENTATIONS USING CUSTOMER'S MEDIUM
2.2 ACTIVITIES
2.2.1 Receive fermentation process details, medium and relevant
safety information from the Customer to enable Substage to
commence.
2.2.2 Revive cells from an ampoule of the Cell Line received
from the Customer in the medium supplied by Customer.
2.2.3 Carry out a time course of cell growth and Product
accumulation in duplicate laboratory scale stirred and
airlift ferementers *** Confidential Treatment Requested
as to this information *** using the medium supplied by
the Customer and fermentation conditions supplied by the
Customer.
2.2.4 Measure Product concentration using methods established
under Stage 4a.
2.2.5 Harvest the cell culture supernatants and purify using
S-Sepharose.
2.2.6 Deliver the material to the Customer to enable the
Customer to determine product quality.
2.2.7 Issue a summary report of results to Customer.
SUBSTAGE 2b - FERMENTATIONS USING MEDIUM SELECTED UNDER STAGE 1
2.2.8 Revive cells from an ampoule of the Cell Line received
from the Customer in the medium selected in Stage 1
(1.2.6).
2.2.9 Perform up to 4 pairs of laboratory scale *** Confidential
Treatment Requested as to this information ***
fermentations using the Cell Line received from the
Customer. These studies will be agreed with the Customer
and will assess the key fermentation parameters for this
Cell Line and Product for example:
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- An evaluation of Lonza's generic fermentation Process
operating conditions.
- An assessment of whether adjustment to the medium
formulation will be required to produce Product of similar
quality to previous Customer fermentations, e.g. effect of
sodium bicarbonate concentration, effect of feeding
regimes.
2.2.10 Deliver samples of the cell culture supernatants (10ml)
from 2.2.8 to the Customer to enable the Customer to
confirm Product concentrations and Product quality.
2.2.11 Assess Product concentrations and Product quality using
assays established under Stage 4.
2.2.12 Review the results from 2.2.10 with the Customer and
select the optimum fermentation Process.
2.2.13 Using the PSS of the lead Cell Line (1.2.9) perform up to
two pairs of laboratory scale fermentations. Monitor cell
growth and Product accumulation to determine the optimum
point to harvest culture supernatant.
2.2.14 Deliver samples of the cell culture supernatant (10ml) to
the Customer to enable the Customer to confirm Product
concentrations and Product quality.
2.2.15 Assess Product concentrations and Product quality using
assays established under Stage 4.
2.2.16 Issue a report of activities to Customer. This report
shall include the following:
- Details of the key experimental data generated in Stage 2.
- An assessment of the performance of the Cell Line at
laboratory scale.
- A preliminary estimate of the expected productivity of the
Cell Line at production scale.
EVALUATION POINT
At this point the Customer and Lonza Biologics will assess whether
the selected medium is suitable to proceed with the Services. If
it is agreed that the selected medium is unsuitable to proceed
with the Services, then Lonza and the Customer will agree an
alternative work programme.
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2.3 TIMESCALE
Stage 2 shall be complete on the issue of the report of activities
and it is estimated that this report will be issued ***
Confidential Treatment Requested as to this information *** from
the start of Stage 2.
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3.0 STAGE 3 - MASTER AND WORKINQ CELL BANK PREPARATION AND ANALYSIS
3.1 OBJECTIVES
3.1.1 To test the PSS created under Stage 1 (1.2.9) such that
sufficient test information is available for rapid
transfer of the Cell Line to Lonza's GMP manufacturing
facility. Testing for potential adventitious agents is
required so that all cell line and products are protected
for customers.
3.1.2 To create and characterise a master cell bank (MCB) and a
working cell bank (WCB).
3.2 ACTIVITIES
3.2.1 Send an ampoule of the PSS (1.2.9) of the Lead Cell line
and two backup candidate Cell Lines to a testing
laboratory to be tested by assay for mycoplasma.
3.2.2 Send ampoules of the Cell Line to Testing Laboratories to
be tested by:
a) Assay for viruses:
*** Confidential Treatment Requested as to this
information ***
b) Isoenzyme analysis
3.2.3 Prepare GMP documentation, for the preparation of the cell
banks from the selected Cell Line.
3.2.4 Establish a 200 ampoule MCB and a 250 ampoule WCB
according to the principles of GMP. The MCB will be
derived from one ampoule of the PSS and the WCB will be
derived from one ampoule of the MCB. Methotrexate will be
used in the cell culture medium. The cell banking system
has been designed with reference to the "Points to
Consider in the Characterisation of Cell line used to
Produce Biologicals" (1993 -CBER, Food and Drug
Administration), and the"Production and Quality Control of
Monoclonal Antibodies" (1995, Commission of the European
Communities).
3.2.5 Establish standard maintenance, storage and release
procedures for the MCB and WCB at two separate Lonza
sites.
3.2.6 Characterise the MCB and WCB :-
- Assess sterility (21 CFR 610.12) and mycoplasma
(FDA PTC 1993) status.
- Assess cell bank viability from 5 ampoules
distributed through the bank.
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- Evaluate growth of cells from the MCB and WCB
following Lonza's generic inoculum regime to
measure doubling time, cell growth and split
ratios.
3.2.7 Issue report of activities to Customer. The report shall
include:
- a description of preparation of the cell banks;
- details of the history of the Cell Line at Lonza;
- mycoplasma and sterility test results on the cell
banks;
- details of cell growth characteristics for the
Cell Line i.e. doubling time, cell concentration,
split ratios, viability;
- details of materials and methods used for
activities under sections 3.2.4; 3.2.5 and 3.2.6;
- a summary of Lonza's storage and control
procedures for the cell banks;
- Testing Laboratory results.
3.3 CELL BANK CHARACTERISATION (VIRUS TESTING)
Additional viral characterisation of the cell banks will be
required in order to support regulatory applications to conduct
clinical trials, or market a product, including testing of a
post-production cell bank (PPCB) as prepared in Stage 8 of these
Services. Lonza can arrange for such testing at Lonza's approved
contractors on Customer's behalf on terms to be agreed or
alternatively deliver ampoules of the Cell Line to Customer for
performance of this testing.
Note: THIS PROPOSAL MAKES PROVISION FOR TESTING OF THE PSS TO
ENABLE RAPID TRANSFER OF THE CELL LINE INTO LONZA'S MANUFACTURING
FACILITY. THESE TESTS ON THE PSS ENABLE THE CELL BANKS TO MEET THE
CELL BANK SPECIFICATION (SCHEDULE 1). HOWEVER FOR INITIATION OF
PHASE I CLINICAL TRIALS THE CELL BANKS ALSO NEED TO BE TESTED.
