EXHIBIT 10.50
Confidential Materials omitted and filed separately with the
Securities and Exchange Commission. Asterisks denote omissions.
[LAUREATEPHARMA LOGO]
[GRAPHIC OMITTED]
QUALITY
AGREEMENT
Laureate Pharma, LP
And
Cytogen Corporation
For the manufacture, conjugation and packaging
Of
ProstaScint
Page 1 of 17
Standard Quality Agreement
--------------------------
This Quality Agreement is a required and integral part of the Contract
Manufacturing Agreement between Cytogen Corporation and Laureate Pharma, LP,
dated January 15, 2003 ("Agreement"). The parties hereto have each caused this
Quality Agreement to be executed by their duly authorized representatives on the
date indicated below. This Agreement will be in effect during the term of the
Contract Manufacturing Agreement. Renewal of the Quality Agreement will require
re-approval of this document.
Cytogen Approval Laureate Pharma, LP Approval
---------------- ----------------------------
By: /s/ William F. Goeckeler By: /s/ Robert J. Broeze
-------------------------------- --------------------------
(Signature) (Signature)
By: William F. Goeckeler, Ph.D. By: Robert J. Broeze, Ph.D.
-------------------------------- --------------------------
(Print) (Print)
Title: Vice President Research and Development Title: President
--------------------------------------- -----------------------
(Print) (Print)
Date: January 15, 2003 Date: January 15, 2003
------------------------------ ------------------------
Page 2 of 17
Matrix of Responsibilities Index
Responsibility
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
No. Subject Applicable Cytogen Laureate Page
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
1 Annual Product Reviews X X 7
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
2 Annual Reports X X 7
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
3 Drug Master Files NA 7
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
4 New Submissions X X 7
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
5 Deficiency Letters X X 8
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
6 Audits and Re-inspections X X 8
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
7 Regulatory Authority Inspections X X X 9
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
8 Certificates of Analysis X X X 9
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
9 Product Dating X X 10
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
10 Stability Testing X X 10
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
11 Reserve Samples X X X 10
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
12 Change Control X X* X 11
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
13 Equipment, Calibration and Preventative X X 11
Maintenance
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
14 Process Validation and Qualification X X X 12
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
15 Computer Systems and Software NA 13
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
17 Components and Packaging Commodity Vendors X X 13
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
18 Labeling X X X 13
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
19 Manufacturing Process X X X 14
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
20 Batch Size X X 14
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
21 Deviations, Incidents and Investigations X X X 14
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
23 Batch Records X X 15
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
24 Product Testing and Lot Release X X X 15
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
25 Contract Laboratories X X X 15
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
26 Product Storage and Transportation X X X 16
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
27 Record Retention X X X 16
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
28 Product Complaints X X 16
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
29 Returned Goods X X 17
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
30 Field Alerts and Recalls X X 17
- --------- --------------------------------------------- ---------------- --------------- --------------- ---------
X = applicable
* Only as applicable to Cytogen product N/A = not applicable A.
Page 3 of 17
Quality Agreement
A.1 Provisions
This agreement outlines the responsibilities of Cytogen Corporation
(Cytogen) and Laureate Pharma L.P. (Laureate) with respect to the
quality assurance of Product referenced in the Agreement. Laureate
agrees to manufacture Cytogen's Product to cGMPs. Laureate agrees not
to subcontract any of the manufacturing, packaging, labeling, testing,
release and/or handling of Cytogen's Product unless prior written
authorization is obtained from Cytogen. If subcontracting is necessary,
the vendor must be qualified to perform the required work. Cytogen must
approve all subcontractors.
The `Matrix of Responsibilities' listed on page 3 of this document
delineates the primary party responsible for the various aspects of the
Quality Agreement.
