Guide To Inspections Of Bulk Pharmaceutical Chemicals

GUIDE TO INSPECTIONS OF BULK PHARMACEUTICAL CHEMICALS

Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).

This guide, originally published in April 1984, was first revised in February 1987, and again in September 1991. This May 1994 printing is the same as the 1991 revision except for a few editorial changes.

CONTENTS

PART I GENERAL GUIDANCE

Subject ..............................................................................Page

Introduction ..........................................................................1

Status of Bulk Pharmaceutical Chemicals ...............................2

Scope ...................................................................................3

General Guidance - Bulk GMPs ............................................3

Inspectional Approach ..........................................................4

Registration ...........................................................................5

Product of Foreign Origin ......................................................5

Relationship to Dosage Forms/Dosage Form Approval ..........6

PART II SPECIFIC INTERPRETATIONS FOR

BPC OPERATIONS

General ..................................................................................6

Buildings and Facilities.............................................................6

Equipment ..............................................................................9

Raw Materials ........................................................................10

Containers, Closures, and Packaging Components ..................11

Production and Process Controls ............................................11

In-Process Testing ..................................................................13

Packaging and Labeling of Finished BPC ................................13

Expiration Dating or Re-evaluation Dating ...............................13

Laboratory Controls ...............................................................14

Stability Testing ......................................................................14

Reserve Samples ....................................................................15

Batch Production Records ......................................................15

APPENDIX

A. Impurities ..........................................................................15

B. References.........................................................................16

PART I - GENERAL GUIDANCE

Introduction

This document is intended to aid agency personnel in determining whether the methods used in, and the facilities and manufacturing controls used for, the production of Bulk Pharmaceutical Chemicals (BPCs) are adequate to assure that they have the quality and purity which they purport or are represented to possess.

There are basic differences between the processes used for the production of BPCs and the processes used for the production of finished products. BPCs usually are made by chemical synthesis, by recombinant DNA technology, fermentation, enzymatic reactions, recovery from natural materials, or combinations of these processes. On the other hand, finished drug products are usually the result of a formulation from bulk materials whose quality can be measured against fixed specifications.

In almost every case in the production of BPCs, the starting materials, or derivatives of the starting materials, undergo some significant chemical change. Impurities, contaminants, carriers, vehicles, inerts, diluents, and/or unwanted crystalline or molecular forms which may be present in the raw materials are largely removed by various treatments in the production process. Purification is the ultimate objective and is effected by various chemical, physical, and/or biological processing steps. The effectiveness of these steps is in turn confirmed by various chemical, biological, and physical tests of the BPC.

In contrast, in finished drug product production, the quality of the drug ingredients (the components), and the care exercised in handling them, somewhat predetermines the purity of the finished drug product. Purification steps usually are not involved.

The use of precision automated, mechanical, or electronic control and recording equipment and of automated processing equipment is even more likely to be found in a BPC plant than in a finished drug product plant. Use of such equipment is appropriate when adequate inspection, calibration, and maintenance procedures are utilized.

Production equipment and operations will vary widely depending on the type of BPC in production, the scale of production, and the type of operation (batch vs. continuous). In general, the environmental conditions, equipment, and operational techniques employed are those associated with the chemical industry rather than the finished drug product industry. Chemical processes frequently are performed in closed systems, which tends to provide protection against contamination, even when the reaction vessels are not enclosed in buildings. However, this does not preclude the introduction of contaminants from equipment, materials used to protect equipment, corrosion, cleaning, and personnel.

In evaluating the adequacy of measures taken to preclude contamination of, or by, materials in the process, it is appropriate to consider the type of system (open or closed), form of the material (wet or dry), stage of processing and use of the equipment and/or area (multi-purpose or dedicated). "Closed" systems in chemical plants are often not closed when they are being charged and/or when the final product is being emptied. Also, the same reaction vessels are frequently used for different reactants.

Other factors that an investigator must consider in evaluating a BPC plant are:

(a) Degree of exposure of the material to adverse environmental conditions;

(b) Potential for cross-contamination from any source;

(d) Sterile vs. non-sterile operations.

