Exhibit 10.13.5
---------------
QUALITY AGREEMENT
between
INyX PHARMA LIMITED
and
STIEFEL LABORATORIES INC.
Date: March 6, 2003
For INyX Pharma Limited /S/ Colin Hunter
Position: Director
For Stiefel Laboratories Inc. /S/ Tessie L. Brunker
Position: Vice President, CFO and Treasurer
Table of Contents
Page
----
1.0 General Quality Policies.................................................4
2.0 Documentation Practices..................................................5
2.1 Regulatory Filings...............................................5
2.2 Technology Transfer..............................................5
2.3 Controlled Documents.............................................5
2.4 Change Control...................................................6
2.5 Deviations, Non-Conformances, and Failure Investigations.........7
2.6 Document Retention...............................................8
2.7 Customer Complaints..............................................8
2.8 Annual Product Review............................................9
2.9 Annual Reports...................................................9
2.10 Training.........................................................9
3.0 Manufacturing Standards.................................................10
3.1 Facilities......................................................10
3.2 Equipment.......................................................10
3.3 Material Control................................................10
3.4 Manufacturing / Cleaning........................................11
4.0 Inspection and Testing Requirements.....................................11
4.1 Inspection......................................................11
4.2 Quality Control Testing.........................................12
4.3 Stability Program...............................................12
5.0 Audits 13
5.1 External Audits.................................................13
5.2 Internal Audits.................................................13
5.3 Vendor/Supplier Qualification Program...........................13
6.0 Product Release.........................................................14
6.1 Batch Manufacturing Record......................................14
6.2 Analytical Results..............................................14
6.3 Certificate of Analysis and Certificate of Conformance..........14
6.4 Reserve Samples.................................................14
6.5 Release Authorization and Shipping..............................15
INTRODUCTION
As a condition of business, Stiefel Laboratories Inc (a New York
corporation with its principal place of business at 255 Alhambra Circle, Coral
Gables, Florida 33134) requires that all Products be manufactured in accordance
with all appropriate current Good Manufacturing Practices (cGMP's) as described
in 21CFR part 211 and other pertinent regulatory authority requirements) and all
applicable international, federal, state and local regulations.
This Quality and Technical Agreement between Stiefel Laboratories Inc
("Stiefel") and INyX Pharma Limited ("INyX") (located at Runcorn, England)
defines Quality responsibilities as they are related to the formulation and
filling/packaging of Stiefel Products in accordance with the terms of that
certain Supply Agreement, as amended, which currently exists between the
parties. This Agreement shall be effective Tuesday, March 6th, 2003. In the
event of any conflict between the interpretation of this Agreement and the
interpretation of the Supply Agreement (as it may be amended from time to time),
the terms of the Supply Agreement shall govern all aspects of the relationship
between the Parties except that this Agreement shall govern with respect to
quality matters.
A Generalized Process and Control Flow Diagram describing the general
flow of Product through the INyX facilities is enclosed as Schedule A to this
Agreement.
Changes to this Agreement may be made solely by an amendment in writing
signed by both parties.
DEFINITIONS
All capitalized terms herein shall have the same meanings as are
ascribed to such terms in the Supply Agreement, unless otherwise defined herein.
For the purposes of this Agreement, the following terms shall have the
meanings set forth below:
"Annual Product Review": The review of manufacturing and control
activities to be undertaken on an annual basis as defined by 21 CFR Part 211.
"Active Ingredient": Any component of the Product that is intended to
furnish pharmacological activity or other direct effect in the diagnosis, cure,
mitigation, treatment, or prevention of disease, or to affect the structure or
any function of the body of man or animals, but does not include intermediates
used in the synthesis of such ingredients.
"Batch Record": An accurate reproduction of the Product Master Batch
Record, checked for accuracy, dated and signed by INyX.
"Batch or Production Lot": A specific quantity of Active Ingredient,
excipients, and components processed in accordance with the Product Master Batch
Record and identified by a distinctive lot number.
"Bulk Product": A drug Product that has been manufactured but not
filled or packaged into a final dosage presentation.
"C of A" or "Certificate of Analysis": A summary of the quality control
testing, as described in the Specifications, performed by INyX for Finished
Product supplied under this Agreement.