The Quality Agreement is effective upon final signature approvals, will
be updated as needed and will terminate on the expiration date of the
last batch produced for commercial distribution. In the event that the
Supply Agreement with Cytogen is terminated for any reason, the Quality
Agreement shall also immediately terminate. In addition all stability
samples, studies, storage and holding of bulk, finished or in process
intermediates, if applicable, will be immediately returned to Cytogen.
A.2 Approvals
The Quality Agreement will be approved by the Heads (i.e., Vice
President or Director) of Quality Assurance for Cytogen and Laureate
and the duly authorized Officers of each company.
A.3 Procedures for Revision
If revisions to this Quality Agreement are required, Laureate Quality
Assurance Department will circulate the revised document to Heads of
Quality Assurance at Cytogen and Laureate for approval. If Cytogen
identifies a necessary change, a written description of the change will
be provided to Laureate QA for processing.
A.4 Abbreviations
Certificate of Analysis: COA
current Good Manufacturing Practices: cGMP's
Standard Operating Procedures: SOPs
Page 4 of 17
A.5 Definitions of Terms
All defined terms unless otherwise set forth below, have the meaning
set forth in the Agreement.
Product
-------
The term "Product" hereby refers to the manufacturing, conjugation and
filling of ProstaScint; CYT-351, CYT-356 and Sodium Acetate solution
Contractor, Sub-Contractor
--------------------------
Any manufacturer, packager, analytical laboratory or other Product
support service provider who performs processing, testing and/or
packaging of a Product or any intermediate step of manufacture, or
other Product support service, is a contractor, sub-contractor.
Batch Record
------------
The batch record consists of the master manufacturing formula,
appropriate bills of material, equipment, components, packaging and
shipping instructions, and exception documentation, such as,
deviations, incidents and investigation reports, and additional
documentation which may have been generated as part of the production
record of the batch. The Master Batch Record will remain the property
of Cytogen and will be issues to Laureate when requested. The Cytogen
lot-numbering system will be used to identify the lot of Product,
following Cytogen's SOP.
Deviation Report
----------------
This document is used to obtain approvals to temporarily modify or to
document excursions from operating, manufacturing, testing
instructions, target/informational test results, or procedures. The
deviation does not permanently change existing instructions/SOP's or
procedures; it is intended to be a specific or one time use document
for a specific lot of Product.
Formal Investigation
--------------------
Formal Investigations: Written reports detailing the specifics of an
investigation resulting from an exceptional event. The investigation
includes a description of the incident, investigation, conclusions and
corrective action or action plan, if applicable. Laureate Pharma will
provide notification to Cytogen prior to commencing an investigation.
The final report will be approved by Laureate's and Cytogen's Quality
Departments.
Lot Number
----------
A Lot Number is used to identify a specific lot or batch of
manufactured material. Note: This definition may be elaborated upon
to include Part Number or other additional supporting information.
Material
--------
All raw materials, components, printed or unprinted commodities that
are used during the manufacturing or finishing process for Product.
Re-inspection
-------------
A visual or mechanical evaluation performed to remove or correct
defective units for which the process is not expected to have an
adverse effect on Product quality. Re-inspection should involve the use
of a deviation, or investigation, except where standard procedure
allows for such routine activity in the course of normal processing.
Page 5 of 17
Proprietary Information
-----------------------
Information owned by Cytogen or Laureate as defined in the Contract
Manufacturing Agreement.
A.6 Documents
Product Requirements
--------------------
Manufacturing and Product testing requirements utilized to release
Product to Cytogen These requirements have been approved in the Cytogen
BLA and will be adhered to in the manufacture, conjugation and filling
of the Product. Cytogen will provide the current, approved versions of
the test methods, SOPs, and specifications to Laureate prior to the
commencement of manufacturing or testing.
Product Specifications
----------------------
The chemical, physical, microbiological and biological test methods and
specifications required for the release of Product by Cytogen. These
specifications have been approved in Cytogen's BLA and will be provided
to Laureate by Cytogen prior to the commencement of manufacturing or
testing.
