Guidance for Industry
(Continued)

Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients

Draft - Not for Implementation

XV. APIs FOR CLINICAL TRIALS

A. Quality Assurance Measures

Appropriate quality control measures and CGMP concepts should be applied in the production of APIs for clinical trials with a suitable mechanism for approval of each batch.

The manufacturing practices used in the production of clinical APIs should be consistent with the stage of development of the drug product incorporating the API. Processes and analytical methods should be flexible to provide for changes as knowledge of the API process increases and testing of a drug product progresses from preclinical through clinical stages.

Once drug development reaches the stage where the API is produced for use in drug products intended for clinical trials in humans or animals, manufacturers should ensure that the clinical API is manufactured in qualified facilities using appropriate production and control procedures to ensure the safety, quality, and homogeneity of the API.

B. Quality Control Unit

An independent quality control unit similar to that used in commercial production should be established in clinical production of APIs for the approval or rejection of each batch of API. Some of the testing functions commonly performed by the quality control uit could be performed within other areas.

Quality control measures should include a system for testing of raw materials, packaging materials, intermediates, and APIs. Labeling for APIs intended for clinical trials should be appropriately controlled. Labeling for such APIs should identify the material as intended for investigational use.

C. Equipment and Facilities

During all phases of clinical development, including the use of small-scale facilities or laboratories to manufacture clinical API batches, procedures should be in place to ensure that equipment is calibrated, clean, and suitable for its intended use.

Procedures for the use of facilities should ensure that materials are handled in a manner that prevents contamination and cross-contamination.

D. Control of Raw Materials

Raw materials used in early stages of clinical API production should be evaluated by analytical testing, or received with a supplier’s certificate of analysis and subjected to identity testing.

E. Production and Process Controls

Laboratory notebooks or batch records can be used to document the production of clinical APIs. These should include all pertinent production materials, equipment, processing, and scientific observations.

Expected yields might be more variable and less defined than the expected yields used in commercial processes.

F. Process Validation

At early clinical stages, where a single API batch is often produced and where significant processing changes often make batch replication difficult or inexact, only limited process validation is possible.

Concurrent validation might be appropriate in situations where a single or limited number of API batches are produced for clinical trials. This involves obtaining data from extensive in-process and end testing to demonstrate that the instant process run yields an API meeting established specifications and quality characteristics. Process validation should be completed once additional batches are produced under replicated conditions.

Prospective validation should be used when multiple batches are initially produced for clinical trials, even when such batches are produced on a pilot scale or small scale. Once pilot- or small-scale production process are scaled up, the commercial production process should be subjected to full validation studies.

G. Change Documentation

Changes to the process are expected during clinical development as knowledge of the process is gained and the production is scaled up. All process modifications should be adequately documented.

H. Laboratory Controls

All analysis performed to evaluate a batch of API for clinical trials should be scientifically sound.

A system for retaining reserve samples of APIs should be established and followed. This system should ensure that reserve samples are retained for an appropriate lenth of time after approval, termination, or discontinuation of an investigational new drug application (IND), a new drug application (NDA), or biologics license application (BLA). Additional reserve samples should be maintained for API batches used in pivotal toxicological and/or biobatches.

I. Documentation

A system should be in place to ensure that information obtained during the development and production of APIs for clinical trials is documented. This information should be integrated into a process development report.

The development and implementation of the analytical methods used to support the release of a batch of APIs for clinical trials should be appropriately documented.

A system for retaining production and control records should be used. This system should ensure that records are retained for an appropriate length of time after the approval, termination, or discontinuation of an IND or NDA.

BIBLIOGRAPHY

Avallone, H.L., "GMP Inspections of Drug-Substance Manufacturers," Pharmaceutical Technology, June 1992, pp. 46-55.

Barr, D.B., W.C. Crabbs, and D. Cooper, "FDA Regulation of Bulk Pharmaceutical Chemical Production," Pharmaceutical Technology, September 1993, pp. 54-70.

Bulk Pharmaceuticals Committee, PMA QC Section,"Concepts for the Process Validation of Bulk Pharmaceutical Chemicals," Pharmaceutical Technology, December 1993, pp. 32-40.

Cooper, D.E., "Problems in Bulk Pharmaceutical Chemical Production: An FDA Investigator's View," Pharmaceutical Technology, June 1984, pp. 72-80.

Demmer, F., et al., "FDA Regulation of Bulk Pharmaceutical Chemicals -- An Industrial Commentary: Part I," Pharmaceutical Technology, October 1994, pp. 80-90.

