1
THIS THIRD AMENDMENT is made the twenty-sixth day of September 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. Stages 16, 17b and 18 of the Services are to be performed in accordance
with the provisions of separate amendments to the Agreement.
[*] Confidential treatment requested pursuant to a request for confidential
treatment filed with the Securities and Exchange Commission. Omitted
portions have been filed separately with the Commission.
2
2. A new Stage 19 shall be added to Schedule 2 as follows:
"Stage 19 - Preparation of a Biologics License Application (BLA) to
Support the Customer's Regulatory Filing to the US FDA for the Product.
19.1 Objectives
19.1.1 To prepare for submission to the US FDA Lonza's License
Application (BLA) for bulk purified Product.
19.1.2 To answer questions that the US FDA might have on the
BLA submitted by Lonza.
19.1.3 To host a pre-licensing inspection of Lonza's facility
by the US FDA with reference to the manufacture and
testing of bulk purified Product. Up to six employee
representatives of the Customer shall be entitled to be
present at Lonza's premises (but not directly involved
in the inspection) during the period of the inspection
and may, at Lonza's request, attend to participate in
the inspection.
Lonza agrees to report to the Customer on the progress
of the inspection at appropriate points during its
conduct.
19.2 Activities
19.2.1 Assemble the reports and provide data to the Customer as
appropriate for all the studies carried out at Lonza
under this Agreement to validate the Product and
Process.
19.2.2 Prepare the BLA for the Product including the reports
assembled under activity 19.2.1 above, and all necessary
Product and Process information.
[*] Confidential treatment requested pursuant to a request for confidential
treatment filed with the Securities and Exchange Commission. Omitted
portions have been filed separately with the Commission.
3
The BLA will be prepared based on the draft BLA Working
Check List in Appendix 1. Details of the information to
be supplied under each heading, page numbers, and the
content, format and mode of submission of the
information to the US FDA will be agreed between Lonza
and Customer.
19.2.3 If requested by the Customer provide Lonza personnel to attend
up to two pre-submission meetings with the FDA in the US and
prepare appropriate briefing documents for these meetings,
containing some but not all of the information detailed in the
Working Checklist to be agreed under 19.2.2.
19.2.4 Forward the BLA in appropriate sections to the Customer for
review before filing with the US FDA. Customer agrees wherever
possible to review and comment upon the draft BLA within five
working days of its receipt from Lonza. Customer acknowledges
that any delay in conducting such review will result in a delay
to completion of this Stage 19 of the Services. For the
avoidance of doubt the document forwarded to Customer will not
contain information which is proprietary to Lonza or is a
subject to obligations of confidence to third parties.
19.2.5 Revise the BLA as requested by the Customer if the revisions are
agreed between the parties. When requested by the Customer
submit the BLA to the US FDA.
19.2.6 Inform Customer of questions raised which specifically relate to
Product. Respond to any questions from the US FDA with relation
to the BLA.
19.2.7 If requested by the US FDA and/or Customer host a pre-licensing
inspection at Lonza with respect to the Product and the BLA.
[*] Confidential treatment requested pursuant to a request for confidential
treatment filed with the Securities and Exchange Commission. Omitted
portions have been filed separately with the Commission.
4
19.2.8 Inform Customer of questions raised which specifically
relate to Product. Prepare responses to any requests for
further information resulting from the US FDA inspection
of Lonza's facility.
19.3. Timescale
Stage 19 shall be complete when Lonza have responded to all US
FDA questions relating to the Product and the BLA to the
satisfaction of the US FDA.
It is estimated that activities 19.2.1 to 19.2.4 shall be
complete seven months from commencement of Stage 19. Timing of
subsequent activities is dependent on the Customer and the US
FDA and can not be estimated by Lonza. Lonza agrees to provide
responses to questions from the US FDA, received under
activities 19.2.6 and 19.2.8, in a reasonable time frame. An
initial or, if practicable, a full response to such questions
shall be provided by Lonza within thirty days of Lonza receiving
the same."
3. A new Stage 20 shall be added to Schedule 2 as follows:
"Stage 20 - Manufacture of [*] cGMP Batches of Product
20.1 Objectives
Manufacture [*] batches of Product at [*] scale in accordance
with the principles of GMP for delivery to Customer.
20.2 Activities
20.2.1 Recover one vial of the Cell Line from the WCB and
expand culture to inoculate a [*] fermenter.
[*] Confidential treatment requested pursuant to a request for confidential
treatment filed with the Securities and Exchange Commission. Omitted
portions have been filed separately with the Commission.