3.4 TIMESCALE
Stage 3 shall be complete with the issue of the report of
activities and it is estimated that this report will be issued ***
Confidential Treatment Requested as to this information *** from
the start of Stage 3. It is estimated that he 200 ampoule MCB will
be established *** Confidential Treatment Requested as to this
information *** from the start of Stage 3 the 250 ampoule WCB will
be established *** Confidential Treatment Requested as to this
information *** from the start of Stage 3 and the report will be
complete *** Confidential Treatment Requested as to this
information *** from the start of Stage 3. The duration of cell
bank virus testing will depend on the range of tests chosen by the
Customer and on the Testing Laboratory that is selected.
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4.0 STAGE 4 - ASSAY TRANSFER AND VALIDATION
SUBSTAGE 4a - PRODUCT ELISA ASSAY TRANSFER
4.1 OBJECTIVES
4.1.1 To transfer an assay for measurement of Product
concentration in cell culture supernatants, to be used as
an assay in the Lonza development laboratories to support
the work programme.
4.2 ACTIVITIES
4.2.1 Receive protocols from the Customer for the Product ELISA
assay to be used in development. Key reagents will be
provided if they are not readily available commercially.
4.2.2 Assess the performance of the assay on cell culture
supernatants from the Cell Line. Compare data to data
generated by the Customer.
4.2.3 Validate the assay for working range, accuracy and
precision.
4.2.4 Issue a report on the activities in Stage 4a to the
Customer.
4.3 TIMESCALE
Substage 4a can commence as soon as protocols and reagents and
reference standards are received from the Customer. It is
estimated that Stage 4 will take *** Confidential Treatment
Requested as to this information *** to complete.
SUBSTAGE 4b - ASSAY TRANSFER AND VALIDATION
4.4 OBJECTIVES
4.4.1 To establish and where appropriate validate assays for
determination of Product quality during the development
programme and for draft Specification testing.
4.4.2 To agree with the Customer which assays to apply at which
stages of the work programme.
4.4.3 To evaluate the performance of Lonza's standard QC assays
for the Product/Process.
4.4.4 To establish assays as required for testing of new GMP raw
materials.
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4.5 ACTIVITIES
4.5.1 Receive protocols from the Customer for the assays to be
used in development and QC. Key reagents will be provided
if they are not readily available commercially.
4.5.2 Assess the performance of these Customer assays with
Product.
4.5.3 Evaluate the performance of Lonza Biologics' QC assays
with Product as appropriate.
4.5.4 Perform validation as appropriate to this phase of the
clinical programme according to ICH requirements.
4.5.5 Transfer the assays to Lonza Biologics Quality Department.
4.5.6 Issue a report on the activities in Substage 4b to the
Customer.
Note: The timescale for this programme are estimates only
and make assumptions on the number of assays to be
transferred and that the assays are transferred smoothly
and no unexpected issues arise.
4.6 TIMESCALE
Substage 4b can commence as soon as protocols and reagents and
reference standards are received from the Customer. The timescale
for Substage 4b will be discussed and agreed with the Customer.
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5.0 STAGE 5 - PURIFICATION PROCESS TRANSFER
5.1 OBIECTIVES
5.1.1 To transfer to Lonza a one step (S-Sepharose) sample
purification method for use in the assessment of Product
quality.
5.1.2 To establish purification process suitable for manufacture
of the Product at *** Confidential Treatment Requested as
to this information ***.
5.1.3 To design a purification process as close as possible to
the Customer's process that will fit with Lonza's
equipment and procedures.
5.1.4 To provide a sample of Product purified using the selected
process to the Customer for evaluation.
5.2 ACTIVITIES
5.2.1 Receive complete information from the Customer on
performance of the purification process at the Customer's
facility. Source and qualify new raw materials as
required. Identify changes that can be made to the
existing purification process.
5.2.2 Observe the purification process at the Customer's
laboratories.
Note: If at this point difficulties in supply or
adaptation to Lonza's equipment and procedures are
identified, these will be discussed with the Customer.
Extra costs may be incurred if specialist equipment or
resins have to be sourced.
5.2.3 Under Stage 2 of the Services provide cell culture
supernatant from cell cultures.
5.2.4 Purify Product from the bulk supernatant using the
procedure provided by the Customer, modified to fit
Lonza's large scale equipment.
5.2.5 Measure yield after each purification step.
5.2.6 Analyse selected in Process samples and final Product for
purity by methods to be established under Stage 4b.
5.2.7 Deliver a sample of the Product to the Customer for
evaluation.
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EVALUATION POINT
At this point the Customer and Lonza Biologics will assess the
capability of the adapted purification process to produce GMP
Product that meets the draft Specification. Agree with the
Customer any additional work which may be needed to produce such
Product. Any further work will be carried out at a price to be
agreed.
5.2.8 Issue report of activities to Customer. This report shall
include:
- step yields for each chromatography and buffer
exchange operation; copies of analytical results;
details of materials and methods used for
activities under Stage 5;
- an outline of the recommended manufacturing
process including an estimate of the expected
yield of Product at the chosen production scale.
- a recommendation of any process modifications that
might be required to purify Product to meet the
draft Specification.
5.3 TIME SCALE
Stage 5 shall be complete with the issue of the, report of
activities and it is estimated that this report will be issued
*** Confidential Treatment Requested as to this information ***
from the start of Stage 5.
Stage 5 shall commence as soon as cell culture supernatant is
available from Stage 2.
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6.0 STAGE 6 - DEVELOPMENT PILOT BATCH
6.1 OBJECTIVES
6.1.1 To carry out a development pilot fermentation at ***
Confidential Treatment Requested as to this information
***
6.1.2 To evaluate the ability of the process to produce Product
meeting the purity limits included in the draft
Specification eg *** Confidential Treatment Requested as
to this information *** if appropriate
6.1.3 To produce bulk purified non-GMP Product that the Customer
may use for non-clinical studies.
6.2 ACTIVITIES
6.2.1 Recover one vial from the PSS (Stage 1) and expand culture
to inoculate a *** Confidential Treatment Requested as to
this information ***
6.2.1 Carry out *** Confidential Treatment Requested as to this
information *** using process established in Stage 2.
6.2.3 Clarify culture broth and concentrate supernatant.
Refine key operational parameters of this primary recovery
process, including the intermediate filtration step.