"C of C" or "Certificate of Conformance": A written certificate issued
by INyX stating that the final Finished Product has been manufactured under
appropriate cGMP requirements and that no outstanding deviations or
non-conformances remain unresolved.
"cGMPs": The current Good Manufacturing Practices of FDA, as set forth
in Title 21 of the U.S. Code of Federal Regulations, Part 211.
"CMC": The Chemistry, Manufacturing and Controls section of an NDA.
"Change": A planned, permanent alteration or replacement of an
established or validated specification, process, existing equipment type,
service, or facility used in the manufacture of bulk or finished Product.
"Stiefel Quality Assurance": The Quality Assurance department of
Stiefel.
"Date of Manufacture": Date of introduction of the Active Ingredient
into the manufacturing process.
"DMF" The Drug Master File for a Product, as filed by Miza with the
FDA.
"Excipient": Any substance other than the Active Ingredient present in
the Product.
"FDA": The Food and Drug Administration of the United States of
America.
"FDA483": Any FDA Form 483 to review observational findings by FDA
delivered following the inspection by the FDA.
"Finished Product": The finished dosage form that contains the
ingredients and packaging components as specified by the Master Batch Record.
"IND": An Investigational New Drug Application for a Stiefel Product,
as filled by Stiefel with the FDA.
"Manufacturing and Supply Agreement": Agreement between INyX and
Stiefel Labs for the Commercial manufacture of the Products in Exhibit A.
"Master Production Record": A written document, approved by both INyX
and Stiefel QA, which stipulates the unique Product formula and provides
detailed instruction for the manufacture, filling, and packaging of individual
Products.
"NDA": A New Drug Application for a Stiefel Product, as filed by
Stiefel with, and approved by, the FDA.
"Non-Conformance": A departure from an established quality standard.
For the purposes of this Agreement, an "established quality standard" includes
any GMP Standard Operating Procedure, manufacturing work order, packaging order,
raw material or Product specification, analytical control procedure, water
monitoring procedure, and/or equipment maintenance schedule, or any unusual
occurrence as may be defined in INyX non-conformance procedures).
Non-conformances may be either anticipated or unanticipated departures from
established quality standards; may have the potential to affect the safety,
identity, strength, quality or purity of a bulk or Finished Product.
"OOS": Out of Specification
"Product Master Batch Record": The signed master copy of the Product
Batch Record.
"Primary Packaging Component": That portion of the container/closure
system which is in direct contact with the Product at all times, as well as all
other container materials which could reasonably affect the identity, strength,
quality or purity of the Drug Product during its shelf life.
"Product Batch Record File": The compilation of batch-specific batch
records, test and inspection reports, non-conformance and deviation files, and
other associated records that fully describe the manufacture and testing of a
single lot of Product.
"Product(s)": means the Products described on Exhibit A to the
Manufacturing and Supply Agreement between INyX and Stiefel, as it may be
amended from time to time, and which is incorporated by this reference as though
fully set forth in this paragraph.
"Quarantine Shipment Authorization": A written request and
authorization from Stiefel QA for INyX to prepare and ship a lot of Product that
has been completed, tested, and internally reviewed by INyX QA.
"Regulatory Authority": means the MCA / FDA and any equivalent or
additional governmental or regulatory agencies having authority over INyX,
INyX's facilities, or the Products including, but not limited to, the MCA in
Europe and the U.S. Drug Enforcement Agency.
"Release Memo": Stiefel final release authorization prepared, approved,
and issued by Stiefel QA after review of all relevant batch Production and
testing records.
"SOP" or "Standard Operating Procedure": Written document, approved by
QA, which provides instruction on performing tasks essential to the operation of
a facility or process.
"USP": The most current edition of the United States Pharmacopoeia,
including any revisions.
"Validation": Documented evidence that the process consistently
produces a Product or result that meets its predetermined quality requirement.
1.0 General Quality Policies
INyX is a pharmaceutical manufacturer that holds an appropriate
Manufacturing License authorization and license for the Product(s) that
are the subject of this Agreement. Any changes in the place of
manufacture of the Products, including changes made under that
Manufacturing License, require the prior agreement of Stiefel Quality
Assurance. In addition, while maintaining other client confidentiality,
INyX shall inform Stiefel without delay of any restrictions to the
manufacturing authorization and license for the Products covered by
this Agreement or for any other Products which may affect the Products
covered by this Agreement.