_____, "FDA Regulation of Bulk Pharmaceutical Chemicals -- An Industrial Commentary: Part II," Pharmaceutical Technology, December 1994, pp. 36-43.

European Federation of Pharmaceutical Industries' Associations/European Chemistry Industry Council, EFPIA/CEFIC Final Draft Good Manufacturing Practices for Active Ingredient Manufacturers, August 1996.

Federal Ministry of Health, Republic of Germany, "Commercial Executive Order for the Manufactures of Active Ingredients for Drugs," October 26, 1994.

Food and Drug Administration (FDA), Biotechnology Inspection Guide, Office of Regional Operations, November 1991.

FDA, "Current Good Manufacturing Practices for Finished Pharmaceuticals," 21 CFR part 211.

_____, Guide to Inspections of Bulk Pharmaceutical Chemicals, Office of Regional Operations and Center for Drug Evaluation and Research, September 1991, Reformatted May 1994.

_____, Guide to Inspections of High Purity Water Systems, Office of Regional Operations, July 1993.

_____, Guideline to Inspection of Validation of Cleaning Processes, Office of Regulatory Affairs, July 1993.

_____, Guideline for Submitting Documentation for the Stability of Human Drugs and Biologics, Center for Drugs and Biologics, February 1987.

_____, Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances, Center for Drugs and Biologics, February 1987.

Fry, E.M., "An FDA Perspective on Bulk Pharmaceutical Chemicals," Pharmaceutical Technology, February 1984, pp. 48-53.

Gold, D.H., "GMP Issues in Bulk Pharmaceutical Chemical Manufacturing," Pharmaceutical Technology, April 1992, pp. 74-84.

International Conference on Harmonisation (ICH), Q1A Stability Testing of New Drug Substances and Products, FDA, September 1994.

ICH, Q3A Impurities in New Drug Substances, FDA, January 1996.

International Pharmaceutical Excipients Council, Good Manufacturing Practices Guide for Bulk Pharmaceutical Excipients, July 1995.

Lord, A.G., "BPC's and cGmp's," Pharmaceutical Engineering, May/June 1988, vol. 8, no. 3, pp. 30-35.

Martinez, E.R., "An FDA Perspective on Bulk Pharmaceutical Chemical GMPs, Control and Validation," Pharmaceutical Engineering, May/June 1994, vol. 14, no. 3, pp. 8-14.

Moore, R.E., "FDA's Guideline for Bulk Pharmaceutical Chemicals - A Consultant's Interpretation," Pharmaceutical Technology, September 1992, pp. 88-100.

Pharmaceutical Inspection Convention, Guidelines for the Manufacture of Active Pharmaceutical Ingredients (Bulk Drug Substances), PH 2/87, June 6, 1987.

PMA Committee on Guidelines for Bulk Pharmaceutical Chemicals, PMA Guidelines for the Production, Packing, Repacking, or Holding of Bulk Pharmaceutical Chemicals, Second Edition, Revised - June 1978.

QC Bulk Pharmaceuticals Work Group, "PhRMA Guidelines for the Production, Packing, Repacking or Holding of Drug Substances," Quality Steering Committee, PhRMA Science and Regulatory Section, Part I and Part II, Pharmaceutical Technology, December 1995 and January 1996.

World Health Organization (WHO), "Good Manufacturing Practices for Pharmaceutical Products," Thirty-second Report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations, Annex 1, Technical Report Series No. 823, Geneva, 1992.

GLOSSARY

The following terms and definitions are provided to assist the reader in using this guidance document. Unless otherwise stated, when the following definitions address APIs, the Agency intends to apply the same definitions to drug, veterinary, and biologic APIs.

Acceptance Criteria: The specifications and acceptance/rejection criteria, such as acceptable quality level and unacceptable quality level, with an associated sampling plan that are necessary for making a decision to accept or reject a lot or batch of raw material, intermediate, packaging material, or active pharmaceutical ingredient. This term can also be applied to validation.

Act: The Federal Food, Drug, and Cosmetic Act, as amended (21 U.S.C. 301 et seq.).

Actual Yield: The quantity that is actually produced at any appropriate phase of manufacture, processing, or packing of a particular API or intermediate.

Active Pharmaceutical Ingredient (API): Any substance that is represented for use in a drug and that, when used in the manufacturing, processing, or packaging of a drug, becomes an active ingredient or a finished dosage form of the drug. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure and function of the body of humans or other animals. APIs include substances manufactured by processes such as (1) chemical synthesis; (2) fermentation; (3) recombinant DNA or other biotechnology methods; (4) isolation/recovery from natural sources; or (5) any combination of these processes.

Agency: The United States Food and Drug Administration (FDA).

