Guidance for Industry1
(Continued)

Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients

Draft - Not for Implementation

I.     INTRODUCTION

This document is intended to provide guidance on FDA's expectations regarding current good manufacturing practices (CGMP) for manufacturing, processing, packing, or holding (i.e., storage) of active pharmaceutical ingredients (APIs). Although this document focuses on the manufacture of APIs, much of the guidance provided may be useful for the manufacture of excipients. This guidance does not in any way affect the ability of the Agency to establish specific requirements or standards regarding APIs within the context of new drug application reviews. Likewise, it is not intended to address specific issues relating to the filing of such applications.

This guidance applies to the manufacture and control of drug and biologic APIs for use in human and veterinary drug products. In addition, the guidance applies to the later chemical isolation and purification steps of APIs derived from biological or fermentation processes. It also applies to sterile APIs, but only up to the point where the API is rendered sterile. The sterilization and aseptic processing of sterile APIs should be performed in accordance with CGMP regulations for finished pharmaceuticals (Title 21 Code of Federal Regulations Parts 210 & 211). This guidance also identifies CGMPs for the manufacture of APIs used in the production of drug products for clinical trials. However, it does not apply to medical gases, bulk-packaged drug products (final dosage forms), and manufacturing/control aspects specific to radiopharmaceuticals.

FDA expects appropriate CGMPs to be applied to all steps of an API manufacturing process, beginning with the use of starting materials. Such practices include the validation of processes determined to impact the quality and purity of the API. The Agency recognizes that the stringency of CGMPs in API production, such as the extent of written instructions, in-process controls, sampling, testing, monitoring and documentation, should increase as the process proceeds from early steps to final synthesis and purification stages. In this guidance, the Agency attempts to clarify its expectations regarding the stringency of CGMPs at different processing steps.

APIs not manufactured in accordance with CGMPs are adulterated under Section 501(a)(2)(B) of the Federal Food, Drug and Cosmetic Act (the Act). This section of the Act deems a drug to be adulterated if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMPs to ensure that such drug meets the requirements of the Act as to safety, and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.

II. ORGANIZATION AND PERSONNEL

A. Responsibilities of the Quality Control Unit

There should be a quality control unit that:

1. Has the responsibility and authority to approve or reject all raw materials, packaging materials, labels, and APIs;

2. Has the authority to review and approve production records to ensure that no errors or deviations have occurred and, if errors or deviations have occurred, that they have been fully investigated and resolved;

3. Is responsible for approving or rejecting intermediates and APIs manufactured, processed, packed, or held under contract by another company, or establishing appropriate systems to ensure that this is done by the contractor's quality control unit;

4. Is one of the organizational units responsible for the review and approval of validation protocols, changes in product, process, equipment, or other changes to determine if and when revalidation is warranted; C Has adequate laboratory facilities for the testing and approval (or rejection) of raw materials, packaging materials, and APIs; C Is responsible for approving or rejecting all procedures, specifications, and investigations affecting the quality and purity of APIs and intermediates; and

5. Is responsible for performing periodic assessments of procedures, policies, manufacturing, and control operations.

The quality control unit may delegate to the manufacturing department the responsibility and authority to perform in-process testing and release of intermediates. For example, where intermediates are not isolated and stored before use, production employees could check or test the intermediate and then immediately approve it for use in further processing.

The responsibilities and procedures applicable to the quality control unit should be in writing and followed.

B. Personnel Qualifications

Personnel engaged in the manufacture, processing, packing, holding, or testing of an API and/or intermediate should have the education, training, and experience, or any combination thereof, to enable them to perform their assigned functions. Training should extend to CGMPs as well as the particular operations employees perform. Training in CGMPs should be conducted regularly by qualified individuals and with sufficient frequency to ensure that employees remain familiar with CGMP requirements applicable to them.

An adequate number of qualified personnel should be available to perform and supervise the manufacture, processing, packing, holding, or testing of each API and/or intermediate.

C. Personnel Responsibilities

Personnel engaged in the manufacture, processing, packing, or holding of an API or intermediate should wear clean clothing appropriate for the duties they perform. Protective apparel, such as head, face, hand, and arm coverings, should be worn as necessary to protect APIs and intermediates from contamination.

Personnel should practice good sanitation and health habits, including abstention from eating, drinking, or smoking in areas designated for production, storage, and quality control testing. Only persons authorized by supervisory personnel should enter those areas of buildings and facilities designated as limited-access areas.

Any person shown anytime (either by medical examination or supervisory observation) to have an apparent illness or open lesion that may adversely affect the safety and quality of APIs should be excluded from direct contact with raw materials, intermediates, packaging materials, or APIs until the condition is corrected or determined not to jeopardize the safety or quality of APIs. All personnel should be instructed to report any health conditions that may adversely affect APIs to supervisory personnel.

D. Consultants

Consultants advising on the manufacture, processing, packing, or holding of APIs and intermediates should have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained. Records should be maintained stating the name, address, and qualifications of any consultants and the types of service they provide.