In the production of BPCs, the recycling of process liquors and recovery from waste streams which have been tested and meet appropriate standards often are necessary for quality, economic, and environmental reasons. In addition, the production of some BPCs involves processes in which chemical and biochemical mechanisms have not been fully understood and scientifically documented. Therefore, the methods and procedures for materials accountability will often differ from those applicable to the manufacture of dosage form drug products.

The producer of BPCs must recognize the need for appropriate evaluation, using appropriate standards and/or test procedures, of raw materials before their introduction into the process. In addition, as chemical processing proceeds, a chain of documentation should be established which at the minimum includes a written process and appropriate production records, records of raw materials used, records of initial and subsequent batch numbers, records of the critical processing steps accomplished, and intermediate test results with meaningful standards. It should be recognized that all intermediates need not be tested. A firm should, however, be able to identify critical or key points in the process where sampling and testing selective intermediates is necessary in order to monitor the performance of the process. As the end of the process is approached, the completeness of the records should increase, and the latter finishing steps should be thoroughly documented and conducted under appropriate conditions to avoid contamination and mixups.

Status of Bulk Pharmaceutical Chemicals

BPCs are components of drug products. The manufacture of BPCs should be carried out in accordance with concepts of good manufacturing practice (GMP) consistent with this guide whether or not the manufacturers are required to register under 21 CFR 207. The manufacturers of inactive ingredients may not be required to register with FDA, but they are not exempt from complying with GMP concepts, and they are not exempt from inspection. Whether or not this type of firm will be inspected on a surveillance basis is generally discretionary. However, such a firm is always subject to "for cause" inspection.

The question of when an industrial chemical becomes a BPC can be complex, and there is no satisfactory answer. However, criteria such as the following can be used to identify a chemical as a BPC:

(a) When there is no recognized non-drug commercial use for the chemical.

(b) When it reaches the point in its isolation and purification where it is intended that the substances will be used in a drug product.

Many elements and simple compounds that will ultimately comprise the molecule of BPC originate from botanicals, mines, oil wells, and sea water. It would be unrealistic to expect drug product GMP concepts to apply to the production of these progenitors. As a general rule, however, it is reasonable to expect GMP concepts to start to become applicable at that point where a starting material enters a biological or chemical synthesis or series of processing steps, where it is known that the end product will be a BPC.

Scope

This guide is applicable to all BPCs produced in the United States. It is also applicable to BPCs produced in foreign countries intended to be exported to the United States or to be delivered to a U.S. overseas base. This guide applies to: a) human drugs; b) veterinary drugs; and c) biologics.

The guide applies when the BPC is: a) a drug of animal, botanical, synthetic or biological origin, including those produced with rDNA technology; b) an inactive ingredient (although inspections will only be conducted by special assignment, or for cause); c) a component not appearing in the finished drug product; and d) a bulk intended for use in placebos.

Excluded from consideration are medical gases and bulk-packaged drug products (final dosage forms), which are subject to other requirements and full CGMPs.

General Guidance - Bulk GMPs

Although the GMP regulations under 21 CFR, Parts 210 and 211, apply only to finished dosage form drugs, Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act requires that all drugs be manufactured, processed, packed, and held in accordance with current good manufacturing practice (CGMP). No distinction is made between BPCs and finished pharmaceuticals, and failure of either to comply with CGMP constitutes a failure to comply with the requirements of the Act. There are many cases where GMPs for dosage form drugs and BPCs are parallel. For this reason, the requirements under Part 211 will be used as guidelines for inspection of BPC manufacturers, as interpreted in this document. This document does not supersede the GMP regulations, rather it provides general guidance to inspectional personnel as to the extent and point of application of some of the concepts of Parts 210 and 211 to BPC production.

Although strict observance of GMPs, approaching or equaling those expected for finished drug products, may be expected in some types of bulk processes, in most others it is neither feasible nor required to apply rigid controls during the early processing steps. In all processes of this type, however, the requirements should be increasingly tightened according to some reasonable rationale. At some logical processing step, usually well before the final finishing operation, appropriate GMPs should be imposed and maintained throughout the remainder of the process.