Analytical Methods Validation: The process by which it is established, by laboratory studies, that the performance characteristics of the method meet the requirements for the intended analytical applications.

Batch: A specific quantity of an intermediate or API intended to have uniform character and quality, within specified limits, and produced according to a single manufacturing order during the same cycle of manufacture. A batch may also mean a specific quantity of material or API processed in one process or series of processes so that it could be expected to be homogenous.

Biologic Active Pharmaceutical Ingredient: A material originating from a biological manufacturing process intended to furnish pharmacological activity or other direct effect in the cure, treatment, or prevention of disease or conditions of human beings.

Biologic Product: Any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment, or cure of diseases or conditions of human beings.

Calibration: The demonstration that a particular instrument or device produces results within specified limits by comparison with those produced by a traceable standard over an appropriate range of measurements.

Chemical Reaction: A process that involves a chemical transformation of a starting material or intermediate to form a new compound (e.g., bond formation, oxidation, reduction).

Cleaning Agent: Any material used to clean process equipment, utensils, and storage vessels. These may include soaps, detergents, surfactants, alkalis, acids, or other materials, such as organic solvents, if the solvent is specifically used for cleaning and is not a solvent used in the next processing step.

Concurrent Validation: A subset of prospective validation in which API batches are released for distribution, based on extensive testing, before completion of process validation. Once data from additional batches produced under replicated conditions show uniformity, the process may be considered validated.

Containment: Achieving a level of control over a raw material, intermediate, or API that provides proper protection of these materials from external contamination and cross-contamination.

Contamination: The introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or onto a raw material, intermediate, or API (e.g., occurring during production, sampling, packaging or repackaging, storage or transport).

Continuous Production: A process in which a material is continuously produced in a step or series of steps. In a continuous process, the batches of raw materials and the process parameters can be statistically, but not absolutely, correlated to the material produced in a given period of time.

Critical Process Parameters: Process parameters that must be controlled within established operating ranges to ensure that the API or intermediate will meet specifications for quality and purity.

Critical Process Steps: Process steps that must be controlled within established operating ranges to ensure that the API or intermediate will meet specifications for quality and purity.

Cross-contamination: A contamination of a material or product with another material or product.

Development Report: A report that summarizes the major stages of API development from early stages through large-scale manufacturing.

Drug: As defined in Section 201(g)(1) of the Act means (a) articles that are recognized in the official United States Pharmacopeia, official Homeopathic Pharmacopeia of the United States, or official National Formulary, or any supplement to them; (b) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals; and articles (other than food) intended to affect the structure or any function of the body of humans or other animals.

Drug Product: A finished dosage form, for example, a tablet, capsule or solution, that contains an active pharmaceutical ingredient, generally, but not necessarily, in association with inactive ingredients. The term also includes a finished dosage form that does not contain an API but is intended to be used as a placebo.

Enantiomers: Compounds with the same molecular formula as the API, which differ in the spatial arrangement of atoms within the molecule and are nonsuperimposable mirror images.

Expected Yield: The quantity of API or intermediate or the percentage of theoretical yield anticipated at any appropriate phase of production based on data from process development or process validation.

Expiry/Expiration Date: The date (usually placed on the containers/labels of an API) designating the time during which the API is expected to remain within established shelf-life specifications if stored under defined conditions and after which it should not be used.

Extraneous Substance: An impurity arising from any source extraneous to the manufacturing process.

Identified Impurity: An impurity for which a structural characterization has been achieved.

Impurity: Any component of an API that is not the entity defined as the API.

Impurity Profile: A description of the identified and unidentified impurities present in an API.

In-Process Controls: Testing and activities performed during production to monitor and, if necessary, adjust the process.

In-Process Material: Any material manufactured, blended, or derived by chemical reaction that is produced for, and used in, the preparation of an API.

Intermediate: A material produced during steps in the synthesis of an API that must undergo further molecular change or processing before it becomes an API.

Ligand: An agent with a strong affinity to a metal ion.

Lot: A batch, or a specific identified portion of a batch having uniform character and quality within specified limits. For an API produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that ensures its having uniform character and quality within specified limits.

Lot Number (Control Number, or Batch Number): Any distinctive combination of letters, numbers, or symbols, or any combination of them, from which the complete history of the manufacture, processing, packing, holding, and distribution of a batch or lot of an API or other material can be determined.

Manufacture, Processing, Packing, or Holding: All operations used to manufacture an API to include packaging and labeling operations, testing, and quality control of an API.

Mother Liquor: The residual saturated liquid that remains after crystallization. A mother liquor may contain unrecovered or unreacted starting materials, intermediates, the API and/or impurities.

