Guidance for Industry

Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients

Draft - Not for Implementation


A. Written Procedures and Deviations

Written production and process control procedures should be established and followed to ensure that APIs and intermediates have the quality and purity they purport or are represented to possess. These procedures, including any changes, should be drafted, reviewed, and approved by the responsible organizational units and reviewed and approved by the quality control unit. The written procedures should be reviewed at defined intervals and updated whenever necessary. Outdated procedures should be withdrawn from circulation and archived.

Production and process control procedures should be followed in the execution of the various production and process control functions and should be documented promptly. Deviations from written procedures should be documented and explained.

B. Raw Material Weighing and Measuring

Raw materials used for manufacturing APIs and intermediates should be weighed or measured asappropriate to maintain their identity, quality, and purity. Suitable equipment and procedures should be used during these activities to prevent raw material contamination or cross-contamination. Weighing and measuring devices should be of suitable accuracy for the intended use. Where necessary, they should be calibrated to ensure accurate results within appropriate ranges.

Raw materials subdivided for later use in manufacturing operations should be transferred into suitable containers and appropriately labeled with the following information:

1. Material name and item code;

2. Receiving or control number; and

3. Weight or quantity of raw material in the new container.

Weighing, measuring, or subdividing operations for raw materials should be adequately supervised. Raw materials should be verified prior to use to ensure that they are those specified in the batch record for the intended API or intermediate.

C. Calculation of Yield

Actual yields and percentages of expected yields should be determined at the conclusion of each appropriate phase of manufacturing or processing of an API or intermediate. Expected yields with appropriate ranges should be established based on previous laboratory, pilot scale, or manufacturing data.

Deviations from expected yields should be investigated and documented. Investigations should include:

1. Determining the disposition of affected lots; and

2. Taking corrective action, where needed, to minimize the likelihood of problem recurrence.

D. Equipment Identification

Major equipment (e.g., reactors, storage containers) and permanently installed processing lines used during the production of an API or intermediate should be identified appropriately. This can be accomplished by identifying individual vessels, documentation, computer control systems, or alternative means.

Batch production records should identify the major equipment used in the manufacture of each batch of an API and intermediate.

E. In-Process Controls, Sampling/Testing of APIs and Intermediates

Written procedures should be established and followed that describe the sampling methods for in-process materials, intermediates, and APIs. Sampling plans and procedures should be based on valid data and scientifically sound sampling practices. Sampling should be conducted in an area and using procedures designed to prevent contamination of the sampled material and other APIsor intermediates. Procedures should be established to ensure the integrity of samples after collection. Each sample should be labeled to establish its identity.

Written procedures should be established to monitor the progress and control the performance of those manufacturing processes that may cause variability in the quality characteristics of APIs and intermediates. In-process controls and specifications should be derived from laboratory-, or pilot-scale batches and may be adjusted later based on data obtained from full-scale production batches.

The type and extent of in-process controls should depend on several considerations, including:

1. The nature of the API or intermediate being manufactured

2. The reaction or process step being conducted; and

3. The degree to which the step introduces variability in the process.

Less stringent in-process controls may be appropriate in early processing steps whereas tighter controls should be applied to later synthesis, isolation, and purification steps.

In-process tests may be performed by qualified production department personnel and the process adjusted without prior quality control approval, provided adjustments are made within preestablished limits approved by the quality control unit. All in-process tests and results should be documented in the batch record.

APIs and intermediates failing to meet established specifications should be rejected and held under quarantine until an investigation determines the appropriate disposition of the materials. Materials to be reprocessed or reworked should be appropriately identified.

F. Time Limits on Production of APIs and Intermediates

When appropriate, time limits for the completion of manufacturing steps should be established to ensure the quality of APIs and intermediates. Deviations from established time limits should not compromise the quality or purity of the API or intermediate. Such deviations should be documented and explained.

Written procedures should be established for intermediates that are stored before further processing. Where necessary, these procedures should specify appropriate storage conditions, packaging materials, temperature, time, and protection from humidity and light when these are critical for maintaining the quality of the intermediate.

G. Control of API Contamination

Appropriate measures should be taken during final filtration and isolation steps to avoid contamination or cross-contamination of APIs. Such measures should include:

1. Use of equipment designed to minimize contamination;

2. Use of adequately cleaned and maintained equipment, and where necessary, dedicated equipment;

3. Location of equipment in a controlled environment;

4. Use of suitably filtered liquid and gaseous materials (e.g., gases that are used to vent or blanket dryers); and

5. Use of adequately purified solvents and other purified raw materials.

In addition, special precautions should be taken during drying, milling, micronizing, sieving, blending, and packaging operations due to the contamination risks associated with handling dry powders. Such precautions should include:

1. Use of closed systems for isolation and drying, where possible;

2. Use of automated powder transfer systems (e.g., vacuum, gravity systems) when charging and discharging vessels; and

3. Use of appropriate air handling and dust extraction systems.

When appropriate, written procedures should be established and followed to minimize objectionable microbiological contamination in APIs and intermediates that (1) are of biologic origin; (2) are sensitive to microbiological deterioration; or (3) have established microbiological specifications.

Written procedures should be established and measures taken to control bioburden and endotoxin contamination of nonsterile APIs intended for use in the preparation of parenteral drug products.

