  |
|
 |
|
FDA Home Page | Federal-State | Import Program | Compliance | Inspection | Science | ORA Search  | ||
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
A. Impurities ..........................................................................15
B. References.........................................................................16
PART I - GENERAL GUIDANCE
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;
(c) Relative ease and thoroughness of clean-up;
(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.
(c) When the manufacturer sells the product or offers it for sale to a pharmaceutical firm for use 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.
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.
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).
(c) Is homogenous.
(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.
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.
Drug Master Files (DMFs) are a valuable source of detailed information regarding the process and controls for BPCs. Although DMFs are not mandatory, most firms, particularly foreign manufacturers, have submitted them to FDA. A review of a process flow chart is helpful in understanding the various processing stages. Then, in conjunction with the review of the processing records, the critical stages should be identified, typically those where in-process samples are collected. The information expected from in-process testing should be determined along with the action to be taken by the firm should these specification limits be exceeded. For example, an in-process test result may show the presence of some unreacted material which may indicate that the process time should be extended.
A good starting point for the BPC inspection is a review of product failures evidenced by the rejection of a batch that did not meet specifications, return of a product by a customer, or recall of the product. The cause of the failure should have been determined by the manufacture, a report of the investigation prepared, and subsequent corrective action initiated and documented. Such records and documents should be reviewed to ensure that such product failures are not the result of a process that has been poorly developed or one that does not perform consistently.
Complaint files should also be reviewed since customers may report some aspects of product attributes that are not entirely suitable for their use. These may be caused by impurities or inconsistencies in the BPC manufacturing process. Also, storage areas in the warehouse may hold rejected product. In addition, a review of change control logs, material review board documents, and master formula and batch production records showing frequent revisions may reveal problems in the BPC production process.
In the analytical laboratory, specifications for the presence of unreacted intermediates and solvent residues in the finished BPC should be reviewed. These ranges should be at or near irreducible levels.
An inspectional team consisting of investigators and engineers, laboratory analysts or computer experts should participate in the inspection, as appropriate, when resources permit.
Domestic manufacturers of bulk pharmaceutical chemicals are required to register (and list their products) in accordance with section 510 of the Act if they meet the definition of a "bulk drug substance" under 21 CFR 207.3(a)(4), i.e., a substance that is represented as a drug and, when used, becomes an active ingredient or finished dosage form of such drug. Specifically excluded from registration are manufacturers of intermediates (21 CFR 207.3(a)(4)) and inactive ingredients which are excipients, colorings, etc. (21 CFR 207.10(e)).
The results of inspections of foreign manufacturers of BPCs directly affect the status of these products when offered for entry into this country. BPC's may be sampled, detained, and/or refused entry into the United States if an inspection of the foreign manufacturer reveals that the firm is not complying with GMPs. This would also be the case if the products demonstrate actual adulteration or misbranding.
Although foreign firms are not required to register in accordance with section 510 of the Act, they are required to list all of their products (21 CFR 207.40(a)). Products not listed are subject to detention and/or refusal of entry.
Relationship to Dosage Forms and Dosage Form Approval
The finished product formulator is highly dependent on the BPC manufacturer to provide bulk substances uniform in chemical and physical characteristics. This is particularly important in the context of the product approval process where bioequivalency comparisons are made between clinical production or biobatches and commercial batches. The BPC used to manufacture commercial batches must not significantly differ from that used on these test batches to provide adequate assurance of product performance. Where significant differences occur, additional testing by the dose form manufacturer to establish the equivalence of the finished product may be required. This remains equally important post-approval for subsequent commercial batches to assure that marketed products are not adversely affected over time.
Manufacturers holding DMFs covering production of BPCs (21 CFR 314.420) must update such DMFs with any changes. The DMF holders must also notify each dose form manufacturer referencing the DMF of any such changes to the DMF.
In general, BPCs are used as purchased, with no further refining or purification taking place. Consequently, impurities present in the BPC will be present in the finished dosage form.
While dosage form manufacturers may have limited control over BPC quality (obtaining certificates of analysis and testing representative samples), the BPC manufacturer has ultimate control over physical characteristics, quality, and the presence of trace-level impurities in the BPC.
Many bulk substances are used in different types of dosage forms including oral, topical and parenteral products where physical characteristics, particularly particle size, may be important. While it is primarily the dosage form manufacturer's responsibility to identify the particular physical characteristics needed, it is the responsibility of the BPC manufacturer to adequately control processes to consistently provide BPCs complying with physical specifications.