Commodity Specifications
------------------------
A composite of the specifications and testing instructions for raw
materials. It describes the chemical, physical, microbiological and
biological requirements of the raw materials. It also contains testing
instructions that are used to test the raw materials.
Summary of Specifications
-------------------------
A summary of specifications pertinent to the manufacturing, packaging,
labeling, testing and release of Product. Only Cytogen approved
specifications will be used.
Standard Test Method
--------------------
Describes uniform chemical testing procedures and equipment within
Laureate's laboratories. Only Cytogen approved methods will be used.
Printed Material Authorization to Label Documents
-------------------------------------------------
A summary of approved controlled labeling and stencil copy along with
implementation instructions for the manufacturing plant including an
Authorization to Label document signed by Cytogen prior to the
initiation of labeling activities. Only Cytogen approved labeling will
be used.
Page 6 of 17
B. Key Contacts
Cytogen* Laureate
-------- --------
Quality Assurance Quality Assurance
----------------- -----------------
Name John L. Tedesco 78 Mary Joan Hampson-Carlin
Title Director, Quality and Operations Executive Director, Quality Systems
Phone 609- 750- 8271 609 919 3375
Fax 609- 452- 2363 609 452 7653
E-mail jtedesco@cyctogen.com Mary.Hampson-carlin@laureatepharma.com
Product Complaints Product Complaints
------------------ ------------------
Name Maria P. Cimarusti Michiel Ultee, Ph. D.
Title Manager, Regulatory Affairs and Quality Sr. Director, Manufacturing
Assurance
Phone 609- 750-8288 609 919 3390
Fax 609- 452- 2363
E-mail mcimarusti@cytogen.com Michiel.ultee@laureatepharma.com
Commercial Manager, Labeling Commercial Manager, Labeling
---------------------------- ----------------------------
Name Maria P. Cimarusti Keith Smith
Title Manager, Regulatory Affairs and Quality Manager, Manufacturing
Assurance
Phone 609- 750-8288 609 919 3405
Fax 609- 452- 2363 609 452 7653
E-mail mcimarusti@cytogen.com Keith.smith@laureatepharma.com
*Either Cytogen contact may be used
1. Annual Product Reviews
Cytogen will handle annual Product Reviews. Laureate Pharma, when
requested, in writing will provide necessary information.
2. Annual Reports
Cytogen will handle Annual Reports. Laureate Pharma when requested in
writing will provide necessary information.
3. Drug Master Files
Laureate Pharma does not have a Drug Master File for its facility
4. New Submissions
Cytogen and Laureate will handle any new submissions under a separate
document.
Page 7 of 17
5. Deficiency Letters
Cytogen shall notify Laureate within 2 working days of receipt of any
deficiency letter that contains observations pertaining to Laureate
Pharma's manufacturing operations as they relate to Product, or in the
case of an investigation, within 2 working days of a determinant cause
involving Laureate's facility or operations. Cytogen shall provide a
copy of the deficiency letter to Laureate, redacted to exclude any
information proprietary to Cytogen. Cytogen shall submit a written
response to each minor observation to Laureate within 10 working days
of notification. Timing of responses to major observations will be
negotiated between Laureate and Cytogen on a case-by-case basis.
Laureate is only obligated to provide regulatory support in regard to
the systems and facilities at the Laureate site specifically used for
the manufacture of the Cytogen Product.
6. Audits and Re-Inspections
Cytogen may audit Laureate's facilities and systems one time each year,
such time being scheduled at least 2 weeks in advance and agreed upon
by both parties and such audit not to exceed 3 days in length, as they
relate to the manufacture of Product, with the exception of information
and operations regarded by Laureate Pharma as Proprietary Information.