6.2.4 Purify bulk concentrate by procedure established during
Stage 5.
6.2.5 Test Product purity eg *** Confidential Treatment
Requested as to this information *** if appropriate, and
the *** Confidential Treatment Requested as to this
information *** will also be carried out on this
development batch.
6.2.6 Review requirements (if any) for process modifications
that may be needed following this study before Stage 8.
Any such process modifications are subject to agreement.
6.2.7 Deliver remainder of bulk purified Product produced from
the development batch to the Customer.
6.2.8 Report on the pilot fermentation and primary recovery
investigations, including an estimate of the expected
yield from the Cell Line at production scale in the Stage
2 report. Report on the pilot purification and testing
results in the Stage 5 report
If requested by the Customer carry out further pilot
fermentations.
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6.3 TIMESCALE
Stage 6 shall be complete upon delivery of Product from the
development batch. It is estimated that such Product will be
delivered *** Confidential Treatment Requested as to this
information *** from commencement of Stage 6. Stage 6 can commence
as soon as the purification process transfer programme is complete
(Stage 5) and the PSS is available (Stage i ). If the Customer
requires the Product can be shipped prior to completion of
testing (6.2.5).
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7.0 STAGE 7 - GMP DOCUMENTATION
7.1 OBJECTIVE
7.1.1. To prepare GMP documentation for use in manufacture of
Product at *** Confidential Treatment Requested as to this
information ***
7.2 ACTIVITIES
7.2.1 Prepare GMP documentation. The documentation shall cover:
- Inoculum, fermentation, primary recovery and
purification process manufacturing directions, and
in-process controls contained in the manufacturing
directions.
- Materials specifications (as required).
- Sampling protocols.
- Product specifications.
7.3 TIMESCALE
It is estimated that Stage 7 will take *** Confidential Treatment
Requested as to this information *** from the commencement of work
and will be complete on notification by Lonza to the Customer that
the documentation has been approved by Lonza's QA Department.
Stage 7 will be scheduled such that it is not a rate limiting
activity.
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8.0 STAGE 8 - PRODUCTION OF CLINICAL MATERIAL AT *** Confidential Treatment
Requested as to this information ***
8.1 OBJECTIVES
8.1.1 To manufacture clinical grade Product at *** Confidential
Treatment Requested as to this information *** (depending
on Customer requirement) in an *** Confidential Treatment
Requested as to this information *** in accordance with
the principles of Good Manufacturing Practice (GMP).
8.1.2 To further evaluate the ability of the Process to produce
Product meeting the draft Specification.
8.2 ACTIVITIES
8.2.1 After receiving adequate virus testing data on the PSS and
sterility, viability and mycoplasma testing data on the
MCB (Stage 3), recover one vial from the MCB and expand
culture to inoculate a fermenter.
8.2.2 Carry out *** Confidential Treatment Requested as to this
information ***.
8.2.3 Prepare a post-production cell bank (PPCB) from the
fermentation. This bank is available for testing as
required by the Customer.
8.2.3 Clarify culture supernatant and concentrate by the
procedure established in Stage 6.
8.2.4 Purify concentrate by procedure established during
Stage 5.
8.2.5 Test Product against the draft Specification.
8.2.6 Undertake quality assurance review of lot documentation
and issue a Certificate of Analysis.
8.2.7 Review requirements (if any) for process modifications in
order to meet Specification for manufacture of subsequent
lots. Any such process modifications are subject to
agreement.
8.2.8 Deliver Product to the Customer.
8.3 TIMESCALE
Stage 8 shall commence as soon as adequate virus testing data and
the sterility viability and mycoplasma testing data is available
on the MCB (Stage 3).
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Stage 8 shall lid complete upon delivery of Product. It is
estimated that Product will be delivered *** Confidential
Treatment Requested as to this information *** from commencement
of Stage 8.
22
Note: PRODUCT CAN BE SHIPPED IN QUARANTINE WITH THE CERTIFICATE OF ANALYSIS TO
FOLLOW IN ORDER TO FACILITATE THE QUICKEST DELIVERY OF PRODUCT. A LETTER IS
REQUESTED BY LONZA BIOLOGICS FROM THE CUSTOMER STATING THAT THE PRODUCT WILL NOT
BE USED IN HUMAN STUDIES UNTIL THE CERTIFICATE OF ANALYSIS IS ISSUED BY LONZA
BIOLOGICS. THE CUSTOMER MUST INFORM LONZA BIOLOGICS OF THE EXTENT OF LONZA
BIOLOGICS' IN HOUSE TESTING REQUIRED TO BE COMPLETE BEFORE THE PRODUCT IS TO BE
SHIPPED IN QUARANTINE.
23
9.0 STAGE 9 - REGULATORY DOCUMENTATION/SUPPORT
9.1 OBJECTIVES
9.1.1 To prepare regulatory documentation and regulatory support
as required by the Customer to support Phase III Studies.
9.2 ACTIVITIES
9.2.1 To provide regulatory documentation covering work under
all stages of these Services in a format appropriate for
the country of application and as requested by the
Customer.
9.2.2 To attend Customer and regulatory agency meetings as
required by the Customer.
9.2.3 To advise on additional studies that may be required for
regulatory Applications.
9.3 TIMESCALE
The duration of Stage 9 will depend on the extent of regulatory
support requested by the Customer. Lonza will aim to complete the
regulatory work as soon as possible after receiving all the
relevant data from these Services, in anticipation of the Customer
requiring the earliest possible filing date.
24
10.0 STAGE 10 - EVALUATION OF VIRUS CLEARANCE
10.1 OBJECTIVES
10.1.1 To obtain data for clearance of one model virus by the
column chromatography and virus inactivation steps used in
the purification of bulk Product.
10.2 ACTIVITIES
10.2.1 Design a scaled down process for each column
chromatography and inactivation step. The scaled down
process will mimic as closely as reasonably possible the
manufacturing scale process.
10.2.2 Prepare a GLP study protocol and agree the model virus
with the Customer.
10.2.3 Collect column load samples from the appropriate steps of
the full scale manufacturing process during Stage 8 of the
Services.
10.2.4 Carry out the scaled down process for appropriate
chromatography steps without the virus spike. Compare the
elution profile, Product yield and purity with the full
scale manufacturing process. This is designed to
demonstrate that the scaled down process does mimic the
manufacturing process and to generate control samples to
test for cytotoxicity in the virus assay.