In the manufacture of all Products, INyX shall abide by cGMPs and
applicable international or local regulations as they may apply to the
Products subject to this Agreement.
INyX shall take all appropriate precautions within the
manufacturing/filling, warehouse, or Product testing facilities to
prevent actions which may adversely affect the quality of Products
manufactured for Stiefel.
In the event of a Product recall or field alert (or other activity
relating to Product quality) INyX shall facilitate access to
manufacturing, analytical, storage, or shipping records as may be
required to develop an appropriate regulatory strategy. Stiefel shall
be responsible for coordinating all Product recall activities, as set
forth in greater detail in the Manufacturing and Supply Agreement.
INyX shall operate a Quality Assurance Unit which has specific
responsibilities and authorities including review and approval of
materials and Products, investigation of deviations and
Non-Conformances, and approving procedures and specifications impacting
on the identity, strength, quality and purity of Drug Products.
Stiefel and INyX shall each identify key quality personnel who will be
responsible for specific areas of Quality Assurance activities,
including quality control, stability, Product release, and resolution
of quality issues.
2.0 Documentation Practices
2.1 Regulatory Filings
2.1.1 INyX shall maintain appropriate U.K., EU, or local licenses
required for the manufacture of pharmaceutical Products.
2.2 Technology Transfer
2.2.1 Stiefel shall provide INyX with Product manufacturing and
testing instructions and specifications, and a representative
of Stiefel shall (at Stiefel's Cost) in the technology
transfer and implementation of the manufacturing, packaging or
testing process.
2.2.2 When appropriate, Stiefel and INyX shall jointly develop a
written technology transfer plan that clearly stipulates
responsibilities, accountabilities, and timelines for
technical transfer activities.
2.3 Controlled Documents
2.3.1 INyX manufacturing and analytical documentation practices
shall be subject to frequent review by both parties to ensure
compliance with the most current recognized interpretation of
cGMPs for the appropriate phase of Product development or
commercial manufacturing.
2.3.2 Standard operating procedures, specifications, test methods,
and Master Batch Production Records shall be consistent with
the ANDA filing and any subsequent supplements
2.3.3 Stiefel and INyX shall be jointly responsible for the approval
of controlled documents (specifications, test methods,
stability protocols, batch records, etc.) will be established
and approved for use.
2.3.4 Stiefel shall provide all necessary source data to facilitate
the completion of relevant specifications, etc. INyX shall
provide for review and signature approval by Stiefel for the
following documents prior to implementation, and any
subsequent changes must be made in accordance with the change
control procedures set forth in Section 2.4:
o Master Production Records
o Specifications for Finished Product, Active
Ingredient(s), Excipients, primary containers, and
labeling materials.
o Test methods for active drug substance, intermediate
and Finished Product, cleaning evaluation
o Stability protocols and monographs
o Process validation and cleaning validation protocols
and reports
o Test methods validation protocols and reports
o Technical protocols and reports specifically relating
to Stiefel Products
2.4 Change Control
2.4.1 INyX change control procedures shall address, when
appropriate, , computer systems, validated equipment,
facilities and utilities, personnel training, in-process
controls, laboratory instrumentation and methods, materials
specifications, printed components, validated manufacturing
processes, engineering drawings, and standard operating
procedures.
2.4.2 All proposed changes to controlled equipment or documents
pertaining to the Products shall be reviewed and approved by
INyX QA and Stiefel QA, and shall be made in accordance with
INyX change control procedures.
2.4.3 In addition, INyX shall notify Stiefel of the following
changes prior to implementation:
o Major equipment, utilities and facility modifications
that materially impact on Stiefel Products
o Specifications and test methods changes for
non-compendial Excipients
o Test method changes for packaging components
o Changes to standard operating procedures that have
significant impact on Stiefel Products, other than
changes which require Stiefel's approval pursuant to
Section 2.4.2.
