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EXHIBIT 10.16
*** Text Omitted and Filed Separately
Confidential Treatment Requested
Under 17 C.F.R. Sections 200.80(b)(4),
200.83 and 240.24b-2
THIS FIFTH AMENDMENT is made the 27th day of October, 1997 to an Agreement dated
20 August 1996, by agreement between the parties ("the Agreement")
BETWEEN
XXXXXXX PHARMACEUTICAL INC. of 000 Xxxxxxxxxx Xxxxxx, Xxxxx 000, Xxxx Xxxx, XX
00000, XXX ("the Customer")
AND
LONZA BIOLOGICS PLC of 000 Xxxx Xxxx, Xxxxxx, Xxxxxxxxx, XX0 0XX, Xxxxxxx
("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 which agreement has been previously amended; 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. A new Stage 16 shall be added to Schedule 2 as follows:
"Stage 16 - Validation of [...***...]
16.1 Objectives
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16.1.1 To obtain [...***...] data for each of the [...***...]
steps used in the manufacture of bulk Product.
16.1.2 To investigate the [...***...] during the primary recovery
operations by analysing [...***...] extracted from samples
collected throughout the Process.
16.1.3 To carry out [...***...] studies to determine the
[...***...].
16.2 Activities
16.2.1 Agree a GMP study protocol with the Customer.
16.2.2 Extract and purify [...***...] from [...***...]. Determine
the [...***...].
16.2.3 Collect samples from a [...***...] manufacturing batch of
Product. Samples will be collected throughout the primary
recovery operation and appropriate load samples taken
prior to each [...***...] step.
16.2.4 Extract and purify [...***...] from samples collected
throughout the primary recovery Process and analyse the
[...***...] by [...***...].
16.2.5 Carry out the scaled down Process for each of the
[...***...] without labelled [...***...] spike. Compare
the elution profile, Product yield and purity with the
full manufacturing Process.
16.2.6 Repeat the scaled-down Process with each column load
sample spiked with [...***...]. Analyse load and eluate
samples.
16.2.7 Calculate [...***...] factors for each column step.
16.2.8 Issue a final study report to the Customer, copies of data
generated under Stage 16 if requested by the Customer and
deviations and amendments to the protocol agreed under
16.2.1. [...***...] during the course of this Stage 16 if
requested by the Customer (and more frequently if agreed
between the parties) Lonza will issue to the Customer
unaudited interim data
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summaries provided such requests from the Customer are
reasonable in nature.
16.3 Timescale
Stage 16 will be complete on issue of the final study report
under activity 16.2.8. It is estimated that this final report
will be issued [...***...] from commencement of Stage 16."
2. A new Stage 17b shall be added to Schedule 2 as follows:
"Stage 17b Validation of [...***...] for Bulk Purified Product
17b.1 Objective
To validate these Product release assays to ensure their accuracy
and reliability for Product release and for Product stability
testing where this is relevant. Data will be generated by
specific assay validation studies and also taken from assays
carried out as part of the [...***...] of the Product. Product
made by the manufacturing `Process will be used for the specific
assay validation studies.
17b.2 Activities
17b.2.1 [...***...] (Reduced and Non-reduced)
Agree a GMP study protocol with the Customer. This will be
a Product-specific study; the following assay performance
areas will be defined:
o [...***...]
o [...***...]
o [...***...]
o [...***...]
o [...***...]
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o [...***...]
Accuracy and precision of the method using the Product
will be determined for reduced and non-reduced
[...***...], with particular attention being paid to
[...***...] obtained as part of an estimate of the
precision of the method.
17b.2.2 [...***...] Assay
o Isolate [...***...] from the supernatant and cell
fractions from a large-scale fermenter harvest of
the Cell Line.
o Purify the [...***...] from each fraction.
o Assess the quantity and quality of the [...***...]
using appropriate procedures. Compare the
[...***...] by [...***...] to that of the Lonza
generic [...***...] standard. If the generic
standard and the [...***...] from the Cell Line are
not comparable then a new Cell Line-specific
standard will need to be prepared.
o Determine the degree of cross-reactivity between
the [...***...] and the generic [...***...]
standard in the [...***...] assay.
o Issue a report of activities containing a
recommendation on the most appropriate course of
action for routine testing to the Customer and
outline testing procedures. Issue copies of data
generated under activity 17b.2.2 if requested by
the Customer. [...***...] during the course of this
activity 17b.2.2 if requested by the Customer (and
more frequently if agreed between the parties)
Lonza will issue to the Customer interim data
summaries provided such requests from the Customer
are reasonable in nature.
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17b.2.3 [...***...]
Agree a GMP study protocol with the Customer.
Carry out a study to compare the performance of the
Product in the [...***...] assay with results obtained for
a range of different monoclonal antibodies. Accuracy and
precision of the method using the Product will be
determined using the following criteria:
o [...***...]
o [...***...]
o [...***...]
o [...***...]
o [...***...]
o [...***...]
17b.2.4 [...***...]
Agree a GMP study protocol with the Customer.