5
20.2.2 Carry out airlift fermentation at [*] scale.
20.2.3 Clarify, harvest and concentrate supernatant.
20.2.4 Purify Product from the concentrate.
20.2.5 Test Product against Specification.
20.2.6 Undertake Quality Assurance review of lot documentation.
20.2.7 Issue lot release for Product internally.
20.2.8 Issue certificate of analysis and consolidated Customer
batch record to Customer.
20.2.9 Delivery Product to Customer.
20.2.10 Repeat activities 20.2.1 to 20.2.9 (inclusive) [*]
further times.
20.3 Timescale
Stage 20 shall be complete upon delivery of the [*] batch of
Product to the Customer. It is estimated that the first [*]
batches will be delivered during the fourth quarter of 1998. It
is estimated that the [*] batch of Product will also be
delivered during the fourth quarter of 1998 but may, at
Customer's written request, to be received by Biologics no later
than 31 March 1998, be delayed for delivery no later than 31
March 1999".
[*] Confidential treatment requested pursuant to a request for confidential
treatment filed with the Securities and Exchange Commission. Omitted
portions have been filed separately with the Commission.
6
4. 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 and 20) the Customer shall pay Lonza as follows:
Stage 19 Preparation of a Biologic License Application (BLA) to support
the Customer's Regulatory Filing to the US FDA of the Product.
Activities 19.2.1 to 19.2.4: [*]
Activities 19.2.5 to 19.2.8: [*] per man day*
*[*] per man day for services performed in 1998. Thereafter the price
per man day shall be revised in accordance with Lonza's standard man day
rates applying at the time in question.
For the purpose of calculating the Price for activities 19.2.5 to 19.2.8
Lonza will not charge for any Lonza man days that might be required to
conform with requests by the Customer (under activity 19.2.5) or the FDA
(under activities 19.2.6 or 19.2.8) to add to the BLA submitted to the
Customer or to the FDA because of omissions by Lonza of items listed
under the Working Check List as set out in Appendix 1. Lonza will only
charge for man days required to perform work additional to that set out
under activities 19.2.1 to 19.2.4. If, as a result of the pre-licensing
inspection outlined in activity 19.2.7, Lonza receives a 483 or any
other deficiency notification from the FDA, the Customer will not pay
for time spent responding to such 483s or other deficiency notifications
unless these are received as a result of Customer direction or
information provided by the Customer.
Stage 20 Supply of Product at [*] Scale not to exceed [*]
per batch
[*] Confidential treatment requested pursuant to a request for confidential
treatment filed with the Securities and Exchange Commission. Omitted
portions have been filed separately with the Commission.
7
2. Payment
2.1 For Stage 19 activities 19.2.1 to 19.2.4
[*] upon commencement of activity 19.2.1
[*] upon completion of activities 19.2.1 to 19.2.4
2.2 For Stage 19 activities 19.2.5 to 19.2.8
Lonza will present invoices to the Customer at the end of each
calendar quarter itemising work done at Lonza that quarter and
man days to be charged under activities 19.2.5 to 19.2.8.
Lonza will provide the Customer with an estimate at the
beginning of each calendar quarter of the man days that will be
incurred in carrying out work under activities 19.2.5 to 19.2.8.
The Customer shall approve this estimate of the work in any
calendar quarter before the work commences. Any significant
variance in the estimated work for a calendar quarter shall be
approved by the Customer prior to commencement of the work.
2.3 For Stage 20
100% (not to exceed [*] per batch) upon delivery of the batch
of Product in question".
5. a. Save as provided below, Customer acknowledges and hereby agrees
that, on signature of this Amendment to the Agreement, Customer
has made a binding and irrevocable commitment to accept and pay
for the supply of the Services set out in sections 2 and 3 of
this Amendment (above).
[*] Confidential treatment requested pursuant to a request for confidential
treatment filed with the Securities and Exchange Commission. Omitted
portions have been filed separately with the Commission.
8
b. In the event Lonza fails to perform stage 19.2.1 to stage 19.2.4
of the Services in a diligent manner, Customer shall be entitled
to request that performance of stage 20 of the Services be
delayed by a period equivalent to the delay which has been
caused in completing stage 19.2.4 due solely to Lonza's lack of
diligence.
c. Customer expressly agrees that in order to enable Lonza to
perform Stage 19 of the Services Customer must agree to purchase
additional DNA clearance services and assay validation services.
Customer further agrees that its obligations to purchase the
Services set out in Stage 20 will not in any way be diminished
by failure to formalise an amendment to the Agreement for supply
of such Services.
8. The parties are currently negotiating a form of quality statement
relating to those stages of the Services which are to be performed in
accordance with the principles of GMP and which statement may, if
required, be supplied to relevant regulatory authorities.
The parties agree to use all reasonable endeavours to finalise the above
mentioned quality statement by 31 December 1997.