10.2.5 Repeat the scaled down process for each column step, each
spiked separately with the selected virus. The virus will
be prepared and assayed by a suitable Testing Laboratory.
The column chromatography and inactivation studies will be
carried out by Lonza staff working in the laboratories of
the Testing Laboratory.
10.2.6 Assay infectious virus recovered in Product containing
fractions (to allow calculation of clearance factors) and
in selected unbound and wash fractions to determine (where
possible) where infectious virus is removed and hence
identify critical steps in the process.
10.2.7 Measure the rate of inactivation of virus by treating the
selected model virus in the inactivation steps, developed
in Stage 5 in the purification process for Product.
10.2.8 Measure the clearance of the virus across the virus
removing filter step, if included in the process. i
10.2.9 Calculate virus clearance factors for each step by
dividing total infectious virus applied by that recovered
with purified Product or after treatment at low pH.
25
10.2.10 Issue an audited report of the activities to the Customer.
10.3 TIMESCALE
Stage 10 shall commence once Product samples are obtained from Stage 8.
It is estimated that Stage 10 shall be complete *** Confidential
Treatment Requested as to this information *** from commencement.
26
SCHEDULE 3
PRICE AND TERMS OF PAYMENT
1.0 PRICE
In consideration for Lonza carrying out the Services as detailed in
Schedule 2 the Customer shall pay Lonza, as follows :-
- -----------------------------------------------------------------------------------------------------------
STAGE PRICE (UK L STERLING)
- -----------------------------------------------------------------------------------------------------------
1. Substage 1 a - Media Selection *** Confidential Treatment Requested
as to this information ***
- -----------------------------------------------------------------------------------------------------------
Substage 1 b - Cloning and Cell Line Selection "
- -----------------------------------------------------------------------------------------------------------
2. Fermentation Studies "
- -----------------------------------------------------------------------------------------------------------
Substage 2a "
- -----------------------------------------------------------------------------------------------------------
Substage 2b "
- -----------------------------------------------------------------------------------------------------------
3. Master and Working Cell Bank Preparation and Analysis "
- -----------------------------------------------------------------------------------------------------------
4. Substage 4a - Product ELISA Assay Transfer "
- -----------------------------------------------------------------------------------------------------------
Sybstage 4b - Assay Transfer and Validation "
- -----------------------------------------------------------------------------------------------------------
5. Purification Process Transfer "
- -----------------------------------------------------------------------------------------------------------
6. Development Pilot Batch "
- -----------------------------------------------------------------------------------------------------------
7. GMP Documentation "
- -----------------------------------------------------------------------------------------------------------
8. Production of Clinical Material(2) "
- -----------------------------------------------------------------------------------------------------------
9. Regulatory Documentation Support "
- -----------------------------------------------------------------------------------------------------------
10. Evaluation of Virus Clearance "
- -----------------------------------------------------------------------------------------------------------
Notes
(1) This Price includes only cell bank testing as specified in Stage 3
activities, sufficient to allow entry of the Cell Line into Lonza's GMP
facility.
27
(2) This prices may be reviewed depending on the cost of the commercial media
selected and the costs of the resins used during the purification
Process.
(3) These are Lonza's cost prices for GMP batches produced in the early stage
of a product development programme. Once a long term supply arrangement
is entered into, it is anticipated that considerable price reductions
could be offered.
28
2.0 PAYMENT
Payment by the Customer of the Price for each Stage shall be made against
Lonza's invoices as follows:
2.1 For
Substage 1a
*** Confidential Treatment Requested as to this information ***
Substage 1b
*** Confidential Treatment Requested as to this information ***
2.2 For
Stage 2
Substage 2a
*** Confidential Treatment Requested as to this information ***
Substage 2b
*** Confidential Treatment Requested as to this information ***
2.3 For Stage 3
*** Confidential Treatment Requested as to this information ***
2.4 For Stage 4
Substage 4a
*** Confidential Treatment Requested as to this information ***
Substage 4b
Payment schedule to be agreed.
2.5 For Stage 5
*** Confidential Treatment Requested as to this information ***
2.6 For Stage 6
*** Confidential Treatment Requested as to this information ***
2.7 For Stage 7
*** Confidential Treatment Requested as to this information ***
2.8 For Stage 8
*** Confidential Treatment Requested as to this information ***
29
2.9 For Stage 9
*** Confidential Treatment Requested as to this information ***
2.10 For Stage 10
*** Confidential Treatment Requested as to this information ***
30
SCHEDULE 4
1. LB and Customer may negotiate in good faith amendments to the scope of
the activities set out in Schedule 2 in the event that:
a. Customer determines that additional activities to the Services are
required to meet its objectives or to accelerate where possible
performance of the proposed services. Customer acknowledges that
LB may have regard to its other third party commitments, and
b. Customer's requirements change resulting in certain activities to
the Services no longer being required to meet Customer's
objectives, Customer having regard to its obligations under
Clause 4.3 and Clause 9.2 of. Schedule 5.
2. The parties recognise that it may become necessary or desirable for
Customer to manufacture *** Confidential Treatment Requested as to this
information *** itself or through another manufacturer. LB is willing
to effect a process transfer on commercially reasonable terms. ***
Confidential Treatment Requested as to this information ***
31
SCHEDULE 5
STANDARD TERMS FOR CONTRACT SERVICES
AVANT IMMUNOTHERAPEUTICS INC
1. INTERPRETATION
1.1 In these Standard Terms, unless the context requires otherwise
1.1.1 "Affiliate" means any Company, partnership or other entity
which directly or indirectly controls, is controlled by or
is under common control with the relevant party to this
Agreement. "control" means the ownership of more than
fifty per cent (5096) of the issued share capital or the
legal power to direct or cause the direction of the
general management and policies of the party in question.
1.1.2 "Agreement" means any contract between LB and a Customer
incorporating these Standard Terms.
1.1.3 "Cell Line" means the cell line, particulars of which are
set out in Schedule 1.
1.1.4 "cGMP" means Good Manufacturing Practices and General
Biologics Products Standards as promulgated under the US
Federal Food Drug and Cosmetic Act at 21CFR (Chapters 210,
211, 600 and 610) and the Guide to Good Manufacturing
Practices for Medicinal Products as promulgated under
European Directive 91/356/EEC. LB's operational quality
standards are defined in internal GMP policy documents.
Additional product-specific development documentation and
validation work may be required to support regulatory
applications to conduct clinical trials or market a
product.
