Guidance for Industry
(Continued)

Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients

Draft - Not for Implementation

IX. LABORATORY CONTROLS

A. General Controls

Specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms, including changes in same, should be drafted by the appropriate organizational unit and reviewed and approved by the quality control unit. Laboratory controls should be followed and documented at the time of performance. Deviations from written specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms should be documented and justified.

Laboratory controls should include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures to ensure that raw materials, intermediates, APIs, and containers conform to established standards of quality and purity.

Procedures should be established to determine conformance to appropriate written specifications for the acceptance of each lot of raw materials, containers, intermediates, and APIs. Such procedures should also cover appropriate sampling and retesting of any materials used in the manufacturing or holding of an intermediate or API that are subject to deterioration or degradation. Laboratory test samples should be representative, properly handled, and adequately identified.

A program should be in place to calibrate or demonstrate suitability of instruments, apparatus, gauges, and recording devices at suitable intervals. The program should contain specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met. Instruments, apparatus, gauges, and recording devices not meeting established specifications should not be used.

Secondary laboratory reference standards (e.g., production lots that are further purified and qualified in the laboratory) should be appropriately prepared, identified, stored, and tested, as necessary, to ensure their suitability for use. The suitability of each lot of secondary reference standard should be determined prior to use by comparing against a primary reference standard obtained from an official source and periodically requalifying each lot in accordance with a written protocol. Primary reference standards need not be tested if stored under conditions consistent with those described in the labeling.

Analytical reagents should be prepared and labeled following established procedures. Retest or expiration dates should be used, as appropriate, for analytical reagents, or standard solutions.

Analytical methods should be validated unless the method employed is set forth in the current revision of the United States Pharmacopeia/National Formulary, Association of Official Analytical Chemists, Book of Methods,2 or other recognized standard references, or detailed in a 2 Drug Master File or approved new drug application and are used unmodified. The suitability of all testing methods used should nonetheless be verified under actual conditions of use and documented.

B. Testing and Release for Distribution

Appropriate laboratory tests should be conducted on each lot of API or intermediate to determine satisfactory conformance to established specifications. Intermediates should be tested as appropriate for conformance to specifications.

Microbiological testing should be conducted on each lot of API required to be free of objectionable microorganisms. Appropriate testing should also be conducted on each lot of API required to be pyrogen free or with a specified endotoxin limit (e.g., APIs intended for use in the preparation of parenteral drug products).

Impurity profiles should be established and maintained for each API that identify or quantify each impurity observed (i.e., organic impurities, inorganic impurities, and residual solvents). In general, all impurities at or above 0.1% should be identified.3  Test procedures for establishing  impurity profiles should be written and followed.

Intermediates and APIs failing to meet established standards or specifications should be rejected. Adequate written procedures should be followed for rejected materials that are reprocessed or reworked.

C. Stability Testing

A formal testing program should be established to assess the stability characteristics of APIs. The results of such testing should be used to determine appropriate storage conditions and retest or expiration dates. The testing program should be ongoing and include:

1. The number of lots placed on stability per year, sample size, and test intervals;

2. Storage conditions for samples retained for testing; and

3. Stability indicating test methods.4

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

An adequate number of batches of each API should be tested at suitable intervals to determine an appropriate retest or expiration date. This generally includes samples from the first three commercial size batches, but fewer batches may be appropriate in the initial testing program if data from previous studies or from literature show that the API is stable for at least two years. For those biotechnological/biologic and other APIs having shelf-lives of one-year or less, stability samples should be obtained and tested monthly for the first three months, and at three-month intervals thereafter.

When stability data from pilot-scale batches are used to establish a tentative expiration date:

1. The pilot batches should be manufactured by procedures that simulate the final process to be used on a commercial manufacturing scale;

2. The quality of the API should represent the material to be made on a commercial scale.

After the initial retest or expiration date has been established, at least one batch of API manufactured during a given year should be added to the stability testing program to detect changes in the stability profile. Changes in manufacturing site, materials, or manufacturing processes should be evaluated to determine if these changes affect API stability.