Proprietary Information may include, but is not limited to, information
pertaining to proprietary products and/or processes developed and/or
owned by Laureate Pharma, and products and/or processes developed
and/or owned by other third party companies (client companies of
Laureate). Cytogen's Quality and Regulatory personnel may schedule a
visit and/or request Product specific documents (as defined by the
appropriate specification) for review to assure continued adherence to
the agreed upon manufacturing process, cGMPs and other applicable
requirements. Written communication will be used to document audit
observations and to resolve specific issues. Access to Laureate's
facilities for Product specific audits will be granted subject to
facility availability - for example, Regulatory Authority inspections
take the highest priority, and therefore the facility may not be
accessible at a given time for an audit by Cytogen
To assure adequate time and resources are provided for an audit, an
audit plan and audit duration must be agreed upon by the Quality
Assurance representatives of Laureate Pharma and Cytogen prior to
initiation of the audit. Where there is a periodic
re-certification/approval process, the requirements of the program must
be outlined herein. Cytogen will retain possession of all batch record
and ancillary documentation for each Product or subpart thereof. Audits
will therefore be limited to the Laureate Pharma facilities and process
systems only as they affect the Product.
Manufacturer Confidentiality
----------------------------
Laureate Pharma will maintain manufacturer confidentiality in all
audits, visits or reviews. All documentation reviewed remains the
property of Cytogen and is not for communication outside Cytogen and
Laureate unless otherwise agreed to in writing or required by law or
regulation. When utilizing a third-party consultant for periodic
audits, all confidentiality agreements must cover Laureate. Specific
confidentiality provisions are set forth in the Supply Agreement.
Resolution of Findings
----------------------
Cytogen will issue Laureate a confidential audit report summarizing any
and all audit observations. Laureate will issue responses to all
observations in writing to Cytogen Quality Assurance within 30 calendar
days of receipt, unless an alternate agreement is reached. Cytogen will
Page 8 of 17
be responsible for audit findings associated with the documentation
they retain. Laureate will be responsible for the facilities, personnel
and systems. Responses that are deemed not acceptable or incomplete or
inadequate, and impact either Laureate or Cytogen quality systems will
be reviewed with the respective Quality Assurance management and
commercial business representatives from both companies for resolution.
7. Regulatory Authority Inspections
Cytogen shall inform Laureate of any communication or action (e.g.,
telephone call, record or sample request, pre-approval inspection,
recall, etc.) initiated by a pharmaceutical Regulatory Authority (US or
international) as it pertains to the manufacturing of Cytogen's Product
at Laureate's facility within 1 working day of the occurrence.
Cytogen shall provide a copy of the Regulatory Authority inspection
report, deficiency letter, or regulatory compliance observations
redacted to exclude any Proprietary Information to Cytogen within 5
days of receipt. Laureate will be allowed to review and comment on
Product deficiency letter responses prior to Cytogen submission to the
Regulatory Authority.
8. Certificates of Analysis
A Certificate of Analysis (COA) will be generated for each batch of
Product manufactured for Cytogen. The COA will certify that Product was
manufactured in a cGMP compliant facility and was tested in accordance
with the batch record and associated specifications. COA's for Product
will contain the following information:
- Part number
- Lot number (as provided by Cytogen)
- Name of Product
- Name(s) of the test (s)
- Specification limit (s)
- Test result (s) as a numerical value unless designated Pass/Fail in
the specification limit (s)
- Signature indicting review by Laureate Quality Assurance and date
- Date of manufacture
- Expiration Date (as provided by Cytogen)
9. Product Dating
Laureate is responsible for labeling the primary package for Product
with dating information. Cytogen agrees that the following Product
dating information (to be completed as available) will appear on the
primary package:
Page 9 of 17
Country #1: United States
- Product Name:
- Expiration Date: (date format)
-------------
- Manufacturing Date: (date format)
-------------
- Lot Number: (number format)
---------------
- Storage Conditions
Cytogen is responsible for labeling the final product vials with
approved labels for the market. Such labels will include expiry-dating
information as determined by Cytogen.
