1
***TEXT OMITTED AND FILED SEPERATELY
CONFIDENTIAL TREATMENT REQUESTED
UNDER 17, C.F.R. SECTIONS 200.80(b)(4),
200.83 AND 240.24b-2
SECOND AMENDMENT TO LONZA AGREEMENT
THIS SECOND AMENDMENT is made the 30th day of June, 1997 to an
Agreement dated 20 August 1996, and amended 18th November 1996, ("the
Agreement") between COULTER PHARMACEUTICAL, INC. of 550, California Avenue,
Suite 200, Palo Alto, CA 94306, USA ("the Customer") and LONZA BIOLOGICS PLC of
228 Bath Road, Slough, Berkshire, SL1 4DY, England ("Lonza").
WHEREAS:
A. The parties entered into the Agreement pursuant to which Lonza
agreed to provide Services to the Customer to develop a Process for production
of Product; and
B. Customer now wishes Lonza to perform certain additional Services in
association with the above mentioned development and manufacture of Product; and
C. Lonza is prepared to provide such additional Services on the terms
and conditions set out herein.
NOW, THEREFORE, it is hereby agreed to amend the terms of the Agreement
as follows:
1.
2
2. A new Stage 12 shall be added to Schedule 2 as follows:
"Stage 12 - Production and Characterisation of a Post-Production
Cell Bank for the Cell Line.
12.1 OBJECTIVES
12.1.1 To prepare Post-Production Cell Banks from the Cell
Line.
12.1.2 To characterise one Post-Production Cell Bank.
12.2 ACTIVITIES
12.2.1 Take [. . . *** . . .].
12.2.2 Select [. . . *** . . .] for further
characterisation.
12.2.3 Characterise the cells from the selected
[. . . ***. . .] in the following tests:
[. . . *** . . .]
12.2.4 Issue cell bank testing results to the Customer.
12.3 TIMESCALE
As at the date of signature of this amendment [. . . *** . . .]."
* CONFIDENTIAL TREATMENT REQUESTED
2.
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2. A new Stage 13 shall be added to Schedule 2 as follows:
"Stage 13 - Consistency Studies on Manufacture of Product
13.1 OBJECTIVES
13.1.1 To demonstrate batch to batch consistency of
[. . .*** . . .] and Product [. . . *** . . .].
13.1.2 To demonstrate batch to batch consistency of
[. . .*** . . .] and Product [. . . *** . . .].
13.1.3 To determine the [. . . *** . . .].
13.1.4 To evaluate the [. . . *** . . .].
13.2 ACTIVITIES
13.2.1 Agree GLP protocols for the consistency studies
with the Customer.
13.2.2 Prepare a sampling schedule for [. . . *** . . .].
These samples are in addition to the routine samples collected for GMP
compliance. [. . . *** . . .].
Record [. . . *** . . .] to provide [. . . *** . . .].
13.2.3 Analyse the samples [. . . *** . . .], as detailed
in the agreed protocols.
13.2.4 Carry out [. . . *** . . .]. Summarise and review
the key analytical and technical data as follows:
[. . . *** . . .]
13.2.5 Prepare a sampling schedule for [. . . *** . . .].
Record [. . . *** . . .].
13.2.6 Analyse the samples [. . . *** . . .]. The assays
to be performed will be as set out below.
Note: The Customer [. . . *** . . .].
* CONFIDENTIAL TREATMENT REQUESTED
3.
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SCHEDULE OF SAMPLES TO BE ASSAYED IN THE CONSISTENCY STUDY
(PURIFICATION)
===============================================================================================================================
Assay [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
PROCESS SAMPLES:
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
===============================================================================================================================
Assay [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
PROCESS SAMPLES:
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
[...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...] [...***...]
===============================================================================================================================
T = Test X = Not Test
* CONFIDENTIAL TREATMENT REQUESTED
4.
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13.2.7 Determine [. . . *** . . .] where assays have been
performed according to activity 13.2.6.
13.2.8 Where appropriate, determine [. . . *** . . .].
Assess from [. . . *** . . .]