2.4.4 INyX shall provide Stiefel with controlled copies of changed
documentation within ten (10) working days of issuance for use
within INyX's facilities. Specifically:
o Specifications for Finished Drug Product
o Specifications for raw material including active drug
substance
o Specifications for packaging components
o Test methods for active drug substance, intermediate
and finished drug Product, and cleaning evaluation
o Master Production Records (non-controlled copies
acceptable)
2.4.5 INyX shall provide Stiefel with reference copies of the
following approved documents:
o Stability protocols and monographs
o Process validation protocols and reports
o Cleaning validation protocols and reports
o Test methods validation protocols and reports
o Technical protocols and reports relating to Stiefel
Products
2.5 Deviations, Non-Conformances, and Failure Investigations
2.5.1 INyX shall not deviate from the manufacturing procedure
identified in the ANDA and shall not introduce any significant
changes in the manufacturing or testing procedure without
prior approval from Stiefel.
2.5.2 INyX shall have in place a written procedure describing the
criteria and process by which deviations and non-conformances
relating to the manufacture, processing, packaging, testing,
or storage of drug Product or its associated components that
may affect the safety, efficacy, quality, or purity are
investigated, evaluated, reviewed and dispositioned.
2.5.3 In the absence of an approved SOP specifically describing the
nature of major or minor non-conformances, INyX QA and Stiefel
shall jointly agree if a deviation or non-conformance is of a
major or minor nature. Refer to Schedule B for a list of minor
deviations or non-conformances. Non-conformances not listed on
Schedule B shall be considered as Major.
2.5.4 For minor deviations or non-conformances, documentation and
resolution shall be included in final batch Production package
sent to Stiefel for review.
2.5.5 For major deviations or non-conformances, where possible, INyX
shall immediately notify the designated person within Stiefel
prior to proceeding or continuing with Production. If this is
not feasible, INyX shall notify Stiefel QA as soon as possible
and prior to INyX QA disposition of the non-conformance..
2.5.6 All deviations and non-conformances will be summarized and the
summary included in the batch Production package provided to
Stiefel.
2.5.7 INyX shall maintain procedures that describe the roles and
responsibilities and activities to be employed for the
investigation of Out-of-Specification results,
out-of-tolerance calibrations, and any unusual occurrences
which require QA investigation beyond normal non-conformance
reporting requirements.
2.6 Document Retention
2.6.1 All documentation relating to the manufacturing, holding or
testing of Stiefel Products, whether in paper or electronic
form shall be retained by INyX for a period of three (3)
years, or one (1) year past the expiration date of the most
recent associated Product, whichever is longer. During this
period, this documentation shall be available for inspection
by Stiefel or by an authorized agent designated by Stiefel.
Notwithstanding the foregoing, INyX shall not willfully
discard or destroy any such documentation during this period.
Thereafter, INyX shall contact Stiefel to determine the
disposition of said documentation as follows:
o Return of the documentation to Stiefel
o Extended storage of documentation
o Disposal of documentation (a formal written request
from Stiefel is required before disposal).
In either event a written request from Stiefel shall determine
disposition. Documentation shall include receiving records,
materials releases and supplier C of A's, packaging component
inspection records, equipment cleaning records, and batch
documents including line clearances, batch production records,
inspection results, yield and reconciliations, deviations and
Non-Conformances, test results and final Product C of A's and
C of C's.
2.6.2 INyX shall retain all other documentation relating to the
manufacturing, holding or testing of Stiefel Products in
accordance with INyX's internal document retention policies.
2.7 Customer Complaints
2.7.1 Stiefel shall notify INyX of customer complaints received
after Product manufactured by INyX is sold, where the
complaint appears to relate to the manufacturing, filling, or
packaging of the Products. At Stiefel's request, INyX shall
conduct internal investigations necessary to determine the
validity of a complaint. INyX shall report the findings of the
investigations to Stiefel QA within thirty (30) days time of
sample return or notification, whichever is later. Where
conclusive investigation is not practical within a 30-day
period, INyX shall provide Stiefel with an interim report as
soon as practical.
2.8 Annual Product Review
2.8.1 INyX shall provide data and on-site assistance to enable
Stiefel to perform the annual Product quality reviews
appropriate to the Product type and stage of development or
commercialization. An annual product quality review summary
report with updated statistical process analysis information
shall be provided to Stiefel no less than thirty (30) calendar
days before the due date of the Annual Report for the Product,
which is due on the anniversary of the date the FDA approved
the Product for commercial sale. Refer to Schedule C for a
detailed listing of the activities and format that shall be
addressed in the Annual Product Review.