Cytogen is responsible for obtaining approval to extend the expiration
dating of Product. If extension of the expiration dating is approved,
Cytogen will provide Laureate with a copy of the approval letter from
the respective Regulatory Authority. Laureate will then update Product
dating documents appropriately.
10. Stability Testing
Cytogen will be responsible for stability testing of raw materials,
intermediates and Product. Laureate will assume no responsibility for
any missed time points. Laureate will assume no responsibility for the
Regulatory Actions that may occur as a result of missed or failing
stability points.
In the event that Cytogen, through an amendment to the Contract
Manufacturing Supply Agreement or a separate agreement, contracts with
Laureate to perform stability testing, this Quality Agreement will be
amended accordingly and attached to that agreement and a specific
stability protocol will be established and approved by Cytogen and
Laureate.
11. Reserve Samples
Laureate shall maintain reserve samples of Product, under appropriate
environmental conditions, in concurrence with Product labeling if so
provided in the Supply Agreement. The number of reserve samples shall
be sufficient to perform all release tests twice except for sterility,
BET and the identification of objectionable microorganisms. The numbers
of reserve samples per batch shall be specified in the manufacturing
batch record. Reserve samples will be held for a minimum of one year
after Product expiration date provided the terms of the Supply
Agreement continue to be honored. Upon completion of the terms of the
Agreement, Laureate will aid Cytogen in the transfer of reserve
samples.
Reserve samples of the active and inactive ingredients used in the
manufacture of Product will be maintained in quantities similar to that
for Product. Active ingredients will be held for a minimum of three
years after receipt, or as specified above. Inactive ingredients will
be held a minimum of two years after receipt. If any ingredient is
retested (to extend expiration past one year) a new reserve sample will
be pulled and held with written approval from both companies.
Solvents, which do not appear in the final formula, compressed gases
and water, are not retained.
Page 10 of 17
All reserve samples will be inspected visually on an annual basis
provided the terms of the Supply Agreement are in effect.
12. Change Control
Laureate utilizes a documented Change Control procedure for the control
of changes to manufacturing components, packaging materials, labeling,
and the method of manufacturing, Product Specifications, and commodity
vendors. Any changes that affect the Cytogen specific materials must be
reviewed and approved by Cytogen and Laureate prior to implementation
and use.
When a change is known to require or has the potential to require a
regulatory submission Cytogen will develop a strategy to secure the
appropriate regulatory approval(s) in sufficient time for the change to
be implemented. The change may be approved and secured in Laureate's
documentation system prior to regulatory approval.
Batch record change control is governed by the guidelines and
procedures of Cytogen. Cytogen maintains the Master Batch Record,
issues Batch Records and is responsible for any changes to the Master
Batch Record. Cytogen will maintain original, executed batch records.
13. Equipment, Calibration and Preventive Maintenance
Laureate is responsible for calibration (where applicable), balance
verification, and maintenance of equipment utilized in the manufacture,
testing and release of Product.
IQ, OQ, PQ
----------
Laureate will perform appropriate installation qualification (IQ),
operational qualification (OQ), and/or performance qualification (PQ)
for the required classes of utilities and services used for the
production and control of Product. Periodic re-evaluation and/or
re-validation of equipment specific to Cytogen's Product (the [**]
purification unit only) are the responsibility of Cytogen and will be
conducted in conjunction with Laureate under a separate written
Agreement and in accordance with appropriate specifications/procedures.
Cytogen will be responsible for protocol and final report approval.
Documentation of such activities and/or schedule of revalidation shall
be the responsibility of Laureate. Documentation shall be reviewed and
approved by Cytogen for the [**] purification unit. Copies of Product
specific documentation will be made available at the request of
Cytogen. All other documentation, if so agreed to be provided, is
considered Confidential Information of Laureate and is not to be
divulged outside of Cytogen's control without prior written permission
by Laureate. Such document might include the annual re-certification of
the aseptic area, validation protocols for facilities and systems
common to the Product and other products, etc. These documents must not
to be used for submission or inspection purposes without the prior
written agreement of Laureate.
