BOX 46 Continued

3. Personnel responsibilities.

4. Consultants.

C. Buildings and Facilities

1. Design and construction features.

2. Lighting.

3. Ventilation, air filtration, air heating, and cooling.

4. Plumbing.

5. Sewage and refuse.

6. Washing and toilet facilities.

7. Sanitation.

8. Maintenance

D. Equipment

1. Equipment design, size, and location.

2. Equipment construction.

3. Equipment cleaning and maintenance.

4. Automatic, mechanical, and electronic equipment.

5. Filters.

E. Control of Components and Drug

Product Containers and Closures

1. General requirements.

2. Receipt and storage of untested components, drug product containers, and closures.

3. Testing and approval or rejection of components, drug product containers, and closures.

4. Use of approved components, drug product containers, and closures.

5. Retesting of approved components, drug product containers, and closures.

6. Rejected components, drug product containers, and closures.

7. Drug product containers and closures.

F. Production and Process Controls

1. Written procedures; deviations.

2. Charge-in of components.

3. Calculation of yield.

4. Equipment identification.

5. Sampling and testing of in-process materials and drug products.

6. Time limitations on production.

7. Control of microbiological contamination.

8. Reprocessing.

G. Packaging and Labeling Control

1. Materials examination and usage criteria.

2. Labeling issuance.

3. Packaging and labeling operations.

4. Tamper-resistant packaging requirements for over-the-counter human drug products.

5. Drug product inspection.

6. Expiration dating.

H. Holding and Distribution

1. Warehousing procedures.

2. Distribution procedures.

I. Laboratory Controls

1. General requirements.

2. Testing and release for distribution.

3. Stability testing.

4. Special testing requirements.

5. Reserve samples.

6. Laboratory animals.

7. Penicillin contamination.

J. Records and Reports

1. General requirements.

2. Equipment cleaning and use log.

3. Component, drug product container, closure, and labeling records.

4. Master production and control records.

5. Batch production and control records.

6. Production record review.

7. Laboratory records.

8. Distribution records.

9. Complaint files.

K. Returned and Salvaged Drug Products

1. Returned drug products.

2. Drug product salvaging.

Adapted from 21 Code of Federal Regulations, Parts 210 and 211.

With the enactment of the BLA process for biotechnology-based pharmaceuticals, any facility holding a current establishment license can manufacture more than one recombinant product, thereby allowing small or start-up biotechnology companies the option of outsourcing production of recombinant products. Facilities manufacturing multiple products are required to establish procedures and documentation of measurements to prevent cross-contamination of products. The establishment must also document and validate manufacturing processes and control procedures, reference standards, analytical and specification methods, storage and shipping containers, and product stability.

Details of the regulatory requirements for establishing a site to manufacture biotechnology products can be found as a part of "Chemistry, Manufacturing, and Controls" (CMC) guidelines developed by the FDA. They are found in the following four sections of the FDA guidelines: (1) Guidance for Industry for the Submission of Chemistry, Manufacturing, and Controls Information for a Therapeutic Recombinant DNA-Derived Product or a Monoclonal Antibody Product for In Vivo Use (61 FR 56243,31 October 1996); (2) Guidance for the Submission of Chemistry, Manufacturing, and Controls Information and Establishment Description for Autolo-gous Somatic Cell Therapy Products (62 FR 1460, 10 January 1997); (3) Guidance for Industry for the Submission of Chemistry, Manufacturing, and Controls Information for Synthetic Peptide Substances; and (4) Draft Guidance for Industry for the Submission of Chemistry, Manufacturing, and Controls and Establishment Description Information for Human Plasma-Derived Biological Products or Animal Plasma or Serum-Derived Products (63 FR 3145,21 January 1998).

In practice, the facility engaged in the manufacture of biological drug candidates usually informs the FDA early in the process to obtain an initial, often unofficial, but helpful response from the agency regarding their advice about the facility. This is almost always done much earlier than the requirements state [i.e.,"... registration (of establishment) shall follow within 5 days after the submission of a biologics license application ...]" (CFR vol. 63,147; section 607.21). Early contact with the FDA, although not a legal requirement, is essentially obligatory to avoid serious delays in product approval and marketing.

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