2.8.2 As part of the annual product review process, Miza shall have
procedures in place to perform annual statistical trend
analysis of all critical raw material, component, in-process,
and final product test results associated with Stiefel
Products. This procedure shall be used to assess the possible
need for changing the raw materials', components' and product
acceptance sampling, inspection and testing requirements.
2.9 Annual Reports
2.9.1 INyX shall provide Stiefel with information necessary for
Stiefel to prepare annual reports for submission to any
Regulatory Authorities. In addition to the information
provided pursuant to Section 2.8.1, InyX shall provide Stiefel
with the descriptions of any CMC change which occurred during
the reporting period, reports on quality investigation, and an
evaluation of stability data. Any information required by this
Section 2.9.1 other than the information included in the
annual product quality review summary report discussed at
Section 2.8.1 must be requested by Stiefel no less than thirty
(30) days before Stiefel must report the information.
2.10 Training
2.10.1 The personnel employed in the manufacture and quality control
of Stiefel Products shall be suitably trained, experienced and
competent for their respective functions.
2.10.2 INyX shall maintain a documented training program to assure
all personnel engaged in the manufacturing, filling,
packaging, shipping and distribution of Stiefel Products have
the education, training, and experience to properly perform
their assigned functions in compliance with cGMP requirements.
2.10.3 INyX shall maintain a system to assure that changes to
controlled documents are conveyed to appropriate personnel and
that training on these changes is successfully completed prior
to the effective date of the change.
3.0 Manufacturing Standards
3.1 Facilities
3.1.1 INyX shall ensure that the buildings and grounds are
maintained in a manner that avoids pest attraction and
ingress. Additionally, pest control servicing of the facility
against insects and rodents shall be scheduled on a routine
basis. All pesticides or fumigants shall be kept in a locked
storage area. Physically separated from any product or raw
material storage area when not in use, and shall be utilized
and controlled so as to preclude contamination of Stiefel
Products.
3.2 Equipment
3.2.1 INyX shall perform appropriate facility and support system
qualifications to maintain the state of cGMP compliance for
all systems supporting manufacturing operations appropriate
for the stage of development or commercialization of Stiefel
Products.
3.2.2 INyX shall perform appropriate installation, operation and /or
performance qualification for all equipment and utilities used
for the Production and control of Stiefel Products.
3.2.3 INyX shall approve all installation and operational
qualification protocols and reports for equipment that is
dedicated to Stiefel Products, including any subsequent
revisions and/or amendments.
3.2.4 INyX shall have in place a written program of calibration and
preventative maintenance. All equipment shall be appropriately
tagged as to its calibration status in line with INyX internal
calibration policy.
3.3 Material Control
3.3.1 INyX shall have written procedures to describe receiving,
sampling, reconciliation, coding and inspection operations for
all materials received and intended for use in Stiefel
Products.
3.3.2 Raw Materials (Active and Excipient) and components used for
the production of Stiefel Products shall be of the appropriate
quality as specified in approved specifications ( as specified
by Stiefel and implemented by InyX) and be sourced from
approved vendors. The procedures outlined in Section 2.4 shall
be followed in the event that INyX is informed of any proposed
processing changes to an active ingredient or a primary
packaging component, and in the event that Stiefel proposes to
change an Active Ingredient or excipient supplier or primary
packaging component. The procedures outlined in Section 2.5
shall be followed in the event that any non-conformance is
encountered during the storage or control of raw materials,
components, or finished Product.
3.3.3 INyX shall have clearly defined, labeled and secured areas for
quarantined, rejected and approved materials, as appropriate.
There shall be a well-defined written system for
identification of materials according to Product type, lot
number, and status.
3.3.4 Raw Material, bulk and finished goods storage conditions shall
be determined by specification or Product labeling.
Environmental controls or monitoring shall be in place to
ensure compliance with appropriate storage conditions.