13.2.9 Carry out [. . . *** . . .]. Summarise and review
the key technical data as follows:
[. . . *** . . .]
13.2.10 Issue a report of activities at Lonza to the
Customer.
Note: Summaries of [. . . *** . . .] results for [. . .
*** . . .] will be presented in the regulatory dossier, to be prepared under
Stage 19, not in this report.
13.3 TIMESCALE
Stage 13 shall be complete upon issue of the report of activities
to the Customer (Section 13.2.10). It is estimated that this report will be
issued [. . . *** . . .] from the approval of the study protocol by the Customer
(13.2.1), provided that [. . . *** . . .] under Stage 5 of the Services and the
sampling (13.2.2) has also been completed by that time."
* CONFIDENTIAL TREATMENT REQUESTED
5.
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3. A new Stage 14 shall be added to Schedule 2 as follows:
"Stage 14 - Stability of Partially Purified Product at Stages
during the Manufacturing Process (Intermediates Stability Study).
14.1 OBJECTIVE
14.1.1 To investigate the stability of Product
[. . . *** . . .] to [. . . *** . . .] and provide an estimate of the stability
of Product intermediates.
14.2 ACTIVITIES
14.2.1 Agree a GLP protocol for the study with the
Customer.
14.2.2 Collect in-process samples of [. . . *** . . .]
from [. . . *** . . .].
14.2.3 At appropriate time points [. . . *** . . .].
14.2.4 At the final time point, [. . . *** . . .]:
[. . . *** . . .]
[. . . *** . . .].
14.2.5 Confirm [. . . *** . . .].
14.2.6 Send [. . . *** . . .] for the [. . . *** . . .] to
perform assays as appropriate.
14.2.7 Issue a report of the activities at Lonza to the
Customer.
14.3 TIMESCALE
Stage 14 shall be complete upon issue of the report of
activities (activity 14.2.6) to the Customer. It is estimated that this report
will be issued [. . . *** . . .] from commencement of activities."
* CONFIDENTIAL TREATMENT REQUESTED
6.
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4. A new Stage 17a shall be added to Schedule 2 as follows:
"Stage 17a - Validation of A280 and Protein A Product Release
Assays for Bulk Purified Product
17a.1 OBJECTIVE
To validate A280 and Protein A Product release assays [. .
. *** . . .]. Data will be generated by [. . . *** . . .]. [. . . *** . . .]
will be used for [. . . *** . . .]. The studies will be carried out to GMP/GLP
and [. . . *** . . .].
17a.2 ACTIVITIES
17a.2.1 Protein A Assay
Agree GMP study protocol with the Customer. Carry
out validation of the assay for Protein A. [. . . *** . . .]. The following
studies will be performed:
[. . . *** . . .]
17a.2.2 A280 Assay
Agree a GMP study protocol with the Customer.
Validate the Lonza A280 assay for Product.
17a.2.3 Performance Review
Review performance of the assays [. . . *** . . .].
17a.2.4 Prepare reports and submit to the Customer.
17a.3 TIMESCALE
Each assay programme will be complete upon issue of the
report for each assay programme to the Customer. Stage 17a shall be complete
upon the issue of the final assay programme report to the Customer. It is
estimated that Stage 17a will take approximately [. . . *** . . .] to complete."
* CONFIDENTIAL TREATMENT REQUESTED
7.
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5. A new Stage 18 will be added to Schedule 2 as follows:
"Stage 18 Analytical Cloning of the Cell Line
18.1 OBJECTIVES
18.1.1 To assess the clonality of the Cell Line by [. . .
*** . . .].
18.2 ACTIVITIES
18.2.1 Prepare a GLP study protocol and review with the
Customer.
18.2.2 Carry out [. . . *** . . .].
18.2.3 Carry out [. . . *** . . .].
18.2.4 Analyse [. . . *** . . .].
18.2.5 Issue a report of activities to the Customer.
18.3 TIMESCALE
Stage 18 will be complete on issue of the report of
activities and it is estimated that this will be issued [. . . *** . . .] from
commencement of Stage 18."