D. Reserve Samples

Appropriately identified reserve samples representative of each lot of API should be retained for one year after the expiration date of the lot, or, for APIs having retest dates, three years after the batch is distributed.

Reserve samples should consist of at least twice the quantity necessary for all tests required to determine whether the API meets its established specifications. The samples should be stored in containers that would be equivalent or more protective than the marketed packaging system. Representative reserve samples should be examined visually at least once a year for evidence of deterioration unless visual examination would affect the integrity of the reserve samples. Any evidence of deterioration should be investigated. The results of the examination should be documented and maintained.

E. Laboratory Animals

Animals used in testing raw materials, in-process materials, intermediates, or APIs for compliance with established specifications should be maintained and controlled to ensure their suitability for their intended use. Animals should be identified and adequate records maintained showing the history of their use.

X. RECORDS AND REPORTS

A. General Controls

Any production, control, or distribution record specifically associated with a batch of API should be retained for at least one year after the expiration date of the batch. For APIs with retest dates, records should be retained for at least three years after the batch is completely distributed to either internal or external recipients.

Records should be maintained for all raw materials and API containers for at least one year after the expiration date of the batch. For APIs with retest dates, these records should be retained for at least three years after the API batch is completely distributed to either internal or external recipients.

All records or copies of such records should be readily available for authorized inspection and copying by FDA during the retention period at the establishment where the activities described in such records occurred. Records kept off site should be promptly retrievable by electronic or other means.

Records may be retained either as originals, electronic records, or as true copies, such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records. Where reduction techniques, such as microfilming, are used, suitable reader and copying equipment should be readily available.

Written records should be maintained so that data therein can be used for evaluating, at least annually, the quality standards of each API to detect the need for changes in specifications or manufacturing or control procedures. Written procedures should be established and followed for such evaluations and should include provisions for:

1. A review of a representative number of batches, whether approved or rejected, and their associated records; and

2. A review of process changes, stability data/protocols, complaints, recalls, returned or salvaged APIs, and deviation investigations conducted for the API being evaluated.

Procedures should be established to ensure that designated officials of the firm, if they are not personally involved in or immediately aware of such actions, are notified in writing of any investigations conducted, any recalls, reports of inspectional observations issued by the FDA, or regulatory actions relating to CGMPs brought by the Agency.

Electronic records and electronic signatures used under this section should comply with Part 11 of Title 21 of the Code of Federal Regulations.

B. Equipment Cleaning and Use Record

A written record should be maintained of major equipment cleaning and maintenance (except routine maintenance such as lubrication and adjustments), that shows the date, time, API or intermediate, the lot number of each batch processed, and the person who performed the cleaning.

Where equipment is dedicated to manufacturing one API or intermediate and lots or batches are manufactured in numerical sequence, the records of cleaning, maintenance, and use should be part of the batch record or maintained separately (e.g., equipment log books). The persons performing and checking the cleaning and maintenance should date and sign or initial the record showing that the work was done. Entries in the record should be in chronological order.

C. Raw Material, API Packaging Materials, and Labeling Records

These records should include the following:

1. The identity and quantity of each shipment of each lot of raw materials, intermediates, API packaging materials, and labeling; the name of the supplier; the supplier's lot number(s) if known; the receiving code; and the date of receipt;

2. The name and location of the manufacturer, if different from the supplier;

3. The results of any test or examination performed and the derived conclusions;

4. Documentation of the examination and review of labeling and API packaging materials for conformity with established specifications; and

5. The disposition of rejected raw materials, API packaging materials, and labeling.

D. Master Production and Control Records

Master production and control records for each API and intermediate, including each batch size thereof, should be prepared, dated, and signed by one person and independently checked, dated, and signed by at least one other person. The quality control unit should review and approve master production and control records. The preparation of master production and control records should be described in a written procedure and followed.