3.3.5 Raw Material retest frequencies and attributes shall be
described in the appropriate raw material specification. INyX
and Stiefel shall agree an SOP to be followed to extend the
shelf-life of the raw material used for Stiefel Products.
3.4 Manufacturing / Cleaning
3.4.1 INyX shall provide Stiefel with a copy of the completed Master
Production Record (in the form approved by Stiefel pursuant to
Section 2.4.4) providing a sufficient level of detail for the
manufacture and control of Stiefel Products.
3.4.2 INyX shall perform appropriate process validation a frequency
as reasonably required by Stiefel QA. 3.4.3 INyX shall issue a
Batch Record, according to cGMP requirements, for every
production batch of Product.
3.4.4 INyX shall perform appropriate cleaning validation of
equipment as part of technology transfer or process validation
activities. All analytical methods used to verify cleaning
shall be appropriately validated and approved by INyX and
Stiefel as agreed with Stiefel QA.
3.4.5 Cleaning validation shall include detailed cleaning procedures
with appropriate sampling techniques to determine Product
residue and cleaning agents, if used. The cleaning validation
shall address the potential of cross contamination of any of
Stiefel Product produced by INyX with other of INyX
manufactured Products and vice versa.
4.0 Inspection and Testing Requirements
4.1 Inspection
4.1.1 Consistent with Section 3.3, INyX shall have written
procedures for inspections that adhere to recognized standards
(e.g., military standards, industry guidelines, etc.) in
conformance with cGMPs.
4.1.2 Incoming raw materials (active and inactive), packaging
components, as well as in-process and Finished Products, shall
be included in inspection programs. Documentation of all
inspection results shall become a part of the permanent Batch
Record or otherwise traceable to a separate storage location.
4.2 Quality Control Testing
4.2.1 INyX shall perform full specification testing on all raw
material and components per approved specifications. With
prior written approval from Stiefel QA, reduced testing may be
allowed for excipient and packaging components, provided that
vendor has established a good performance record and
certification has been completed and approved by Stiefel.
4.2.2 INyX shall test all raw materials and Products using approved
/ validated methods and specifications. For USP Compendia
items, USP methodology must be used for all testing unless
specified otherwise in the regulatory filing or as directed in
writing by Stiefel.
4.2.3 USP/BP/EP and other official pharmacopoeia reference standards
used in material or Product analysis shall be the approved
authentic specimens and suitable for use as comparison
standards in compendia tests and assays. INyX shall maintain
procedures for defining the release and control of reference
standards utilized for the testing of Stiefel Products.
4.2.4 There shall be written procedures in place for investigation
and disposition of out of specification or abnormal testing
results.
4.2.5 INyX shall not subcontract to third parties any of the work
covered by this Agreement without the prior written consent of
Stiefel not to be reasonably withheld.
4.3 Stability Program
4.3.1 When stability programs are carried out at INyX, INyX shall
have in place written procedures to ensure the validation,
calibration, and maintenance of the stability chambers.
4.3.2 Raw data shall be made available in a timely manner for review
by Stiefel. INyX shall communicate any aberrant or failing
results to Stiefel' Quality Control department within three
(3) working days after INyX completes the out-of-specification
investigation.
4.3.3 INyX and Stiefel shall jointly develop and approve a stability
protocol and determine individual company responsibilities of
reporting and evaluation of data. Refer to Schedule D for a
list of testing data requirements.
5.0 Audits
5.1 External Audits
5.1.1 Stiefel shall periodically audit INyX by scheduling an agreed
visit with InyX at least annually, and/or requesting documents
for review to assure continued adherence to the agreed
manufacturing process, cGMPs and other applicable
requirements. Written communication shall be used to document
audit observations and to resolve any identified issues.
Stiefel may use the services of outside contractors to assist
in the audit process in agreement with INyX. Any audit
requested pursuant to this Section 5.1.1 shall be requested in
advance, with no less than thirty (30) days' notice to INyX
and, to the extent practical, shall be conducted during INyX's
normal working hours (without unduly interfering with INyX's
business).
5.1.2 INyX shall ensure that any deficiencies highlighted during the
audit will be dealt with in a prompt manner following receipt
of an official signed Audit Report from Stiefel. Audit
response with action items, assigned responsibilities, and
timelines will be forwarded to Stiefel within forty-five (45)
working days of receipt of the formal audit report.