Good judgement and a thorough knowledge of the process are required to permit sound evaluation of the processing step at which imposition of GMPs should take place. A detailed process flow diagram should be available for the processes used. This diagram should identify the unit operations, equipment used, stages at which various substances are added, key steps in the process, critical parameters (time, temperature, pressure, etc.) and monitoring points. As briefly discussed in the introduction, the documentation system required for the early steps in the process must provide a chain of documentation but need not necessarily be as comprehensive as in the later parts of the process. Complete documentation should, at a minimum, be initiated where:

(a) The bulk pharmaceutical chemical can be identified and quantified for those processes where the molecule is produced during the course of the process (e.g., fermentation, synthesis, or recombinant DNA technology). In this regard, a theoretical yield should be established with appropriate limits, and there should be an investigation if the actual yield falls outside the limits.

(b) A contaminant, impurity, or other substance likely to adversely affect the purity, potency, or form of the molecule, is first identified and subsequent attempts are made to remove it (e.g., removal of crystalline occlusion, etc.).

(c) An attempt is initiated to separate a mixture of different forms of the same molecule and isolate a desired form of the molecule for pharmacological or other reasons (e.g., separation of racemic mixtures).

The complete documentation should be continued throughout the remainder of the process, including the application of full GMP concepts, for all significant processing steps until the BPC is packaged into a bulk container, or is transported without containerization to a location for subsequent manufacture into drug products.

Significant processing steps can involve a number of unit operations or unit processes. Unit operations include those processing steps wherein the material is treated by physical means and/or the transfer and change of energy, but no chemical change of the molecule occurs; unit processes include those processing steps wherein the molecule undergoes a chemical change.

Significant processing steps can include: a) phase changes involving either the desired molecule or the solvent, inert carrier or vehicle, e.g., dissolution, crystallization, evaporation, sublimation, distillation or absorption; b) a phase separation such as filtration or centrifugation; c) any chemical change involving the desired molecule, e.g., removal or addition of water of hydration, acetylization, formation of the salt; d) an adjustment of the solution containing the molecule such as adjustment of pH or pO2; e) a precision measurement of contained or added BPC components, in-process solutions, recycled materials is performed, i.e., weighing, volumetric measuring, optical rotation, spectrophotometric determinations, etc.; and f) changes occur in surface area, particle size, or lot uniformity, e.g., milling, agglomeration, blending.

In order to promote uniformity in inspectional GMP coverage for a BPC, the following minimal criteria should be applied:

The lot of BPC to be released and/or certified is the essential element. A unique lot number should be assigned to this quantity of material. The firm should be prepared to demonstrate that this lot:

(a) Has been prepared under GMP conditions from the processing point as described above.

(b) Has a batch record (as described later in this document).

(d) Is not intermingled with material from other lots for the purpose of hiding or diluting an adulterated substance while completing the processing through packaging.

(e) Has been sampled in accordance with a sampling plan which assures that the sample truly represents the lot.

(f) Has been analyzed using scientifically sound tests and methods designed to assure that the product meets established standards and specifications for quality, identity, and purity.

(g) Has stability data to support the intended period of use.

Inspectional Approach

The inspectional approach for coverage of a BPC operation should be the same whether or not that BPC is referenced as active ingredient in a pending application. The purpose, operational limitations and validation of the critical processing steps of a production process should be examined to determine that the firm adequately controls such steps to assure that the process works consistently. Overall, the inspection must determine the BPC manufacturer's capability to deliver a product that consistently meets the specifications of the bulk drug substance that the finished dosage form manufacturer listed in the application and/or the product needed for research purposes.

BPC manufacturing plants often produce laboratory scale or "pilot" batches. Scale-up to commercial full-scale (routine) production may involve several stages and data should be reviewed to demonstrate the adequacy of the scale-up process. Such scale-ups to commercial size production may produce significant problems in consistency among batches. Pilot batches serve as the basis for establishing in-process and finished product purity specifications. Typically, manufacturers will generate reports that discuss the development and limitation of the manufacturing process. Summaries of such reports should be reviewed to determine if the plant is capable of producing adequately the bulk substance. The reports serve as the basis for the validation of the manufacturing and control process and the basic documentation that the process works consistently.