9. Following signature of this amendment the parties agree to use all
reasonable endeavours to negotiate a long term supply agreement for the
manufacture of Product by Lonza. It is intended that such agreement
shall be finalised by 31 December 1997, and supply of Product under its
terms shall be in addition to the Services provided hereunder. If
concluded, such agreement with included, but not limited to the
following provisions:
a. Customer shall commit to purchase from Lonza at least [*]
batches of Product produced in accordance with the principles of
GMP, in each calendar year during which the said supply
agreement subsists Lonza may be requested to supply up to [*]
batches in each year. Lonza shall agree to
[*] Confidential treatment requested pursuant to a request for confidential
treatment filed with the Securities and Exchange Commission. Omitted
portions have been filed separately with the Commission.
9
use reasonable commercial endeavours to supply such additional
batches if requested; and
b. Lonza shall be entitled to allow the BLA prepared pursuant to
stage 19 of the Services to lapse in the event Customer fails to
abide by the above mentioned minimum purchase requirements; and
c. the price for Product supplied to customer pursuant to the above
mentioned supply agreement will initially be charged per batch
of Product. It is the intention that, following supply of at
least [*] batches of Product under the supply agreement the
Product will be supplied on a "per gram" basis. The initial
price of Product per gram will be determined by the average
yield of at least [*] consecutive batches of Product purchased
under the supply agreement.
A mechanism for increasing the price of Product to account for
inflation and other increases in the cost of supplying Product
and/or the costs of maintaining the BLA will be negotiated; and
d. the parties shall agree to review options to reduce the price of
producing Product by cost saving initiatives and to agree a
mechanism by which the benefit of such initiatives can be shared
between the parties.
10. Save as expressly provided herein, the terms and conditions of the
Agreement shall remain in full force and effect.
[*] Confidential treatment requested pursuant to a request for confidential
treatment filed with the Securities and Exchange Commission. Omitted
portions have been filed separately with the Commission.
10
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/ Xxxxx Xxxxxx
-----------------------------------
LONZA BIOLOGICS PLC CEO
-----------------------------------
Signed for and on behalf of /s/ Xxxxxxx X. Xxxxxx
-----------------------------------
XXXXXXX PHARMACEUTICAL INC Vice President and CFO
-----------------------------------
* Confidential treatment requested pursuant to a request for confidential
treatment filed with the Securities and Exchange Commission. Omitted
portions have been filed separately with the Commission.
11
-11-
APPENDIX 1
Biologics License Application
Working Check List
[*] Confidential treatment requested pursuant to a request for confidential
treatment filed with the Securities and Exchange Commission. Omitted
portions have been filed separately with the Commission.
12
Project Filing Date: 4/98
BLA WORKING CHECKLIST
====================================================================================================================================
FDA Item Title Authors Deliverable Publication Comments
No. Format
------------------------------------------
Due In Rec'd TOC Rules Scan Tables Other
====================================================================================================================================
COVER LETTER
FORM 3439 (or 3561)
LETTER OF AUTHORIZATION
1 INDEX (TOC) X
2 LABELING Printed draft or final
package insert, vial
label and carton.
3 OVERALL SUMMARY Heading X
3.1 Annotated Package Insert Heading
3.2 Summary Heading
3.2.1 Pharmacologic Class, Scientific
Rationale, Intended Use, and
Potential Clinical Benefit
3.2.2 Foreign Marketing History
3.2.3 Chemistry, Manufacturing and Control
Summary
3.2.4 Nonclinical Pharmacology and
Toxicology Summary
3.2.5 Human Pharmacokinetics and
Bioavailability
3.2.6 Clinical Data Summary and Heading X
Results of Statistical Analysis
3.2.6.1 Clinical Pharmacology
3.2.6.2 Overview
3.2.6.3 Controlled Clinical Trials
3.2.6.4 Uncontrolled Clinical Trials
3.2.6.5 Other Studies
3.2.6.6 Safety Summary - General Safety
Information
3.2.7 Discussion of Benefit/Risk Relationship Heading
4 CHEMISTRY SECTION Heading X
4.1 Chemistry, Manufacturing, and Heading X
Control Information
4.1.1 Introduction/Manufacturing History
4.1.2 Drug Substance (Lonza) Heading X
4.1.2.1 Description and Characterization Heading X
4.1.2.1.1 Description
4.1.2.1.2 Characterization/Proof of Structure
Physicochemical Characterization of
Reference Standard and Qualifying Lots