Page 11 of 17
Calibration & Preventative Maintenance - Commitment to Execute Program
----------------------------------------------------------------------
Laureate will maintain a calibration, preventative maintenance and user
standardization programs to support the manufacture and validation of
Product. Manufacturing and laboratory equipment calibration data will
be documented and made available upon request by Cytogen or a
Regulatory Authority. All equipment will be tagged, as appropriate, so
that the operating personnel are aware of the calibration status of all
equipment. Product specific documentation will be made available at the
request of Cytogen. All other documentation, if agreed to be provided,
is considered Confidential Information of Laureate and is not to be
divulged outside of Cytogen's control without prior written permission
by Laureate. These documents must not to be used for Submission or
Inspection purposes without the prior written agreement of Laureate.
Customer Notification of Significant Equipment Changes
------------------------------------------------------
Laureate will notify Cytogen of any significant reportable changes to
utilities, systems and equipment (e.g., HEPA filters, WFI systems,
autoclaves, etc.), including location of the equipment if different
from the location in the regulatory filing used for manufacture of
Product that may result in a change to the regulatory application,
prior to implementation.
14. Process Validation and Qualification
New Products Only
The process, manufacturing and control procedures (including cleaning
procedures, hold times, mixing studies, sterilization, etc.) shall be
validated and qualified by Laureate utilizing equipment and personnel
in the facility intended for manufacture of new products for Cytogen,
or changes to Product. This will be accomplished under a separate
Agreement.
For Validation of equipment or procedures requested by Cytogen,
Laureate will draft a Validation Protocol containing all required
activities, acceptance criteria and documentation and will submit the
protocol to Cytogen for review and approval. The Validation Protocol
will be executed on at least three (3) batches of new product or
changes to Product, unless otherwise agreed upon between Cytogen and
Laureate. Exceptions encountered during the execution of the Validation
Protocol will be documented and communicated within 30 days to Cytogen.
Exceptions that cannot be resolved may require the Validation Protocol
to be repeated on additional batches until at least three (3)
consecutive batches meet all specification requirements. Laureate must
document any exceptions encountered during the execution of the
Validation Protocol.
All related validation/qualification documents would be assembled in a
validation summary report and provided to Cytogen for review and
approval. Laureate would retain the original of the approved protocol
and final report.
Additional test methods may be developed and/or portions of validation
testing may be performed by Laureate and included in the Validation
Protocol. These commitments shall be detailed in the Validation
Protocol.
All validation work performed by Laureate in support of any new Cytogen
Product will be handled in a separate Supply Agreement. Any additional
validation work performed by Laureate in support of the current Product
will be handled in an amendment to the current supply agreement.
Page 12 of 17
15. Computer Systems and Software
Laureate shall use commercially reasonable efforts to validate computer
systems and associated software if used in the manufacturing,
packaging, storage or controls of Product. Revisions to computer
hardware systems and software packages shall be validated and recorded
in a revision history summary. All computer and software validation
packages, if used in the production of the Product, will be made
available upon request to Cytogen or a Regulatory Authority. Laureate
has a "Part 11 Compliance Plan" in place and is using its commercially
reasonable efforts to complete this program. Cytogen Corporation
acknowledges that the [**] purification unit that is used to purify
CYT-351 does not currently meet the requirements set forth in 21 CFR,
Part 11. Laureate presently does not intend to use the unit for
manufacture of any commercial products other than the purification of
ProstaScint for Cytogen.
16. Irradiation Facilities (not-applicable)
17. Components and Packaging Commodity Vendors
Cytogen Corp must approve components and packaging commodity vendors
used by Laureate in the manufacture of Product for Cytogen in
accordance with existing governmental regulations and Cytogen policies.
