TEVA Quality Standard Manual

Chapter 5 – Materials and Products

5.1 Manufacturer Qualification Program

A manufacturer qualification program shall be in place to ensure that manufacturers are
subjected to a formal approval process. The program relates to each specific material-
manufacturer combination and covers suppliers of the following materials:
• Active pharmaceutical ingredients (APIs)
• Hard gelatin capsules
• Primary packaging Materials
• Printed packaging materials
• Major excipients
• Major secondary packaging materials

The Pharmaceutical Development, Quality Assurance, Quality Control, Regulatory Affairs

and Purchasing departments are responsible for the implementation of the program.

5.1.1 Manufacturer Selection

• The name and street address of the manufacturer shall be known
• The manufacturer must submit a completed, acceptable questionnaire
• A sample of material is tested and approved, including a comparison between
the TEVA and vendor specifications and results, as found on the respective
certificates of analysis.
• Quality Assurance lists the manufacturer in the “Selected Manufacturer List”.

5.1.2 Manufacturer Approval

• One or more pilot batches are manufactured.
• Quality Assurance must review and approve the result data and, if applicable,
provide Regulatory Affairs with the necessary documentation to be submitted to
the market regulatory authority.
• After the market regulatory authority’s approval is obtained, Quality Assurance
lists the manufacturer in the “Approved Manufacturer List”. Commercial
quantities of material may be purchased.

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5.1.3 Manufacturer Certification

To be qualified as a certified manufacturer, an approved manufacturer shall comply
with the following additional requirements:
• At least three consecutive batches of the material are tested and approved by the
Quality Unit.
• The manufacturer has demonstrated a good quality and delivery history.
• Quality Assurance conducts an audit of the manufacturer facility and
procedures and the audit reveals compliance with cGMP and TEVA’s
requirements.
• A formal agreement with the manufacturer, signed by the Purchasing and
Quality Assurance Departments, has been concluded and a mechanism is in
place:
• To keep TEVA informed in advance of any significant change in the route of
synthesis.
• To inform and send to TEVA the documentation of any manufacturing
deviation that might affect the quality of a batch of material supplied.
• Quality Assurance documents the process and lists the manufacturer in the
“Certified Manufacturer List”.

5.1.4 Reduced Testing

A reduced testing program, approved by the Quality Unit, may be instituted for a
material received from a Certified Manufacturer, provided that:
• Reduced testing is allowed under the intended market regulatory requirements.
• At least one batch per year undergoes full monograph testing
• At least one specific identity test is conducted.
• Quality Assurance reviews annually and documents the manufacturer
performance.

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5.1.5 Manufacturer Rejection

Manufacturers, who do not maintain an adequate history of quality and service, will
be relegated to a follow-up status, or will be rejected, depending on the severity of
the non-conformances.

For complete details on this subject, please read Global Corporate Policy
50.20.03"Manufacturer Qualification" and 50.02.01 "Auditing of Vendors."

5.2 Starting Materials

5.2.1 Receipt
5.2.1.1 Starting materials shall only be purchased from approved manufacturers,

who meet the criteria established in the manufacturer qualification program

and in accordance with approved specifications.

5.2.1.2 Each delivery must be accompanied by a delivery note corresponding to the

original purchasing order and each container must be checked for correct
label identification and for damage and evidence of any tampering.

5.2.1.3 The starting materials will be entered into the inventory system (manually

or electronically) and shall be properly identified with at least the following

information:
• Name and internal code
• Batch number
• Retest date and/or expiration date
• Status (quarantined, approved or rejected)

5.2.2 Sampling
5.2.2.1 Each batch shall be sampled separately, in controlled areas and in clean

containers, according to a written sampling program, for testing by the QC

Laboratories. Sterile containers and aseptic sampling techniques shall be

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Chapter 5 – Materials and Products

used to sample sterile materials or materials subject to microbiological

testing. In addition, sterile materials must be sampled in the Sterile
Department under controlled conditions.