5.1.3 INyX shall inform Stiefel of any action taken by a Regulatory
Authority (including telephone conversation, inspection,
FDA483, recall action, etc.) as it may affect the
manufacturing, filling, and distribution of any of Stiefel
Products produced by INyX. During an inspection that involves
any Stiefel Product at which no representative of Stiefel is
present, INyX shall provide Stiefel QA with timely updates
detailing the particulars and issues raised which may affect
the quality or marketability of Stiefel Products. Likewise,
Stiefel shall inform INyX of any action proposed against
Stiefel by a Regulatory Authority which may have impact on
INyX's contract manufacturing operations or business
relationships.
5.2 Internal Audits
5.2.1 INyX shall have in place written procedures intended to ensure
internal monitoring that manufacturing, testing, quality
assurance, packaging, holding and distribution operations are
in compliance with cGMP requirements. These records shall be
available for review by Stiefel.
5.3 Vendor/Supplier Qualification Program
5.3.1 INyX and Stiefel shall jointly be responsible for developing
and implementing a vendor qualification program for all
materials used to manufacture and/or package Stiefel Products.
Such programs shall be described in an SOP, or series of SOPs,
and should address the supplier's ability to adhere to
appropriate cGMPs, that analytical methods used are
appropriate, and that starting materials are adequately
examined and controlled. In addition, such procedures shall
describe the testing requirements for qualifying a new source
of raw material or component.
6.0 Product Release
6.1 Batch Manufacturing Record
6.1.1 For each batch of Product, INyX will provide Stiefel with a
Product Batch Record File, which provides a detailed history
and record of the Production run.
6.1.2 The Product Batch Record File provided to Stiefel shall be
complete such that all documentation required to perform a
thorough review of a Production run are present.
6.1.3 Stiefel and INyX shall jointly and specifically develop the
details of the Batch File and how it is to be conveyed to
Stiefel for final review prior to release of the Product.
Refer to Schedule D for a list of documents to be included in
the Product Batch Record File.
6.2 Analytical Results
6.2.1 Data acquired from analytical and physical testing performed
by the Quality Control Laboratory(ies) shall be reviewed and
approved by the INyX Quality Assurance Unit.
6.2.2 Stiefel and INyX shall jointly determine and specify the type
and level of raw data that will be included in the Product
Batch Record File which is forwarded to Stiefel for final
review. Refer to Schedule D for testing data requirements to
be submitted with the Product Batch Record File.
6.3 Certificate of Analysis and Certificate of Conformance
6.3.1 Upon review of testing results by the Quality Assurance Unit,
INyX shall prepare a Certificate of Analysis detailing the
results of all testing performed on the Final Product. Such C
of A will be approved by responsible Quality Assurance
personnel and forwarded to Stiefel as part of the Product
Batch Record File.
6.3.2 Upon review of the completed Batch Record by its Quality
Assurance Unit, INyX shall prepare a Certificate of
Conformance verifying that the Final Product has been
manufactured under appropriate cGMP requirements and that no
outstanding deviations or Non-Conformances remain unresolved.
Such C of C will be approved by responsible Quality Assurance
personnel and forwarded to Stiefel as part of the Product
Batch Record File.
6.4 Reserve Samples
6.4.1 INyX shall retain adequate representative samples of each
batch or lot of raw materials and packaging components used in
the manufacture of the final Product to enable their
subsequent testing, in duplicate, against approved
specifications. Such samples shall be retained for a period of
no less than one (1) year past expiration date of the last
batch of which that material was used.
6.4.2 INyX shall maintain Final Product reserve samples or any other
samples which may be required to enable their subsequent
testing, in duplicate, against approved Finished Product
Specifications. Such samples shall be retained for a period of
no less than one (1) year past the expiration date of the lot.
6.4.3 Unless otherwise stated in approved Batch Records, INyX shall
provide Stiefel with 36 units of Finished Product as customer
samples (12 Start, 12 Middle, and 12 End). These samples
should be labeled as "Customer Samples" and forwarded to the
designated Stiefel responsible person within thirty (30) days
of the date of release of the lot.