18. Labeling
Shipment of Unlabeled Product for Commercial Supply
---------------------------------------------------
Laureate will not ship Product without Cytogen's written authorization.
Shipment of trays of unlabeled Product vials will be performed
according to approved Cytogen procedures. The tray label will contain
Product-specific information (e.g., lot number, part number, etc.).
Laureate will perform a 100% verification of all containers prior to
packaging. Cytogen will perform a 100% verification upon delivery to
insure that each container bears the correct label prior to application
of the final labeling. Approved Cytogen procedures will be used for the
investigation of containers that do not pass 100% verification and for
the establishment and review of corrective actions.
Note: It is recognized that clinical materials could have different
specific labeling requirements.
19. Manufacturing Process
Laureate will manufacture Product in accordance with approved Cytogen
procedures. Excursions from such procedures will be documented by a
Deviation Report following Laureate's procedures and included in the
Page 13 of 17
batch record. Cytogen must approve the exception document prior to
final release of Product to the market (See section 21).
Laureate shall notify Cytogen of environmental action level outages
that negatively impact the manufacture of Product. Such outages will be
included in an investigation and an exception document within the batch
record that will require Cytogen approval prior to Product release.
20. Batch Size
Batch size is based on cell culture out put and has been consistent.
This topic is addressed in the supply agreement.
21. Deviations and Investigations
Laureate will utilize a documented exception reporting procedure (e.g.,
SOPs) for the identification and disposition of nonconforming materials
and/or processes used in the manufacture of Product. The procedure will
include processes for batch specific corrective actions and for
long-term preventive actions. The procedure will also include provision
and process for assuring the performance of adequate and appropriate
failure investigations.
Cytogen shall approve all deviations or investigations issued for a
specific batch or during the manufacture of Product. Product will not
be released to Cytogen until all Product related deviations and
incidents have been approved and closed. Investigations that are part
of the facilities and systems of Laureate will be shared with Cytogen
and will be closed prior to the release of a batch of Product. Laureate
will approve any facilities related deviations or incidents. Laureate
shall also approve all deviations and incidents and supply a copy with
each batch record.
22. Batch Adjustments and Re-inspection
Approval Requirement
--------------------
Cytogen and Laureate must have prior agreement on the execution of
batch adjustments.
Batch Adjustments
-----------------
Batch adjustments (e.g., pH) may be performed to adjust the bulk
Product solution within the range of an in-process control point.
Manufacturing directions must be established to define the process
criteria and adjustment prior to execution. Batch adjustments require a
documented deviation, and Product samples should be placed on stability
when appropriate.
Re-inspection
-------------
Re-inspection is performed when Product quality requires
re-verification. The re-inspection work shall be approved by both
Laureate and Cytogen and performed by Laureate according to established
procedures. A documented reason, justification and the results of the
re-inspection must be filed in the batch records.
23. Batch Records
A summary of all Product testing, lot release data and exception
documents (e.g., deviations) will be documented in the batch record.
The original batch records will be maintained in accordance with
Page 14 of 17
Cytogen retention requirements. Cytogen will retain all original batch
documentation.
Laureate will review and approve all batch records for Product prior to
release to Cytogen. Batch records are considered Confidential
Information for use by Cytogen and are not to be divulged to a third
party without prior written permission.
24. Product Testing and Lot Release
Final Product testing will be performed per the current version of the
Cytogen test methods and specifications in the Cytogen BLA.
Responsibility for Release of Product
-------------------------------------
Laureate is responsible for the Quality Assurance and technical review
of batch documentation for accuracy and completeness. Release of
Product for commercial or clinical use is the responsibility of
Cytogen. Laureate will not ship Product to any destination without the
prior written authorization of Cytogen.
In situations where Product is required to support a clinical study,
Laureate will implement sufficient controls such that clinical supplies
are accounted for and maintained at its facility until Cytogen
completes final Product release. Cytogen may distribute no clinical
supplies beyond Laureate's immediate facility/control until final
Product release.