1.1.5 "Customer" includes any person to whom a Proposal is
issued by LB.
1.1.6 "Customer information" means all technical and other
information not known to LB or in the public domain
relating to the Cell Line, the Process and the Product,
from time to time supplied by the Customer to LB.
1.1.7 "Customer Materials" means the Materials supplied by
Customer to LB (if any) and identified as such by
Schedule 1 hereto.
1.1.8 "Customer Tests" means the tests to be carried out on
the Product immediately following receipt of the Product
by the Customer, particulars of which are set out in
Schedule 1.
1.1.9 "ex works" means LB has fulfilled its obligation to
deliver when it has made the object of delivery available
at its premises to the Customer or the Customer's agent
(or to LB's carrier if the provisions of Clause 5.1 of
this Schedule 5 apply). For the avoidance of doubt, unless
otherwise agreed in writing, LB is not responsible for
loading the object of delivery on to the vehicle provided
by the Customer or the Customers agent (or to LB's
nominated carrier if Clause 5.1 of this Schedule 5
applies) or for delaying the object of delivery for
export.
1.1.10 "LB Know-How" means all technical and other information
relating to the Process known to LB from time to time
other than confidential Customer Information and
information in the public domain.
32
1.1.11 "Patent Rights" means all patents and patent applications
of any kind throughout the world relating to the Process
which from time to time LB Is the owner of or is entitled
to use.
1.1.12 "Price" means the price specified in Schedule 3 for the
Services.
1.1.13 "Process" means the process for the production of the
Product from the Cell Line, including any improvements
thereto from time to time.
1.1.14 "Product" means all or any part of the product (including
any sample thereof), particulars of which are set out in
Schedule 1.
1.1.15 "Proposal" means any proposal or quotation issued by LB.
1.1.16 "Services" means all or any part of the services the
subject of the Agreement or Proposal (including, without
limitation, cell culture evaluation, purification
evaluation, master, working and extended cell bank
creation, and sample and bulk production), particulars of
which are set out In Schedule 2.
1.1.17 "Special Term" means any term additional or supplemental
to these Standard Terms from time to time agreed In
writing between LB and the Customer. Particulars of any
Special Terms at the date of the Agreement are set out in
Schedule 4.
1.1.18 "Specification" means the specification for Product,
particulars of which are set out in Schedule 1. '
1.1.19 "Terms of Payment" means the terms of payment specified in
Schedule 3.
1.1.20 "Terms means any third party instructed by LB to cant'
out tests on the Cell Line or the Product.
1.2 Unless the context requires otherwise, words and phrases defined
in any other part of the Agreement shall bear the same meanings in
these Standard Terms, references to the singular number include
the plural and vice versa, references to Schedules are references
to schedules to the Agreement, and references to Clauses are
references to clauses of these Standard Terms.
1.3 In the event of a conflict between a Special Term and these
Standard Terms, the Special Term shall prevail.
2. APPLICABILITY OF STANDARD TERMS
2.1 Unless agreed otherwise, these Standard Terms shall apply to every
Proposal and Agreement, and to any services additional to the
Services requested by a Customer: LB shall not be bound by any
terms which may be inconsistent with these Standard Terms and the
Special Terms. No variation of or addition to these Standard Terms
and the Special Terms or any other term of an Agreement shall be
effective unless in writing and signed for and on behalf of LB and
Customer. For the avoidance of doubt, amendments to the draft
Specification or Specification for Product shall be effective if
reduced to writing and signed by the regulatory representative of
both Parties, which regulatory representative shall be nominated
from time to time by the parties.
2.2 Unless previously withdrawn, a Proposal is open for acceptance
within the period stated therein. Where no period is stated, the
Proposal shall be open for acceptance within thirty (30) days from
the date it is issued unless withdrawn in the meantime. Any
acceptance by a Customer of a Proposal shall not create a binding
contract.
33
2.3 A binding contract shall only be created when LB has accepted in
writing an offer placed by a Customer.
3. SUPPLY BY CUSTOMER
3.1 Prior to or immediately following the date of the Agreement the
Customer shall supply to LB the Customer Information, together
with full details of any hazards relating to the Cell Line and/or
the Customer Materials, their storage 'and use. On review of this
Customer Information, the Cell Line and/or the Customer Materials
shall be provided to LB at LB's request. Property in the Cell Line
and/or the Customer Materials supplied to LB shall remain vested
in the Customer.
3.2 The Customer hereby grants LB the non-exclusive right to use the
Cell Line, the Customer Materials and the Customer Information for
the purpose of the Agreement. LB hereby undertakes not to use the
Cell Line, the Customer Materials or the Customer Information (or
any part thereof) for any other purpose.
3.3 LB shall:
3.3.1 at all times use all reasonable endeavours to keep the
Cell Line and/or the Customer Materials secure and safe
from loss and damage in such manner as LB stores its own
material of similar nature;
3.3.2 not part with possession of the Cell Line and/or the
Customer Materials or the Product, save for the purpose
of tests at the Testing Laboratories; and
3.3.3 procure that all Testing Laboratories are subject to
obligations of confidence substantially in the form of
those obligations of confidence imposed on B under these
Standard Terms.
3.4 The Customer warrants to LB that
3.4.1 the Customer is and shall at all times throughout the
duration of the Agreement remain entitled to supply the
Cell Line, the Customer Materials and Customer Information
to LB;
3.4.2 to the best of the Customer's knowledge and belief the use
by LB of the Cell Line, the Customer Materials or and the
Customer Information for the Services will not infringe
any rights (including, without limitation, any
Intellectual or industrial property rights) vested in any
third party; and
3.4.3 the Customer will notify LB, in writing, immediately it
knows or ought to know that it is no longer entitled to
supply the Cell Line, the Customer Materials and/or the
Customer Information to LB or that the use by LB of the
Cell Line, the Customer Materials or the Customer
Information for the Services infringes or is alleged to
infringe any rights (including, without limitation, any
intellectual or industrial property rights) vested in
any third party.
3.5 The Customer undertakes to indemnify and to maintain LB promptly
indemnified against any loss, damage, costs and expenses of any
nature (including court costs and legal fees on a full indemnity
basis), whether direct or consequential, and whether or not
foreseeable or in the contemplation of LB or the Customer, that LB
may suffer arising out of or incidental to any breach of the
warranties given by the Customer under Clause 3.4 above or any
claims alleging LB's use of the Cell Line, the Customer Materials
or the Customer Information infringes any rights (including,
without limitation, any intellectual or industrial property
rights)
34
vested in any third party (whether or not the Customer knows or
ought to have known about the same).