5.2.2.2 Sampling must be performed per approved, written procedures, describing

the following:
• The sampling location
• The sampling method
• The sampling equipment
• The quantity of sample to be taken
• The type of container to be used for the sampling
• The method of identifying the material containers which are
sampled
• Special precautions, for example in the cases of sampling sterile or
highly active materials
• Storage conditions
• The cleaning and storage of sampling equipment

5.2.2.3 Sampling Plan

• Each container of active ingredient must be sampled and tested for

identification. Identification of an active ingredient received from a
dedicated API plant may be waived.
• For inactive ingredients, √ n + 1 of the containers must be sampled.
Other statistical methods may be used.
• Samples of packaging material must be representative of the batch
sampled
• Sample containers must bear a label indicating at least the following
details:
• Contents description
• Batch number

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• Date of sampling and identification of sampler.

• The containers from which the samples were taken
• Sampling shall be performed under the same environmental
conditions, as indicated for the manufacturing process, in which
materials will be used.

5.2.3 Storage
5.2.3.1 Materials shall be stored in a clean environment and as per their

recommended storage conditions (protection from heat, humidity and light).

5.2.3.2 Materials shall be held in a quarantine status (physical or status) before

release by the Quality Unit.

5.2.3.3 Refrigerators and freezers must be available for materials requiring these

storage conditions. Secured storage must be provided for controlled

substances. They shall be monitored and alarmed.

5.2.4 Release
Only materials which have been released by the Quality Unit and which are within
their shelf life shall be used. Released materials shall be identified as such, by
means of a release label or in case of computerized inventory system, by their
release status.

5.2.5 Records
A list of materials received shall be available upon request, either manual or
computer generated.

5.3 Packaging Materials

5.3.1 The purchase, handling and control of primary and printed packaging materials,
shall be similar to that of starting materials.

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5.3.2 Printed materials must be stored in a secure manner, that excludes unauthorized
access, so as to prevent the risk of mix-ups.

5.3.3 A change in packaging material, printed or unprinted, shall be performed according

to the change control procedure.

5.3.4 Only roll labels shall be used. In special cases, where cut labels are used, a strict
control over their handling, from receiving to packaging, shall be exercised.

5.3.5 Printed packaging materials shall be coded (pharmaceutical or commercial bar

code, UV) and codes shall be automatically verified on the packaging line. Online
printed labels are exempted of the barcode requirement.

5.4 Bulk Products

5.4.1 Bulk products must be labeled and kept in a clean controlled environment under
their recommended storage conditions during and after processing.

5.4.2 Time limitations, based on bulk product stability shall be established for each
product, when the start of the next processing step exceeds the usual time needed
for its completion, as indicated in a written procedure.

5.5 Finished Products

5.5.1 Finished products must remain in a physical or status quarantine, until compliance
with approved product specifications is confirmed, and the product is released by
Quality Assurance, after review of the batch records. After closing the batch
records file, it will be archived.

5.5.2 If a problem arises, the affected product will be placed in a “Hold” status, labeled as
such physically and/or in the inventory system. The system will be updated, once a
Quality Assurance decision has been reached.

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5.5.3 After release, finished products shall be stored in a clean environment under their
recommended storage conditions.

5.6 Rejected and Returned Materials

5.6.1 Rejected materials must be clearly identified as such and held in a secure area,
separate from all other goods, or held unavailable for use, by any validated means,
until destroyed or otherwise disposed of. All actions taken shall be approved and
documented by Quality Assurance.

5.6.2 Returned product that has been outside of the company control shall be destroyed,
unless it can be proven beyond any doubt, that the quality has not been adversely
affected by exposure, handling or tampering. Any activity (such as repackaging)
shall be approved by the Quality Assurance Department and documented.

5.7 Distribution
5.7.1 Distribution records shall be kept, for customer traceability, in case of recall .

5.7.2 Finished products shall be delivered on a first-in first-out (FIFO) basis.

5.8 Reserve Samples

Reserve samples of starting materials and finished products shall be kept in a quantity
sufficient for at least two full analyses (not including sterility tests) and for a period of one
year after their expiration date.

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