Carry out a Product specific study to compare the
performance of the Product on [...***...] using Lonza's
[...***...] method with results obtained for a range of
different monoclonals. Precision and limit of detection of
the assay for Product will be determined using the
following criteria:
o [...***...]
o [...***...]
o [...***...]
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Validate [...***...]. Calculate [...***...] values of
major bands. Make a recommendation on the standardisation
of reporting of minor bands.
17b.2.5 [...***...]
Agree a GMP study protocol with the Customer.
Validate the specificity and sensitivity of the assay for
testing of the Product.
17b.2.6 [...***...] Assays
Agree GMP study protocols with the Customer.
Carry out validation of the assays for [...***...].
Accuracy, precision and storage times prior to assay will
be determined. The following studies will be performed:
o [...***...].
o [...***...].
o [...***...].
o [...***...].
17b.2.7 [...***...]
Agree a GMP study protocol with the Customer.
Assay parameters to be validated will be accuracy, cross-
reactivity or specificity, limits of detection and
stability of [...***...] prior to testing.
Study the effect of the load on the sample band profile,
recovery of [...***...] in the presence of Product, within
and between assay precision and the limit of detection of
Product on [...***...].
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Analyse, by [...***...], all contaminant bands that
account for [...***...] or more of total protein, using
[...***...] and [...***...] that distinguish antibody
fragments.
Note: It is understood that the Customer will provide
Lonza with a reagent expected to be suitable for
the detection of antibody light chain for this
Product. If this reagent is not available or not
suitable it is possible some contaminant bands may
not be identified.
17b.2.8 Performance Review
Review performance of the assays during [...***...] of the
Product against the performance required to meet the
Specification for Product and defined in the validation
studies.
17b.2.9 [...***...]
Summarise [...***...] test performance during [...***...]
testing of Product and analyse the suitability of these
tests for Product.
17b.2.10 Prepare final validation reports for activities 17b.2.1,
17b.2.3, 17b.2.4, 17b.2.5, 17b.2.6 and 17b.2.7 and submit
to the Customer together with details of the testing
procedures listed in Appendix 1 hereto and outline summary
procedures for the Customer Tests not included in that
list. Provide the Customer with copies of data generated
under Stage 17b if requested by the Customer and
deviations and amendments to the GMP protocols agreed
under Xxxxx 00x. [...***...] during the course of each
assay validation if requested by the Customer (and more
frequently if agreed between the parties) Lonza will issue
to the Customer unaudited interim data summaries provided
such requests from the Customer are reasonable in nature.
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Note: These Stage 17b reports will not review the
performance of the assays during the Process
validation studies that will be carried out under
other Stages in these Services. Such review will be
incorporated into the reports issued at the end of
the stages in question as appropriate.
Note: Save for those particularised as being released to
the Customer pursuant to Stage 17.b.2.10 of the
Services, analytical procedures will not be issued
to the Customer as part of these Services. It is
Lonza's responsibility to ensure that the Services
are performed in accordance with the regulatory
requirements of this Agreement where applicable.
17b.3 Timescale
Each assay programme will be complete upon issue of the relevant
report to the Customer. Stage 17b shall be complete upon the
issue of the final report. It is estimated that Stage 1To will
take approximately [...***...] to complete."
3. 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 16 and 17b) the Customer shall pay Lonza as
follows:
Stage 16 Evaluation of [...***...] [...***...]
Stage 17b Validation of [...***...] Assays
for Bulk Purified Product
17b.2.1 [...***...] [...***...]
17b.2.2 [...***...] [...***...]
17b.2.3 [...***...] [...***...]
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17b.2.5 [...***...] [...***...]
17b.2.6 [...***...] [...***...]
17b.2.6 [...***...] [...***...]
17b.2.6 [...***...] [...***...]
17b.2.7 [...***...] [...***...]
17b.2.9 [...***...] [...***...]
2. Payment
Payment by the Customer of the Price for Stages 16 and 17b shall
be made against Lonza's invoices as follows:
2.1 For Stage 16
[...***...] Upon commencement of Stage 16
[...***...] Upon completion of Stage 16.
2.2 For Stage 17b
[...***...] of the Price for each assay validation in
Stage 17b upon commencement of the Services on that assay
validation (total on commencement of all assays:
[...***...]).
[...***...] of the Price for each assay validation in
Stage 17b upon completion of the Services on that assay
validation (total on completion of all assays:
[...***...])."
4. Save as expressly provided herein, the terms and conditions of the
Agreement shall remain in full force and effect.
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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 /s/
LONZA BIOLOGICS PLC -------------------------------------------
Assistant Company Secretary
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TITLE
Signed for and on behalf of /s/ Xxxxxxx X. Xxxxx
XXXXXXX PHARMACEUTICALS INC -------------------------------------------
Vice President and Chief Financial Officer
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TITLE
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APPENDIX 1
TEST METHOD SOP
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[...***...] [...***...]
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[...***...] [...***...]
[...***...] [...***...]
[...***...] [...***...]
[...***...] [...***...]
[...***...] [...***...]
[...***...] [...***...]
[...***...] [...***...]
[...***...] [...***...]
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