3.6 The obligations pf the Customer under this Clause 3 shall survive
the termination for whatever reason of the Agreement.
4. PROVISION OF THE SERVICES
4.1 LB shall diligently carry out the Services as provided in
Schedule 2 and shall use all reasonable efforts to achieve the
estimated timescales therefor.
4.2 Due to the unpredictable nature of the biological processes
involved in the Services, the timescales set down for the
performance of the Services (including without limitation the
dates for production and delivery of Product) and the quantities
of Product for delivery set out in Schedule 2 are estimated only.
4.3 Subject to Clause 4.1. the Customer shall not be entitled to
cancel any unfulfilled part of the Services or to refuse to accept
the Services on grounds of late performance, late delivery or
failure to produce the estimated quantities of Product for
delivery. LB shall not be liable for any loss, damage, costs or
expenses of any nature, whether direct or consequential,
occasioned by 4.3.1 any delay in performance or delivery howsoever
caused; or 4.3.2 any failure to produce the estimated quantities
of Product for delivery.
4.4 LB shall comply with the regulatory requirements from time to time
applicable to the Services as set out in Schedule 2 hereto. If the
Customer requests LB to comply with any other regulatory or
similar legislative requirements LB shall use all reasonable
commercial endeavours to do so provided that:
4.4.1 the Customer shall be responsible for informing LB in
writing of the precise foreign requirements which the
Customer is requesting LB to observe;
4.4.2 such foreign requirements do not conflict with any
mandatory requirements under the laws of England;
4.4.3 LB shall be under no obligation to ensure that such
written information complies with the applicable
requirements of any foreign jurisdiction; and
4.4.4 all costs and expenses incurred by LB in complying with
such foreign requirements shall be charged to the Customer
in addition to the Price.
4.5 Delivery of Product shall be ex-works LB's premises (Incoterms
1990). Risk in and title to Product shall pass on delivery.
Transportation of Product, whether or not under any arrangements
made by LB on behalf of the Customer. shall be made at the sole
risk and expense of the Customer.
4.6 Unless otherwise agreed, LB shall package and label Product for
delivery ex-works in accordance with its standard operating
procedures. It shall be the responsibility of the Customer to
inform LB in writing in advance of any special packaging and
labelling requirements for Product. All additional costs and
expenses of whatever nature incurred by LB in complying with such
special requirements shall be charged to the Customer in addition
to the Price.
35
5. TRANSPORTATION OF PRODUCT AND CUSTOMER TESTS
5.1 If requested by the Customer, LB will (acting as agent of the
Customer for such purpose) arrange the transportation of Product
on issue of certificate of analysis or otherwise whichever is the
earlier to occur from LB's premises to the destination indicated
by the Customer together with insurance cover for Product in
transit at its invoiced value. All additional costs and expenses
of whatever nature incurred by LB in arranging such transportation
and insurance shall be charged to the Customer in addition to the
Price.
5.2 Where LB has made arrangements for the transportation of Product,
the Customer shall diligently examine the Product as soon as
practicable after receipt. Notice of all claims (time being of the
essence) arising out of:
5.2.1 damage to or total or partial loss of Product in transit
shall be given in writing to LB and the carrier within
three (3) working days of delivery; or
5.2.2 non-delivery shall be given in writing to LB within ten
(10) days after the date of LB's despatch notice.
5.3 The Customer shall make damaged Product available for inspection
and shall comply with the requirements of any insurance policy
covering the Product notified by LB to the Customer. LB shall
offer the Customer all reasonable assistance (at the cost and
expense of the Customer) in pursuing any claims arising out of the
transportation of Product.
5.4 Promptly following receipt of Product, the Customer shall carry
out the customer Tests.
PROVIDED ALWAYS the Specification for such Product is not stated
to be in draft form, if the Customer Tests show that the Product
fails to meet Specification, the Customer shall give LB written
notice thereof within forty-five (45) days from the date of
delivery of the Product ex works and shall return such Product to
LB's premises for further testing. In the absence of such written
notice Product shall be deemed to have been accepted by the
Customer as meeting Specification. If LB Is satisfied that
Product returned to LB fails to meet Specification and that such
failure Is not due (in whole or in part) to acts or omissions of
the Customer or any third party after delivery of such Product
ex-works, LB shall at Customer's discretion refund that part of
the Price that relates to the production of such Product or
replace such Product at its own cost and expense. In the event
Customer requires LB to replace such Product, LB shall be entitled
to have regard to its commercial commitments to third parties in
the timing of such replacement. Customer acknowledges that there
may, therefore, be a delay in the timing of the replacement of
such Product.
FOR THE AVOIDANCE OF DOUBT, WHERE THE SPECIFICATION IS STATED TO
BE IN DRAFT FORM LB SHALL BE OBLIGED ONLY TO USE ITS REASONABLE
ENDEAVORS TO PRODUCE PRODUCT THAT MEETS SPECIFICATION.
5.5 If there is any dispute concerning whether Product returned to LB
fails to meet Specification or whether such failure Is due (in
whole or in part) to acts or omissions of the Customer or any
third party after delivery of such Product ex-works. such dispute
shall be referred for decision to an independent expert (acting as
an expert and not as an arbitrator) to be appointed by agreement
between LB
36
and the Customer or, in the absence of agreement by the President
for the time being of the Association of the British
Pharmaceutical Industry. The costs of such independent expert
shall be borne equally between LB and the Customer. The decision
of such independent expert shall be in writing and, save for
manifest error on the face of the decision, shall be binding on
both LB and the Customer.
5.6 The provisions of Clauses 5.4 and 5.5 shall be the sole remedy
available to the Customer in respect of Product that fails to meet
Specification.
6. PRICE AND TERMS OF PAYMENT
6.1 The Customer shall pay the Price in accordance with the Terms of
Payment.
6.2 Unless otherwise indicated in writing by LB, all prices and
charges are exclusive of Value Added Tax or of any other
applicable taxes, levies, imposts, duties and fees of whatever
nature imposed by or under the authority of any government or
public authority, which shall be paid by the Customer (other than
taxes on LB's income). All invoices are strictly net and payment
must be made within thirty (30) days of date of invoice. Payment
shall be made without deduction, deferment, set-off, lien or
counterclaim of any nature.