III. BUILDINGS AND FACILITIES

A. Design and Construction Features

Buildings and facilities used in the manufacture, processing, packing, or holding of APIs or intermediates should be of suitable design, size, construction and location to facilitate cleaning, maintenance, and proper operations. Adequate space should be provided for the orderly placement of equipment and materials to prevent mixups and contamination among different raw materials, intermediates, or APIs. The flow of raw materials, intermediates, and APIs through the building or buildings should be designed to prevent mixups and contamination.

To prevent mixups and contamination, there should be defined areas and/or other control systems for the following activities:

1. Receipt, identification, storage, and withholding from use of raw materials or intermediates, pending release for use in manufacturing;

2. Holding rejected raw materials, intermediates, and APIs before final disposition;

3. Storage of released raw materials, intermediates, and APIs;

4. Manufacturing and processing operations;

5. Packaging and labeling operations;

6. Quarantine storage of intermediates and APIs pending release for distribution; and

7. Laboratory operations.

Where microbiological specifications have been established for the API (e.g., nonsterile APIs intended for incorporation into parenteral drug products), facilities should also be designed to limit objectionable microbiological contamination.

Operations relating to the crystallization, drying, and packaging of sensitizing APIs, such as penicillins and cephalosporins, should be performed in dedicated facilities. Dedicated facilities should also be considered for other APIs having high pharmacological activity or toxicity, such as some steroids or cytotoxic anticancer agents.

API manufacturing processes that require viral inactivation or reduction should be appropriately segregated (e.g., pre- and postviral inactivation or reduction activities).

B. Lighting

Adequate lighting should be provided in all areas to facilitate cleaning, maintenance, and proper operations.

C. Ventilation, Air Filtration, Air Heating and Cooling

Adequate ventilation should be provided where necessary. Equipment for the adequate control and monitoring of air pressure, microorganisms, dust, humidity, and temperature should be provided when appropriate (e.g., when APIs are exposed to the environment or handled in the final dry state).

Air filtration, dust collection, and exhaust systems should be used in production areas when appropriate. If air is recirculated to production areas, appropriate measures should be taken to control contamination and cross-contamination. Air from previral inactivation/reduction areas should not be recirculated to other areas used for the manufacture of APIs.

D. Steam, Gases, and Other Utilities

Steam that comes into contact with APIs and intermediates should be tested and monitored to ensure that it is of suitable quality and devoid of contaminants, such as boiler additives, that could adversely affect API quality.

All other utilities (e.g., gases, compressed air) that come into contact with APIs and intermediates should comply with appropriate specifications and not alter API quality beyond its established specifications.

E. Plumbing, Washing, and Toilet Facilities

Potable water should be supplied under continuous positive pressure in a plumbing system free from defects that could lead to the contamination of APIs or intermediates. Potable water should meet the standards prescribed in the Environmental Protection Agency's Primary Drinking Water Regulations (Title 40, Code of Federal Regulations, Part 141). Potable water in facilities outside the United States should meet comparable standards of the European Union, Japan, the World Health Organization, or other authorities. Drains should be of adequate size and provided with an air break or suitable mechanical device to prevent back-siphonage.

Adequate and clean washing and toilet facilities that are easily accessible to working areas should be provided. These should include hot and cold water, soap or detergent, air dryers or single-service towels. Shower facilities should be provided if needed for personnel hygiene and/or reducing the potential of API contamination or cross-contamination.

F. Sewage and Refuse

Sewage, trash, and other waste (e.g., solids, liquids, or gaseous by-products from manufacturing) in and from the building and immediate premises should be disposed of in a safe, timely, and sanitary manner.

G. Sanitation

Any building used in the manufacture, processing, packing, or holding of APIs and intermediates should be maintained in a clean and sanitary condition.

Written procedures should be established assigning responsibility for sanitation and describing the cleaning schedules, methods, equipment, and materials to be used in cleaning buildings and facilities. Such written procedures should be followed. Sanitation procedures should apply to work performed by contractors or temporary employees as well as work performed by full-time employees during the ordinary course of operations.

Written procedures should also be established for use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents to prevent the contamination of equipment, raw materials, packaging materials, labeling materials, intermediates, and APIs. Rodenticides, insecticides, and fungicides should be registered and applied according to the Federal Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. 136), or other locally applicable regulations.

H. Maintenance

Any building used in the manufacture, processing, packing, or holding of APIs and intermediates should be properly maintained and repaired.

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1 This guidance has been prepared by the Division of Manufacturing and Product Quality in the Center for Drug Evaluation and Research (CDER), in a joint effort with CDER’s Office of Pharmaceutical Science, the Center for Biologics Evaluation and Research (CBER) and the Center for Veterinary Medicine (CVM), in cooperation with the Office of Regional Operations (ORA). This guidance document represents the Agency’s current thinking on the manufacture and control of active pharmaceutical ingredients. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both. For additional copies of this guidance, contact (1) the Drug Information Branch, Division of Communications Management, HFD-210, CDER, FDA, 5600 Fishers Lane, Rockville, MD 20857 (Phone: 301-827-4573), or (2) Office of Communication, Training, and Manufacturers Assistance (HFM-40), Center for Biologics Evaluation and Research (CBER), 1401 Rockville Pike, Rockville, MD 20852-1448; (Fax) 888-CBERFAX or 301-827-3844 (Voice Information) 800-835-4709 or 301-827-1800.

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