H. Blending of APIs and Intermediates

In-process blending (e.g., collecting several centrifuge loads in a single dryer or blender, blending of several intermediate batches for use in subsequent process steps, blending of tailings) should be adequately controlled and documented. Appropriate specifications should be established for in-process materials to be blended to ensure the quality of the blend.

Blending of batches or lots that individually do not conform to purity specifications with other lots that do conform for the purpose of salvaging materials or disguising defects should be avoided. When blending several API batches to increase batch size:

1. Each batch incorporated into the blend should meet established purity specifications;

2. Each batch incorporated into the blend should have been produced by the same process;

3. The lot or control number assigned to each blend should allow traceability back to the individual batches that make up the blend; and

4. The expiration or retest date assigned to the blended API batch should be based on the manufacturing date of the oldest batch in the blend.

For dry blended APIs, the maximum lot size for final API blends should be limited to the maximum working capacity of the largest blender used.

Where physical attributes of the API are critical (e.g., APIs intended for use in solid oral dosage forms or suspensions), blending operations should be validated to show homogeneity of the blended batch. Validation should include testing for critical attributes (e.g., particle size distribution, bulk, and tap density) that may be affected by the blending process.


A. Materials Examination and Usage Criteria

There should be written procedures describing the receipt, preparation, identification, storage, handling, sampling, examination, and/or testing of API labeling and packaging materials. Such written procedures should be followed and documented. Labeling and packaging materials should be representatively sampled and examined or tested, as appropriate, before use.

All labeling and packaging materials should conform to established specifications. Those that do not comply with such specifications should be rejected to prevent their use in operations for which they are unsuitable. Records should be maintained for each shipment of labeling and packaging materials showing receipt, examination, or testing, and whether accepted or rejected.

Labeling for each different API form or grade should be stored separately with suitable identification. Such storage should provide adequate security to avoid mix-ups. If gang printed labels are used for different APIs, these should be adequately differentiated by size, shape or color. If cut labels are used, appropriate measures should be taken to prevent label mix-ups.

Obsolete and outdated labeling should be destroyed. Other obsolete packaging materials should be destroyed or otherwise disposed of in a way that precludes mixups with currently acceptable materials.

Printing devices used to print labels during packaging operations should be monitored to ensure that all imprinting conforms to the print specified in the batch production record.

B. API Label Issuance

Strict controls should be exercised over labels issued for use in labeling operations. Labels issued for a batch should be carefully examined for proper identity and conformity to the specifications in the master or batch production records. The results of this examination should be documented.

Quantities of labels issued, used, and returned should be reconciled. Discrepancies should be investigated and documented.

C. Packaging and Labeling Operations

Written procedures should be established to ensure that correct labels, labeling, and packaging materials are used for APIs. Such procedures should be followed and documented.

Physical or spatial separation from other API operations should be provided to prevent mixups and contamination. Packaging and labeling facilities should be inspected immediately before use to ensure that all materials not required for the next packaging run have been removed. This inspection should be documented.

Each API should be identified with a lot or control number that permits determination of the history of its manufacture and control. Packaged and labeled APIs should be examined to ensure that containers and packages in the lot bear the correct label.

API containers that are shipped outside of the manufacturer’s control should be sealed in a manner that alerts the recipient of possible tampering if the seal is breached or missing.

D. API Packaging Materials

API packaging materials should not be reactive, additive, or absorptive so as to alter the quality or purity of the API beyond the official or established requirements. Packaging materials should provide adequate protection against deterioration or contamination that may occur during transportation and recommended storage of the API.

API packaging materials should be cleaned, as appropriate, and where indicated by the nature of the API, sanitized, to ensure that they are suitable for their intended use. Standards or specifications, methods of testing, and, where indicated, methods of cleaning, sanitizing, and processing API packaging materials should be written and followed.

E. Expiration or Retest Dating

Antibiotic APIs and all biologic APIs should be labeled with an expiration date. For other APIs, the container label or certificate of analysis (COA) should specify an appropriate expiration date or retest date to ensure the quality of the API at the time of use. Expiration or retest dates should relate to any storage conditions stated on the label and should be supported by appropriate stability studies, as stipulated in Section IX.C.

Storage conditions should be specified on the label of API containers when it is critical to maintain such conditions to ensure the quality of the API. Where applicable, labeled storage conditions should comply with standard definitions for "Freezer," "Cold," or "Controlled Room Temperature," as defined in the United States Pharmacopeia (USP) or guidelines of the International Conference on Harmonisation (ICH). Statements of specific storage conditions should be used instead of more general terms such as "room temperature" when it is critical for maintaining the quality of APIs.

For most biotechnological and biologic APIs, precisely defined storage temperatures should be established and stated on the label. The label on each container should also bear any warnings to protect the contents from excessive heat, freezing, light or moisture.


A. Warehousing Procedures

Written procedures describing the warehousing of APIs and intermediates should be established and followed. They should include:

1. Storage under a quarantine system before release by the quality control unit; and

2. When appropriate, storage under specified conditions of temperature, humidity, and light so that the quality and purity of APIs and intermediates are not adversely affected.

B. Distribution Procedures

Written procedures should be established and followed describing the distribution of APIs and, where applicable, intermediates. They should include:

1. Distribution of the oldest approved stock of an API or intermediate before distribution of newer stock with deviations recorded and explained;

2. A system by which the distribution of each lot of API or intermediate can be readily determined to facilitate its recall if necessary; and

3. Transportation of APIs and intermediates in a manner that does not adversely affect their purity or quality.

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