6.3 In default of payment on due date:
6.3.1 interest shall accrue on any amount overdue at the rate
of two per cent (2%) above the base lending rate from time
to time of HSBC Bank plc, interest to accrue on a day to
day basis both before and after judgment; and
6.3.2 LB shall, at its sole discretion, and without prejudice to
any other of its accrued rights, be entitled to suspend
the provision of the Services or to treat the Agreement as
repudiated by notice in writing to the Customer exercised
at any time thereafter.
7. WARRANTY AND LIMITATION OF LIABILITY
7.1 LB warrants that:
7.1.1 the Services shall be performed in accordance with
Clause 4.1; and
7.1.2 the Product shall meet Specification, save where the
Specification is stated to be in draft form when LB shall
be obliged only to use its reasonable endeavors to produce
Product that meets Specification.
7.2 Clause 7.1 is in lieu of all conditions, warranties and statements
in respect of the Services and/or the Product whether expressed or
implied by statute, custom of the trade or otherwise (including
but without limitation any such condition, warranty or statement
relating to the description or quality of the Product, its fitness
for a particular purpose or use under any conditions whether or
not known to LB) and any such condition, warranty or statement is
hereby excluded.
7.3 Without prejudice to the terms of Clauses 5.6, 7.1, 7.2, 7.4 and
7.6. the liability of LB for any loss or damage suffered by the
Customer as a direct result of any breach of the Agreement or of
any other liability of LB (including misrepresentation and
negligence) in respect of the Services (including without
limitation the production and/or supply of the Product) shall be
limited to the payment by LB of damages which shall not exceed
pounds sterling one million four hundred and thirty four thousand
(L1,434,000). The aforementioned financial
37
cap in respect of LB's liability shall not apply where damages are
incurred due to willful misconduct or gross negligence on the part
of LB.
7.4 Subject to Clause 7.6, LB shall not be liable for the following
loss or damage howsoever caused (even if foreseeable. or in the
contemplation of LB or the Customer)
7.4.1 loss of profits, business or revenue whether suffered by
the Customer or any other person; or
7.4.2 special, indirect or consequential loss, whether suffered
by the Customer or any other person; and
7.4.3 any loss arising from any claim made against the Customer
by any other person.
7.5 The Customer shall indemnify and maintain LB promptly indemnified
against all claims, actions, costs, expenses (including court
costs and legal fees on a full indemnity basis) or other
liabilities whatsoever in respect of
7.5.1 any liability under the Consumer Protection Act 1987,
unless such liability is caused by the negligent act or
omission of LB in the production and/or supply of the
Product; and
7.5.2 any product liability (other than that referred to in
Clause 7.5.1) in respect of Product, unless such liability
is caused by the negligent act or omission of LB in the
production and/or supply of Product; and
7.5.3 any negligent or willful act or omission of the Customer
in relation to the use, processing, storage or sale of the
Product.
7.6 Nothing contained In these Standard Terms shall purport to exclude
or restrict any liability for death or personal injury resulting
directly from negligence by LB in carrying out the Services or any
liability for breach of the implied undertakings of LB as to
title.
7.7 The obligations of the Customer under this Clause 7 shall survive
the termination for whatever reason of the Agreement.
8. CUSTOMER INFORMATION, LB KNOW-HOW AND PATENT RIGHTS
8.1 The Customer acknowledges that LB Know-How and LB acknowledges
that Customer ' Information with which it is supplied by the other
pursuant to the Agreement is supplied, subject to Clause 8.4, in
circumstances imparting an obligation of confidence and each
agrees to keep such LB Know-How or such Customer Information
secret and confidential and to respect the other's proprietary
rights therein and not at any time for any reason whatsoever to
disclose or permit such LB Know-How or such Customer Information
to be disclosed to any third party save as expressly provided
herein.
8.2 The Customer and LB shall each procure that all their respective
employees, consultants and contractors having access to
confidential LB Know-How or confidential Customer Information
shall be subject to the same obligations of confidence as the
principals pursuant to Clause 8.1 and shall enter into secrecy
agreements in support of such obligations. Insofar as this is not
reasonably practicable, the principals shall take all reasonable
steps to ensure that any such employees, consultants and
contractors are made aware of such obligations.
8.3 LB and the Customer each undertake not to disclose or permit to be
disclosed to any third party, or otherwise make use of or permit
to be made use of, any trade
38
secrets or confidential information relating to the technology,
business affairs or finances of the other, any subsidiary, holding
company or subsidiary or any such holding company of the other, or
of any suppliers, agents, distributors, licensees or other
customers of the other which comes into its possession under this
Agreement.
8.4 The obligations of confidence referred to in this Clause 8 shall
not extend to any information which
8.4.1 is or becomes generally available to the public otherwise
than by reason of a breach by the recipient party of the
provisions of this Clause 8;
8.4.2 is known to the recipient party and is at its free
disposal prior to its receipt from the other;
8.4.3 is subsequently disclosed to the recipient party without
being made subject to an obligation of confidence by a
third party; or
8.4.4 LB or the Customer may be required to disclose under any
statutory, regulatory or similar legislative requirement,
subject to the imposition of obligations of secrecy
wherever possible in that relation.
8.5 The Customer acknowledges that
8.5.1 LB Know-How and the Patent Rights are vested in LB or LB
is otherwise entitled thereto; and
8.5.2 the Customer shall not at any time have any right, title,
license or interest In or to LB Know-How, the Patent
Rights or any other intellectual property rights relating
to the Process which are vested in LB or to which LB is
otherwise entitled.
8.6 LB acknowledges that
8.6.1 Customer has undertaken that the Customer Information is
vested in the Customer or the Customer is otherwise
entitled thereto and LB has no right to use the same save
to the extent those granted by Customer to LB under
Clause 3.2;
8.6.2 save as provided herein LB shall not at any time have any
right, title, license or interest in or to the Customer
Information or any other Intellectual Property rights
vested in Customer or to which the Customer is entitled;
and
8.6.3 LB will provide to the Customer such information relating
to the Process and Product as contained in the Batch
record as requested by the Customer for the performance of
Customer's regulatory requirements subject to the
obligations of confidentiality outlined in Clause 8.
8.7 The obligations of LB and the Customer under this Clause 8 shall
survive the termination for whatever reason of the Agreement.