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Project Filing Date: 4/98
BLA WORKING CHECKLIST
====================================================================================================================================
FDA Item Title Authors Deliverable Publication Comments
No. Format
------------------------------------------
Due In Rec'd TOC Rules Scan Tables Other
====================================================================================================================================
Biological Activity
4.1.2.2 Manufacturer(s) Heading X
4.1.2.2.1 Identification
4.1.2.2.2 Floor Diagrams
4.1.2.2.3 Other Products
4.1.2.2.4 Contamination Precautions
4.1.2.3 Method(s) of Manufacture Heading X
4.1.2.3.1 Raw Materials and Reagents
4.1.2.3.2 Flow Charts of the Manufacuring
Process
4.1.2.3.3 Detailed Description-Cellular Sub- Heading X
strate/Host Cell/Expression/Vector
System
4.1.2.3.4 Cell Seed Lot System Heading
4.1.2.3.4.1 Master Cell Bank
4.1.2.3.4.2 Working Cell Bank
4.1.2.3.4.3 End of Production Cells
4.1.2.3.5 Cell Growth and Harvesting
4.1.2.3.6 Purification and Downstream
Processing
4.1.2.3.7 Batch Records Heading X
4.1.2.4 Process Controls Heading X
4.1.2.4.1 In-Process Controls
4.1.2.4.2 Process Validation Heading X
4.1.2.4.2.1 Validation for Studies for
Cell Growth/Harvest
4.1.2.4.2.2 Validation for Purification
Process
4.1.2.4.2.3 Microbiology
4.1.2.5 Reference Standards Heading X
4.1.2.6 Specifications/Analytical Methods Heading X
4.1.2.6.1 Specifications and Analytical
Methods
4.1.2.6.2 Certificates of Analysis and
Analytical Results
4.1.2.6.3 Impurities Profile
4.1.2.7 Container/Closure Heading
4.1.2.8 Drug Substance Stability Heading
4.1.2.9 References Heading Alphabetical for Drug
Substance with copies
appended
4.1.2.10 Methods Validation Heading If not in Drug Product
Section
4.1.3.3 Manufacturer Heading
4.1.3.3.1 Identification
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14
Project Filing Date: 4/98
BLA WORKING CHECKLIST
====================================================================================================================================
FDA Item Title Authors Deliverable Publication Comments
No. Format
------------------------------------------
Due In Rec'd TOC Rules Scan Tables Other
====================================================================================================================================
4.1.3.3.2 Floor Diagrams
4.1.3.3.3 Facility Systems
4.1.3.4 Methods of Manufacturing and Heading
Packaging
4.1.3.5 Specifications and Test Methods Heading
for Drug Product
4.1.3.5.1 Specifications and Test Methods
4.1.3.5.2 Certificates of Analysis
4.1.3.6 Container/Closure System Heading
4.1.3.7 Microbiology Heading X Aseptic Fill Conney
Report
4.1.3.7.1 Building and Facilities
4.1.3.7.2 Critical Manufacturing Operations
4.1.3.7.3 Specifications for Hold Periods will need for Europe
4.1.3.7.4 Drug Product Filtration Description- will need for Europe
Microbial Retention/Filter
Compatibility
4.1.3.7.5 Sterilization and Depyrogenation of
Containers, Closures, Equipment and
Components
4.1.3.7.6 Procedures and Specifications for
Media Fills
4.1.3.7.7 Actions for Media Fill Failures
4.1.3.7.8 Microbiological Monitoring of the
Environment
4.1.3.7.9 Container/Closure and Packaging Integrity
4.1.3.7.10 Sterility Testing Methods and Release
Criteria
4.1.3.7.11 Bacterial Endotoxins Test and Method
4.1.3.7.12 Evidence of Formal Written Procedures
4.1.3.8 Drug Product Stability Heading
4.1.3.9 Batch Record for Final Product Heading
4.1.4 Investigational Product/Formulation Heading
4.1.5 Environmental Assessment Heading
4.1.5.1 Date
4.1.5.2 Name of Applicant/Petitioner
4.1.5.3 Address
4.1.5.4 Description of Proposed Action
4.1.5.5 Identification of Chemical Substances
4.1.5.6 Introduction of Substances into the
Environment
4.1.5.7 Fate of Emitted Substances in the
Environment
4.1.5.8 Environmental Effects of Released
Substances
4.1.5.9 Use of Resources and Energy
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15
Project Filing Date: 4/98
BLA WORKING CHECKLIST
====================================================================================================================================
FDA Item Title Authors Deliverable Publication Comments
No. Format
------------------------------------------
Due In Rec'd TOC Rules Scan Tables Other
====================================================================================================================================
4.1.5.10 Mitigation Measures
4.1.5.11 Alternatives to the Proposed Action
4.1.5.12 List of Preparers
4.1.5.13 Certification
4.1.5.14 References
4.1.5.15 Appendices
4.1.6 Method Validation Heading
4.1.7 References Alphabetical for Drug
Product Section with
copies appended
4.2 Samples If needed
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