New Molecular Entity: The designated therapeutic moiety (API) in a dosage form that has not been approved for marketing in the United States (also referred to as a new chemical entity or new drug substance). It may be a complex, simple ester, or salt of a previously approved API.

Physical Manipulation: A process other than a chemical reaction that may change the purity or the physical properties of the material, including but not limited to crystallization, recrystallization, gel filtration, chromatography, milling, drying, or blending.

Pilot Scale: The manufacture of an API on a reduced scale by processes representative of and simulating those to be applied on a larger commercial manufacturing scale.

Polymorphism: The occurrence of different crystalline forms of the same API.

Potential Impurity: An impurity that, from theoretical considerations, may arise from or during manufacture. It may or may not actually appear in the API.

Primary Reference Standard: A particular portion, lot or batch of an API or intermediate that has been shown by an extensive set of analytical tests to be of the highest purity. This standard may be purchased from a recognized source or may be prepared by independent synthesis or by further purification of existing production material.

Process Validation: Establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics.

Prospective Validation: Establishing documented evidence that a system does what it purports to do prior to the commercial distribution of a new API or an existing API made by a new or modified process.

Purification Procedure: A process, such as crystallization, distillation, or chromatography, intended to improve the purity of an API or intermediate.

Qualification: The action of proving that any equipment or process works correctly and consistently and produces the expected results. Qualification is part of, but not limited to, a validation process, i.e., installation qualification (IQ), operation qualification (OQ), and performance qualification (PQ).

Quality Assurance: The sum total of the organized activities performed with the intent to ensure that all APIs are of the quality required for their intended use.

Quality Control Unit: Any person or organizational element designated by the firm to be responsible for the duties relating to quality control.

Quarantine: The status of materials isolated physically or by other effective means pending a decision on their subsequent use.

Range for Critical Process Parameter: The range for each process parameter generally developed on laboratory-, pilot-, or plant-scale batches that encompasses values that are capable of producing intermediates and APIs having acceptable quality attributes.

Raw material: Any ingredient intended for use in the production of APIs. These may include starting materials, process aids, solvents, and reagents.

Reagent: A substance, other than a starting material or solvent, that is used in the manufacture of an API or intermediate.

Recovery: Any treatment of materials by a process intended to make them suitable for further use.

Repeating a Chemical Reaction: Adding fresh reagents or solvents to unreacted or base material and repeating a chemical reaction from its beginning. This excludes those situations where a chemical reaction is continued or extended in the same vessel with the addition of more solvent, to ensure completion of a reaction or increase the yield and/or purity of the API (e.g., continuation of a hydrogenation step).

Reprocessing: Introducing an intermediate or API that does not conform to standards or specifications, back into the process and repeating one or more steps that are part of the established manufacturing process (e.g., recrystallization using the same solvent).

Retest Date: The date when the API should be re-examined to ensure that it is still suitable for use.

Retest Period: The period of time during which the API can be considered to remain within specifications, and therefore acceptable for use in the manufacture of a given drug product, provided that it has been stored under defined conditions. After this period, the API should be retested for compliance with specifications before use.

Retrospective Validation: Establishing documented evidence that a system does what it purports to do based on a review and analysis of historic information. It is normally conducted on an API already being commercially distributed and is based on accumulated production, testing, and control data.

Reworking: Subjecting an intermediate or API that does not conform to standards or specifications, to one or more processing steps that are different from the established manufacturing process (e.g., recrystallizing with a different solvent).

Solvent: Any liquid used as a vehicle for the preparation of solutions or suspensions in the synthesis of an API or intermediate.

Starting Material: A material used in the synthesis of an API, which is incorporated as an element into the structure of an intermediate and/or of the API. Starting materials are normally commercially available and of defined chemical and physical properties and structure.

Theoretical Yield: The quantity that would be produced at any appropriate phase of manufacture, processing, or packing of a particular API or intermediate, based upon the quantity of components to be used, in the absence of any loss or error in actual production.

Toxic Impurity: Impurities having significant undesirable biological activity.

Unidentified Impurity: An impurity that is defined solely by qualitative analytical properties (e.g., chromatographic retention time).

Validation Protocol: A written plan stating how validation will be conducted and identifying specific acceptance criteria. For example, the protocol for a typical manufacturing process identifies processing equipment, critical process parameters/operating ranges, product characteristics, sampling and test data to be collected, number of validation runs, and acceptable test results.

Working Standard: An API, intermediate or other substance of established quality and purity, as shown by comparison to a primary reference standard, used as a reference for routine laboratory analysis.