Master production and control records should include:

1. The name of the API or intermediate and an identifying reference code, if applicable;

2. A complete list of raw materials or intermediates designated by names or codes sufficiently specific to indicate any special quality characteristics;

3. An accurate statement of the quantity and unit of measure of each raw material or intermediate (variations in the amounts of raw materials or intermediates should be reasonable and justified);

4. A statement of expected weights or measures at appropriate phases of processing;

5. A statement of expected yields, including the maximum and minimum weights or measures, or the percentages of expected yield beyond which investigation is initiated;

6. The manufacturing location and the major equipment to be used;

7. Complete manufacturing instructions and, where appropriate, special notations and precautions to be followed, or cross references to same;

8. Any sampling instructions and in-process controls with their limits, where appropriate; and

9. Requirements for storage of APIs or intermediates, including the packaging materials, labeling, and special storage conditions, where applicable.

E. Batch Production and Control Records

Batch production and control records should be prepared for each batch of API or intermediate produced and should include complete information relating to the production and control of each batch. These records should include an accurate reproduction or reference to the appropriate master production and control record, checked for accuracy, dated, and signed.

Batch records should include documentation that each significant step in the production of the batch was accomplished including:

1. Dates, and where appropriate, times;

2. Identity of individual major equipment used;

3. Specific identification of each batch, including weights, measures, and batch numbers of raw materials, intermediates, or any reprocessed/reworked materials used during manufacturing;

4. In-process and laboratory control results;

5. A statement of the actual yield compared against an expected yield at appropriate phases of manufacture;

6. Description of API and intermediate packaging and labeling;

7. Any sampling performed;

8. Signatures of the persons performing and directly supervising or checking each significant step in the operation;

9. Any deviation investigations conducted or reference to that investigation if stored separately; and

10. Results of release testing.

F. Production Record Review

Written procedures should be established and followed for the review and approval of batch production, control, and laboratory records, including packaging and labeling, to determine compliance of the API or intermediate with established specifications before a batch is released or distributed.

Batch production and control records for critical process steps should be reviewed and approved by the quality control unit before a batch is released or distributed. Where the quality control unit does not review noncritical process steps, the review should be performed by qualified production personnel or other units following procedures approved by the quality control unit.

Written procedures should be established and followed for investigating unexplained discrepancies, including:

1. Results out of the expected yield range established in master production and control records;

2. Failure of a batch to meet specifications; and

3. Any out-of-specification (OOS) test results.

The investigation should extend to other batches of the API or other batches that may have been associated with the specific failure or discrepancy, regardless of whether the batch has already been distributed.

A written record of the investigation should be prepared and should include:

1. The reason for the investigation;

2. A summary of the investigation conducted, including all laboratory tests and results;

3. Scientifically sound and appropriate justification for excluding any OOS laboratory result;

4. For laboratory results found invalid, the subsequent laboratory results supporting the final determination of conformity to all appropriate specifications for acceptance;

5. The conclusions and corrective actions taken regarding batches associated with the failure or discrepancy; and

6. The signature(s) and date(s) of the person(s) responsible for approving the record of investigation.

G. Laboratory Records

Laboratory records should include complete data derived from all tests necessary to ensure compliance with established specifications and standards, including examinations and assays, as follows:

1. A description of samples received for testing including the source, quantity, lot number or other distinctive code, date sample was taken, and date the sample was received for testing;

2. A statement of or reference to each method used in testing the sample;

3. A statement of the weight or measure of sample used for each test;

4. A complete record of all raw data secured during each test, including graphs, charts, and spectra from laboratory instrumentation, properly

5. identified to show the specific raw material, intermediate, or API, and lot tested;

6. A record of all calculations performed in connection with the test, including units of measure, conversion factors, and equivalency factors;

7. A statement of the test results and how they compare with established standards of quality and purity for the raw material, intermediate, or API tested;