Shipping & Receiving
--------------------
All units of manufactured Product will be accounted for prior to
shipping. All shipping quantities will be verified and signed at the
time of loading. The documentation of the shipping amounts will be
forwarded to Cytogen
Cytogen will verify received quantities, via a signature receipt and
adequate procedures, to ensure control of shipped material. A copy
confirming the receiving quantities will be forwarded to Laureate
Materials Management. Cytogen assumes responsibility for control of
Product once it leaves Laureate Pharma's facility.
Laureate assumes responsibility for proper packing and loading and will
provide an inspection of the shipment prior to release of the shipment
from its dock.
25. Contract Laboratories
Laureate maintains a comprehensive listing of approved third party
contractors who may be contracted to perform analytical services.
Laureate requires all contract laboratories to operate in compliance
with cGMP/GLP, compendia requirements and any other applicable
regulations. Under no circumstances will a contract laboratory
subcontract services to another laboratory without prior written
approval from Cytogen
26. Product Storage and Transportation
Product will be stored under conditions specified in Product labeling
and in a controlled area. If special storage conditions are agreed to
as part of the Supply Agreement, Laureate shall use commercially
reasonable efforts to maintain such conditions. Laureate shall be
responsible for establishment and maintenance of an environmental
monitoring program to document such specified storage conditions.
Page 15 of 17
In the event of an environmental condition that may impact the Product,
Laureate may move the Product to another suitable storage area.
Laureate shall notify Cytogen of the situation within one business day
of becoming aware of the event. Documentation of the event and
subsequent investigation will be performed in conjunction with
Cytogen's Quality Assurance Department upon their request.
27. Record Retention
Cytogen shall retain records pertaining to the manufacture of Product
according to their record retention program. Records retained by
Cytogen will include manufacturing batch record data, incoming,
in-process and final test data, stability records, customer complaints
and, customer, vendor and Regulatory Authority audits. Records of
Laureate Pharma's labeling, equipment and use logs, equipment and
process validation, software validation, preventative maintenance that
support the Cytogen Product must be retained permanently by Laureate
and shall not be destroyed.
28. Product Complaints
Cytogen will notify Laureate within 5 working days of verification of a
determinant cause of any product complaints that implicate Cytogen's
processes (e.g., manufacturing, filling, packaging and/or
distribution). Laureate Pharma, as requested by Cytogen, will conduct
internal investigations to determine the validity of the complaint.
Laureate will use commercially reasonable efforts to report the
findings of the investigation to Cytogen within 10 working days of
notification. Cytogen will be responsible for customer response
communications and for following their approved procedures for handling
product complaints. Medical Adverse Event Reports will be reported to
Laureate if a Product quality record review or analysis of a sample is
required, or if the Adverse Event is related to the manufacture of the
Product. Medical Adverse Event Reports are the responsibility of
Cytogen.
Any complaint received by Laureate for Product will be forwarded to
Cytogen within 2 business days via phone or written communication. This
communication will be directed to those specified in Section B
"Contacts" of this document.
29. Returned Goods
Handled through a distributor.
30. Field Alerts and Recalls
Cytogen and Laureate must notify each other within 2 working days of
confirmation of the event, by telephone or other rapid communication
means, when there is information concerning any Product issues that may
impact the quality, purity, safety and effectiveness of Product in the
field. Examples of such information include any bacterial
contamination, stability failure, certain confirmed Product complaints
or any significant chemical, physical or other change or deterioration
in the distributed Product.
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In the case where a Field Alert or Recall is deemed necessary, Cytogen
will develop the strategy. Cytogen will be responsible for the
initiation, implementation and support of the recall.
In the event that inventory of the subject material remains at the
Laureate facility, Laureate is responsible for providing to Cytogen a
comprehensive list of the remaining quantities on a monthly basis and
for placement of the Product in quarantine if so requested by Cytogen.
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