6.4.4 INyX shall be responsible for the examination of reserve
samples as part of the annual Product review described at
Section 2.8.1 above. The examination shall be conducted as
required by Title 21 U.S. Code of Federal Regulations Section
211.170, and the results of the examination shall be
communicated in accordance with Section 2.8.1 of this
Agreement. Provided InyX allows Stiefel access to reserve
sample storage, Stiefel will assist with the examination of
reserve samples.
6.5 Release Authorization and Shipping
6.5.1 The Quality Assurance Unit of INyX is responsible for internal
release of the Final Product to Stiefel.
6.5.2 Based on review of the Product Batch Record and Stiefel's own
internal release procedures, Stiefel QA is responsible for the
final disposition of the Product to market.
6.5.3 Stiefel QA shall communicate the release of batches to InyX QA
via authorization in the form of a release memo accompanied by
a Stiefel Certificate of Analysis.
6.5.4 In some instances Stiefel may request INyX to ship reviewed
but not yet released Finished Product to Stiefel distribution
center or other firms for the purposes of further processing
or packaging and labeling. In such instances, Stiefel QA will
provide INyX QA with specific written authority and
instructions for shipping under quarantine conditions.
6.5.5 INyX shall have in place an SOP that adequately describes the
requirements and procedures necessary to ship Product and
samples to Stiefel utilizing transportation as directed by
Stiefel.
INDEX OF EXHIBITS
-----------------
Schedule A Generalized Process and Control Flow Diagram
Schedule B List of Minor Deviations
Schedule C Requirements for Annual Product Review
Schedule D Analytical Data Requirements
Schedule E Batch Production Record File
Schedule A
Generalized Process and Control Flow Diagram
Schedule B
List of Minor Deviations
The following non-conformances are considered as "Minor" and do not require
Stiefel's immediate notification:
o Typographical errors in official approved documents that do
not affect the form, fit or function of the intended document
o Deviations from scheduled maintenance or calibration schemes
for equipment used to manufacture or test Stiefel Products,
provided that INyX QA Group has evaluated the consequence of
such deviation and determined that Product quality, safety or
efficacy has not been materially compromised
o Reconciliation of excipient raw material beyond approved
range, provided that INyX QA Group has evaluated the
consequence of such deviation and determined that Product
quality, safety or efficacy has not been materially
compromised
o OOS that have been conclusively determined to be the result of
laboratory error
o Deviations resulting from minor machine adjustment that may
result in rejected Product
o Deviations from Standard Operating Procedures that do not have
a bearing on Product quality
Schedule C
Requirements for Annual Product Review
o Reference: 21CFR170(b) and 180(e)
o All batches manufactured and filled to Anniversary Date
Table of Contents
A. Approval Page
B. Introduction
C. Retain Samples Examination (n= to be determined by procedure)
o Table A
o Visual examination for can corrosion or leakage
D. Batch Document Review
1. Raw Material and Component Review
o Table B
o Non-conformances
o Evaluation against specification limits
2. Bulk Manufacture
o Table C
o Non-conformances
o Evaluation against specification limits
3. Filling
o Table D
o Non-conformances
o Evaluation against specification (table)
4. Finished Product Evaluation
o Table E
o Non-conformances
o Evaluation against final Product specifications including AQL
5. Method Change Review
o Table F
o Evaluation and discussion
6. Process Change Review
o Table G
o Evaluation and discussion
7. Components Documents Review
o Table H
o Evaluation and summary of changes
8. Equipment and Facility Qualification Changes
o Table I
o Evaluation and discussion
9. Stability Evaluation
o Evaluation and discussion
10. Product Complaints
o Table K
o Evaluation and discussion
E. Summary and Conclusion
Typical APR Evaluation Table Headers
Schedule D
Analytical Data Requirements
Schedule E
Product Batch Record File
o Certificate of Analysis
o Certificate of GMP Compliance
o Stiefel's comments and INyX response
o In-Process Specification and Test Result Packet
o Deviation Report Summary
o Individual Deviation Reports
o Manufacturing Batch Production Record
o Engineering Ste-Up Sheet Document
o Filling Batch Production Record
o IPC Filling Record
o Analytical Data Packet
o Cleaning Report
o Authorization to Ship in Quarantine (if any)
o Shipping Documents