A. General Controls (11.1)

The independent quality unit(s) should have at its disposal adequate laboratory facilities.

There should be documented procedures describing sampling, testing, approval, or rejection of

materials and recording and storage of laboratory data. Laboratory records should be maintained in

accordance with Section 6.6.

All specifications, sampling plans, and test procedures should be scientifically sound and appropriate to ensure that raw materials, intermediates, APIs, and labels and packaging materials conform to established standards of quality and/or purity. Specifications and test procedures should be consistent with those included in the registration/filing. There can be specifications in addition to those in the registration/filing. Specifications, sampling plans, and test procedures, including changes to them, should be drafted by the appropriate organizational unit and reviewed and approved by the quality unit(s).

Appropriate specifications should be established for APIs in accordance with accepted standards and consistent with the manufacturing process. The specifications should include control of impurities (e.g., organic impurities, inorganic impurities, and residual solvents). If the API has a specification for microbiological purity, appropriate action limits for total microbial counts and objectionable organisms should be established and met. If the API has a specification for endotoxins, appropriate action limits should be established and met.

Laboratory controls should be followed and documented at the time of performance. Any departures

from the above-described procedures should be documented and explained.

Any out-of-specification result obtained should be investigated and documented according to a

procedure. This procedure should include analysis of the data, assessment of whether a significant

problem exists, allocation of the tasks for corrective actions, and conclusions. Any re-sampling and/or retesting after OOS results should be performed according to a documented procedure.

Reagents and standard solutions should be prepared and labelled following written procedures. Use by dates should be applied, as appropriate, for analytical reagents or standard solutions.

Primary reference standards should be obtained, as appropriate, for the manufacture of APIs. The

source of each primary reference standard should be documented. Records should be maintained of

each primary reference standard’s storage and use in accordance with the supplier’s recommendations.

Primary reference standards obtained from an officially recognized source are normally used without testing if stored under conditions consistent with the supplier’s recommendations.

Where a primary reference standard is not available from an officially recognized source, an in-house primary standard should be established. Appropriate testing should be performed to establish fully the identity and purity of the primary reference standard. Appropriate documentation of this testing should be maintained.

Secondary reference standards should be appropriately prepared, identified, tested, approved, and

stored. The suitability of each batch of secondary reference standard should be determined prior to first use by comparing against a primary reference standard. Each batch of secondary reference standard should be periodically re-qualified in accordance with a written protocol.

B. Testing of Intermediates and APIs (11.2)

For each batch of intermediate and API, appropriate laboratory tests should be conducted to determine conformance to specifications.

An impurity profile describing the identified and unidentified impurities present in a typical batch

produced by a specific controlled production process should normally be established for each API.

The impurity profile should include the identity or some qualitative analytical designation (e.g., retention time), the range of each impurity observed, and classification of each identified impurity (e.g., inorganic, organic, solvent). The impurity profile is normally dependent upon the production process and origin of the API. Impurity profiles are normally not necessary for APIs from herbal or animal tissue origin.

Biotechnology considerations are covered in ICH guidance Q6B.

The impurity profile should be compared at appropriate intervals against the impurity profile in the

regulatory submission or compared against historical data to detect changes to the API resulting from modifications in raw materials, equipment operating parameters, or the production process.

Appropriate microbiological tests should be conducted on each batch of intermediate and API where microbial quality is specified.

C. Validation of Analytical Procedures – See Section 12. (11.3)

D. Certificates of Analysis (11.4)

Authentic certificates of analysis should be issued for each batch of intermediate or API on request.

Information on the name of the intermediate or API including, where appropriate, its grade, the batch number, and the date of release should be provided on the certificate of analysis. For intermediates or APIs with an expiry date, the expiry date should be provided on the label and certificate of analysis. For intermediates or APIs with a retest date, the retest date should be indicated on the label and/or certificate of analysis.

The certificate should list each test performed in accordance with compendial or customer requirements, including the acceptance limits, and the numerical results obtained (if test results are numerical).

Certificates should be dated and signed by authorized personnel of the quality unit(s) and should show the name, address, and telephone number of the original manufacturer. Where the analysis has been carried out by a re-packer or re-processor, the certificate of analysis should show the name, address, and telephone number of the re-packer / re-processor and reference the name of the original manufacturer.

If new certificates are issued by or on behalf of re-packers / re-processors, agents or brokers, these

certificates should show the name, address and telephone number of the laboratory that performed the analysis. They should also contain a reference to the name and address of the original manufacturer and to the original batch certificate, a copy of which should be attached.

E. Stability Monitoring of APIs (11.5)

A documented, on-going testing program should be established to monitor the stability characteristics of APIs, and the results should be used to confirm appropriate storage conditions and retest or expiry dates.

The test procedures used in stability testing should be validated and be stability indicating.

Stability samples should be stored in containers that simulate the market container. For example, if the API is marketed in bags within fiber drums, stability samples can be packaged in bags of the same material and in small-scale drums of similar or identical material composition to the market drums.

Normally, the first three commercial production batches should be placed on the stability monitoring program to confirm the retest or expiry date. However, where data from previous studies show that the API is expected to remain stable for at least 2 years, fewer than three batches can be used.

Thereafter, at least one batch per year of API manufactured (unless none is produced that year) should be added to the stability monitoring program and tested at least annually to confirm the stability.

For APIs with short shelf-lives, testing should be done more frequently. For example, for those

biotechnological/biologic and other APIs with shelf-lives of one year or less, stability samples should be obtained and should be tested monthly for the first 3 months, and at 3-month intervals after that. When data exist that confirm that the stability of the API is not compromised, elimination of specific test intervals (e.g., 9-month testing) can be considered.

Where appropriate, the stability storage conditions should be consistent with the ICH guidances on

stability.

F. Expiry and Retest Dating (11.6)

When an intermediate is intended to be transferred outside the control of the manufacturer’s material management system and an expiry or retest date is assigned, supporting stability information should be available (e.g., published data, test results).

An API expiry or retest date should be based on an evaluation of data derived from stability studies.

Common practice is to use a re-test date, not an expiration date.

Preliminary API expiry or retest dates can be based on pilot scale batches if (1) the pilot batches

employ a method of manufacture and procedure that simulates the final process to be used on a

commercial manufacturing scale and (2) the quality of the API represents the material to be made on a commercial scale.

A representative sample should be taken for the purpose of performing a re-test.

G. Reserve/Retention Samples (11.7)

The packaging and holding of reserve samples is for the purpose of potential future evaluation of the quality of batches of API and not for future stability testing purposes.

Appropriately identified reserve samples of each API batch should be retained for 1 year after the

expiry date of the batch assigned by the manufacturer, or for 3 years after distribution of the batch,

whichever is longer. For APIs with retest dates, similar reserve samples should be retained for 3 years after the batch is completely distributed by the manufacturer.

The reserve sample should be stored in the same packaging system in which the API is stored or in one that is equivalent to or more protective than the marketed packaging system. Sufficient quantities should be retained to conduct at least two full compendial analyses or, when there is no pharmacopoeial monograph, two full specification analyses.

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