8. The initials or signature of the person who performs each test and the date(s) the tests were performed; and

9. The initials or signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards.

Complete records should be maintained for:

1. Any modifications to an established analytical method, to include the reason for the modification and data to verify that the modification produces results that are at least as accurate and reliable as the established method;

2. Preparation and testing of laboratory reference standards, reagents, and standard solutions;

3. Periodic calibration of laboratory instruments, apparatus, gauges, and recording devices;

4. All stability testing performed on APIs; and

5. OOS investigations.

H. Distribution Records

Distribution records should contain the name of the API or intermediate, the name and address of the consignee, date, quantity shipped, and lot or control number.

I. Complaint Files

Written procedures describing the handling of all written and oral complaints regarding an API should be established and followed. Similar procedures should be established for complaints involving marketed intermediates. These procedures should provide for the quality control unit to review of all complaints involving the possible failure of an API to meet any of its specifications, determine the need for an investigation, and ascertain whether the complaint represents a serious and unexpected event that would require notification to users of the API.

A written record of each complaint should be maintained in a file designated for APIs. The file should be kept at the establishment where the API was manufactured, processed, or packed or at another facility if the written records in such files are readily available for inspection at that other facility. Complaint records should be maintained for at least one year after the expiration date of the API, or one year after the date the complaint was received, whichever is longer. For APIs with retest dates, such written records should be maintained for at least three years after the batch is distributed. The written record should include the name of the API, batch or lot number, name and address of the complainant, nature of complaint, and reply to the complainant.

If an investigation is conducted in response to a complaint, the record should include the findings of the investigation and any conclusions or corrective actions taken. The record (or copy) of the investigation should be kept at the establishment where the investigation occurred. If an investigation is not conducted, the written record should include the reason that an investigation was found to be unnecessary, and the name of the responsible person making such a determination.

J. Returned APIs and Intermediates

Written procedures for the receipt, holding, testing, and disposition of returned APIs and intermediates should be established and followed. These procedures should provide for the identification and holding of returned APIs and intermediates. Where an API or intermediate is placed back into inventory, the reason for its return should not have been due to quality issues, and the integrity of the returned material should have been verified. If the quality or purity of the API or intermediate cannot be ensured, the returned material should be destroyed, reprocessed, or reworked as appropriate. If the reason for the return implicates associated batches, an appropriate investigation should be conducted as described in Section XII.F.4.

Records of returned APIs and intermediates should be maintained and should include the name, batch or lot number, reason for the return, quantity returned, date of disposition, and ultimate disposition.

K. API and Intermediate Salvaging

APIs and intermediates that have been subjected to improper storage conditions, including extremes in temperature and humidity, smoke, fumes, pressure, age, or radiation due to natural disasters, fires, accidents, or equipment failures should not be salvaged.

Whenever there are doubts that APIs and intermediates have been subjected to adverse conditions described above, salvaging operations should only be conducted if there is both (1) evidence from inspection of the premises that the APIs and intermediates and their associated packaging were not subjected to improper storage condition and (2) evidence from laboratory tests and assays that the APIs and intermediates meet all applicable standards of quality and purity.

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2 Copies may be obtained from the Association of Official Analytical Chemists, 2200 Wilson Blvd., Suite 400, 2 Arlington, VA 22201-3301.

3 See the January 1996 "Guideline for Industry Impurities in New Drug Substances" and the ICH Harmonized 3 Tripartite Guideline "Impurities in New Drug Substances," recommended for adoption at Step 4 of the ICH process on 30 March 1995.

4 This guidance applies to stability testing for active pharmaceutical ingredients. FDA recommends that manufacturers also consult the Agency’s February 1987 Guideline For Submitting Documentation For The Stability Of Human Drugs And Biologics and the relevant International Conference On Harmonisation (ICH) guidances, including: Stability Testing of New Drug Substances and Products, Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products, and Light Stability Testing of New Drug Substances And Products.

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