The end use of the BPC should be identified and kept in mind during inspections of BPC manufacturers. A particularly important distinction involves whether or not the BPC will be used in the preparation of a sterile dosage form and whether or not it is represented as pyrogen free. The BPC manufacturer is responsible for ensuring that BPCs are pyrogen free if they make such a representation in specifications, labeling, or applications, including DMFs. In addition, any manipulation of sterile BPCs post-sterilization must be performed as a validated aseptic process. This is particularly important for those BPCs which are not further sterilized prior to packaging into final containers (e.g., bulk antibiotic powders).
In some instances, the USP monograph may specify that the BPCs not meeting parenteral grade standards be labeled as not suitable for use in the preparation of injectable products.
PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS
The following sections will discuss those specific points of the CGMPs which are clearly different in a BPC operation in contrast to a finished product operation. Points not separately discussed here should be viewed as appropriate to BPC manufacturing operations using finished product GMPs for guidance.
(a) Contamination/Cross Contamination
Cross contamination is not permitted under any circumstances. However, the fact that a BPC plant is, or can be, used for manufacturing multiple drugs, even simultaneously, is not in itself objectionable with only a few exceptions. There must be separate facilities and completely separate air handling systems for the production of penicillin as the CGMP regulations require for dosage form drug products. It is also encouraged that separate facilities and air handling systems be used for the production of certain steroids, alkaloids, cephalosporins, certain hazardous or toxic drugs, pesticides, chemicals, and/or starting materials.
NOTE: Containment via closed system is considered a separate facility. The intent is to require isolation of penicillin production operations from operations for non-penicillin products. Separation can be achieved in a facility, building, or plant by effectively isolating and sealing off from one another these two types of operations. Isolation of facilities does not necessarily mean separation by geographical distance or the placement of these operations in separate buildings. Effective means can almost certainly be developed to separate activities from one another to prevent cross-contamination problems within a single building. Containment in a fermentor would meet this criterion and they are applicable to both dry and liquid state penicillin production.
Even though penicillin production may take place in the same building as non-penicillin production, air handling systems must at all times be completely separate. This includes fermentation procedures. This is the only means by which cross-contamination can be prevented through air facilities.
The point at which the final BPC product is initially recovered (usually as a moist cake from a centrifuge or filter press) should be in a clean environment and not exposed to airborne contaminants such as dust from other drugs or industrial chemicals. Typically, the damp product will be unloaded into clean, covered containers and transported elsewhere for drying and other manipulations. These subsequent operations should be performed in separate areas because, once dry, the BPC is more likely to contaminate its environment; this in turn makes it likely that other products in the same area might become contaminated. The primary consideration is that the building and facilities should not contribute to an actual or potential contamination of the BPC.
Air handling systems for BPC plants should be designed to prevent cross-contamination. For economic reasons, it is a common practice to recycle a portion of the exhaust air back into the same area. For dedicated areas processing the same BPC, this is not objectionable. The adequacy of such a system of operation for multi-use areas, especially if several products are processed simultaneously, should be carefully analyzed. In multi-use areas where several products are completely confined in closed vessels and piping systems, the extent of filtration of the supply air (combined fresh make-up air and recycled air) is not a problem (although other regulatory agencies or company policy may impose restrictions) except when the closed system must be opened (charging). In those areas where the BPCs are in a damp or moistened form (such as filter or centrifuge cake) and may be exposed to the room air environment, filter efficiencies on the supply air system as low as 85% may be perfectly adequate. In those areas wherein one or more of the products is being processed in a dry form, even total filtration of the entire supply air flow with HEPA filters may not be adequate. In all cases, the firm should be able to demonstrate adequacy of their air handling system with data and (in case of doubt) the investigator should consider collection of product samples for analysis for cross-contamination.
Process wastes and unusable residues should be removed and disposed of in a manner that will insure that they do not interfere with subsequent steps of the process or adulterate the product.
Adequate sanitation of buildings and areas for BPCs requires considerable judgement. Many starting materials, particularly botanicals, may have some unavoidable contamination with rodent or other animal filth or be infested with insects. In such cases, it is not realistic to expect high standards in storage areas for starting materials and perhaps in the limited area of the plant wherein the initial steps of processing are conducted.