9. TERMINATION
9.1 If it becomes apparent to either LB or the Customer at any stage
in the provision of the Services that it will not be possible to
complete the Services for scientific or technical reasons, a
sixty (60) day period shall be allowed for discussion to resolve
such problems. If such problems are not resolved within such
period, LB and the Customer shall each have the right to terminate
the Agreement forthwith by notice in writing. In the event of such
termination, the Customer shall pay to LB -a termination sum
calculated by reference to all the Services performed by
39
!,B prior to such termination (including a pro rata proportion of
the Price for any stage of the Services which Is in process at the
date of termination) and all expenses reasonably incurred by LB in
giving effect to such termination, including the costs of
terminating any commitments' entered into under the Agreement,
such termination sum not to exceed the Price.
9.2 Customer shall be entitled to terminate this Agreement at any time
for any reason by sixty (60) days' notice to LB in writing. In the
event of Customer serving notice to terminate this Agreement which
notice is expressed to be given pursuant to this Clause 9.2.
Customer shall
9.2.1 pay LB a termination sum calculated in accordance with the
principles of Clause 9.1 above, and
9.2.2 i. in the event notice to terminate this Agreement
pursuant to this Clause 9.2 is issued to LB within
four (4) months of LB's then estimated start date
for any stage of the Services which includes cGMP
fermentation activities, Customer shall pay LB a sum
equal to forty percent (40%) of the full Price of
that stage, or those stages, in question which
payment shall fall due to LB on or before the date
of termination of the Services.
ii. in the event notice to terminate this Agreement
pursuant to this Clause 9.2 is issued to LB within
one (1) month of LB's then estimated start date for
any stage of the Services which includes cGMP
fermentation activities, Customer shall pay LB a sum
equal to eighty percent (80%) of the full Price of
that stage, or those stages, in question which
payment shall fall due to LB on or before the date
of termination of the Services.
iii. in the event notice to terminate this Agreement
pursuant to this Clause 9.2 is issued to LB after
the start of a stage or stages of the Services
which includes cGMP fermentation activities,
Customer shall pay LB a sum equal to one hundred
percent (100%) of the full Price of that stage, or
those stages, in question which payment shall fall
due to LB on or before the date of termination of
the Services.
For the avoidance of doubt activities relating to cGMP
fermentation shall be deemed to commence with the date of removal
of the vial of cells for the performance of the fermentation from
frozen storage.
9.3 In the event that notice to terminate is served by Customer under
Clause 9.2 and LB Is successful In allocating Customer's
production slot to a third party customer the provisions of
Clause 9.2.2. shall not apply.
9.4 LB and the Customer may each terminate the Agreement forthwith by
notice in writing to the other upon the occurrence of any of the
following events
9.4.1 if the other commits a breach of the Agreement which (in
the case of a breach capable of remedy) is not remedied
within thirty (30) days of the receipt by the other of
notice identifying the breach and requiring its remedy; or
9.4.2 if the other ceases for any reason to carry on business or
compounds with or convenes a meeting of its creditors or
has a receiver or manager
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appointed in respect of all or any part of its assets or
is the subject of an application for an administration
order or of any proposal for a voluntary arrangement or
enters into liquidation (whether compulsorily or
voluntarily) or undergoes any analogous act or proceedings
under foreign law
9.5 Upon the termination of the Agreement for whatever reason
9.5.1 LB shall promptly return all Customer Information to the
Customer and shall dispose of or return to the Customer
the Customer Materials (and where supplied by Customer the
Cell Line) and any materials therefrom, as directed by the
Customer;
9.5.2 the Customer shall promptly return to LB all LB Know-How
it has received from LB;
9.5.3 the Customer shall not thereafter use or exploit the
Patent Rights or the LB Know-How in any way whatsoever;
9.5.4 LB may thereafter use or exploit the Patent Rights or the
LB Know-How in any way whatsoever without restriction; and
9.5.5 LB and the Customer shall do all such acts and things and
shall sign and execute all such deeds and documents as the
other may reasonably require to evidence compliance with
this Clause 9.5.
9.6 Termination of the Agreement for whatever reason shall not affect
the accrued rights of either LB or the Customer arising under or
out of this Agreement and all provisions which are expressed to
survive the Agreement shall remain in full force and effect.
10. FORCE MAJEURE
10.1 If LB is prevented or delayed in the performance of any of its
obligations under the Agreement by Force Majeure and shall give
written notice thereof to the Customer specifying the matters
constituting Force Majeure together with such evidence as LB
reasonably can give and specifying the period for which it is
estimated that such prevention or delay will continue, LB shall be
excused from the performance or the punctual performance of such
obligations as the case may be from the date of such notice for so
long as such cause of prevention or delay shall continue.
10.2 The expression "Force Majeure" shall be deemed to include any
cause affecting the performance by LB of the Agreement arising
from or attributable to acts, events, acts of God, omissions or
accidents beyond the reasonable control of LB.
11. GOVERNING, LAW. JURISDICTION AND ENFORCEABILITY
11.1 The construction, validity and performance of the Agreement shall
be governed by the laws of England, to the jurisdiction of whose
courts LB and the Customer submit.
11.2 No failure or delay on the part of either LB or the Customer to
exercise or enforce any rights conferred on it by the Agreement
shall be construed or operate as a waiver thereof nor shall any
single or partial exercise of any right, power or privilege or
further exercise thereof operate so as to bar the exercise or
enforcement thereof at any time or times thereafter.
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11.3 The illegality or invalidity of any provision (or any part
thereof) of the Agreement or these Standard Terms shall not affect
the legality, validity or enforceability of the remainder of its
provisions or the other parts of such provision as the case may
be.
12. MISCELLANEOUS
12.1 Neither party shall be entitled to assign, transfer, charge or in
any way make over the benefit and/or the burden of this Agreement
without the prior written consent of the other which consent shall
not be unreasonably withheld or delayed, save that either party
shall be entitled without the prior written consent of the other
to assign, transfer, charge, subcontract, deal with or in any
other manner make over the benefit and/or burden of this Agreement
to an Affiliate or to any 50/50 joint venture company of which the
party in question is the beneficial owner or fifty per cent (50%)
of the issued share capital thereof or to any company with which
the party in question may merge or to any company to which that
party may transfer its assets and undertakings.
12.2 The text of any press release or other communication to be
published by or in the media concerning the subject matter of the
Agreement shall require the prior written approval of LB and the
Customer.
12.3 The Agreement embodies the entire understanding of LB and the
Customer and there are no promises, terms, conditions or
obligations, oral or written, expressed on implied, other than
those contained in the Agreement. The terms of the Agreement shall
supersede all previous agreements (if any) which may exist or have
existed between LB and the Customer relating to the Services.
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