* CONFIDENTIAL TREATMENT REQUESTED
8.
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6. The following Clauses shall be added to Schedule 4:
6.1 "Any proposed amendments to the GLP or GMP study protocols
under which activities in Stages 13, 14, 15, 16 and 17 of the Services are being
performed by Lonza, that Lonza consider to be significant, shall be submitted to
the Customer prior to implementation for approval by the Customer. The Customer
shall notify Lonza within 5 days of receipt of a proposed amendment its approval
or otherwise, if no response is received Lonza shall consider the amendment to
be approved. All deviations to the said GLP or GMP study protocols shall be
notified to the Customer, and follow-up actions will be agreed between Lonza and
the Customer."
6.2 "Lonza will notify the Customer in advance, in writing, of
any proposed changes to the activities outlined in Schedule 2 of the Services.
The Customer will review the proposed changes and inform Lonza within 7 days of
receiving such notification of its approval or otherwise of the proposed
changes. Lonza will not change the work programme outlined in Schedule 2 unless
by agreement with the Customer."
6.3 "Lonza will inform the Customer of any significant GMP
deviations during performance of the Services within 48 hours of the occurrence
of the deviation."
7. The following shall be added to Clauses 1 and 2 of Schedule 3:
"1 Price
In consideration for Lonza carrying out the Services
as detailed in Schedule 2 (Stages 12, 13, 14, 17a and 18) the Customer shall pay
Lonza as follows:-
=============================================================================
PRICE (UK
STAGE STERLING)
- -----------------------------------------------------------------------------
Stage 12 - Production and Characterisation of a Post- L.[...***...](1)
Production Cell Bank for the Cell Line
- -----------------------------------------------------------------------------
Stage 13 - Consistency Studies on Manufacture of L.[...***...]
Product
- -----------------------------------------------------------------------------
Stage 14 - Stability of Partially Purified Product at L.[...***...]
Stages during the Manufacturing Process
(Intermediates Stability Study)
- -----------------------------------------------------------------------------
Stage 17a- Validation of A280 and Protein A Product
Release Assays for Bulk Purified Product
- -----------------------------------------------------------------------------
A280 L.[...***...]
Protein A L.[...***...]
- -----------------------------------------------------------------------------
Stage 18 - Analytical Cloning of the Cell Line L.[...***...]
=============================================================================
(1)The Price for this Stage does not include Testing Laboratory charges
which will be passed on directly to the Customer.
* CONFIDENTIAL TREATMENT REQUESTED
9.
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2. PAYMENT
Payment by the Customer of the Price for Stages 12, 13, 14,
17a and 18 shall be made against Lonza's invoices as follows:
2.1 For Stage 12
50% (L.[...***...]) upon commencement of Stage 12 50%
(L.[...***...]) upon completion of Stage 12 Testing House
Laboratory charges will be invoiced on completion of Stage
12.
2.2 For Stage 13
50% (L.[...***...]) upon commencement of Stage 13
50% (L.[...***...]) upon completion of Stage 13
2.3 For Stage 14
50% (L.[...***...]) upon commencement of Stage 14
50% (L.[...***...]) upon completion of Stage 14
2.4 For Stage 17a
50% of the total Price for Stage 17a (L.[...***...]) upon
commencement of Stage 17a
50% of the Price for the A280 assay (L.[...***...]) upon
completion of the Services on the A280 assay.
50% of the Price for the Protein A assay (L.[...***...])
upon completion of the Services on the Protein A assay.
2.5 For Stage 18
50% (L.[...***...]) upon commencement of StaGE 18
50% (L.[...***...]) upon completion of Stage 18"
* CONFIDENTIAL TREATMENT REQUESTED
10.
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8. Save as expressly provided herein, the terms and conditions
of the Agreement shall continue in full force and effect.
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:
LONZA BIOLOGICS COULTER PHARMACEUTICAL INC.
By: /s/ Simon Sturge By: /s/ Michael F. Bigham
----------------------------- ---------------------------------
Title: Chief Executive Officer Title: President and Chief Executive
-------------------------- -------------------------------
Officer
-------------------------------
11.