The control methods utilized by the firm to prevent an increase of such contamination or infestation in holding areas, or its spread to other areas of the plant, are of primary importance.
(b) Water Systems/Water Quality
Water used in the production of BPCs in many instances (e.g., fermentation of antibiotics) may be potable water obtained from wells or surface sources. This is acceptable provided that water quality standards are established that are consistent with compendial or other regulatory requirements for source drinking water. Although it is not expected that potable water be routinely tested as a component, sufficient data from periodic testing should be available to show compliance with standards from both chemical and microbiological standpoints, including freedom from pathogenic organisms. Where adequate data are available from municipal water authorities, it need not be generated by the manufacturer.
Purified water is widely used in the manufacture of BPCs. Because of the well recognized potential for microbial growth in deionizers and ultrafiltration (UF) or reverse osmosis (RO) systems used to produce purified water, such systems must be properly validated and controlled. Proper control methods include the establishment of water quality specifications and corresponding action levels, remedial action when microbial levels are exceeded, and adequate maintenance procedures such as regeneration and sanitation/sterilization. Appropriate specifications for chemical and microbial quality should be established and periodic testing conducted. Such specifications will vary depending on the process and the point in the process where the water is used. For example, if the water is used in later processing steps such as for a final wash of the filter cake, or if the BPC is crystallized from an aqueous system, the water quality standards should be higher than normally specified for purified water. This is particularly important where the BPC is intended for use in parenteral dosage forms. The frequency of microbial and chemical testing of purified water is dependent upon a variety of factors including the test results and the point in the process (e.g., final wash in centrifuge) at which such water is used.
The USP includes suggested microbial action guidelines for source drinking water and purified water in the General Chapter on Water for Pharmaceutical Purposes and includes standards for specific types of water in monographs (e.g. Purified Water, USP). If the firm specifies a water of compendial quality in an application, the water should meet the standards given in the compendium.
Similar principles to those discussed above for purified water apply to Water For Injection (WFI) utilized in sterile and pyrogen-free BPC processing. The WFI system must be monitored for microorganisms and the validation data and reports of monitoring should be reviewed as is required for the production of finished dosage forms.
Most purified and WFI water systems, including RO and UF systems, have the potential for the development of endotoxins. If the final BPC is purported to be pyrogen free or sterile, or will be used in preparing parenteral products, routine testing of the process water for endotoxins (preferably by the LAL method) is indicated. However, end point testing alone is not adequate and validation of the system to control endotoxin development should be conducted.
(c) Aseptic/Sterile Processing
One of the more difficult processes is the manufacture of a sterile BPC. The aseptic crystallization and subsequent processing (drying, milling, and blending) present unique challenges. Since the operators are the primary source of contamination in an aseptic operation, processes are being designed to eliminate direct operator contact. However, some aseptic bulk operations still utilize considerable operator involvement which requires adequate controls. Major potential problem areas include aseptic removal of the BPC from the centrifuge, manual transfer to drying trays and mills, and the inability to sterilize the dryer.
Unfortunately, not all equipment currently in use can be sterilized. The BPC manufacturer must have data to document the sanitizing of critical processing equipment such as centrifuges and dryers.
Sterilization by use of ethylene oxide is sometimes attempted for powders. In this operation, the powders are spread in a thin layer and exposed to the gas. Typically, however, ethylene oxide does not penetrate the BPC in this powdered form. The manufacturer should validate that the ethylene oxide exposure does, in fact, produce a sterile product.
The Sterile Drug Process Inspections Compliance Program (CP 7356.002A) provides detailed inspectional guidance for coverage of the manufacture of sterile BPCs. Also, the Aseptic Processing Guidelines, although intended for coverage of dosage forms, includes principles that are also applicable to aseptic processing of sterile bulks. Both documents should be reviewed in association with any inspections of the manufacture of sterile BPCs.
(a) Multipurpose Equipment
As is the case with buildings, many BPCs are produced using multipurpose equipment. Fermentation tanks, reactors, centrifuges, and other pieces of equipment are readily used or adapted for a variety of products. With few exceptions, such multiple usage is satisfactory provided that the equipment is cleanable and is in fact cleaned according to written procedures. The cleaning program should take into consideration the need for different procedures depending on what product or intermediate was produced. Equipment that contains tarry or gummy residues that cannot be removed readily should be dedicated for use only with limited portions of a synthesis.
Where temperature control is important, temperature recording devices should be utilized, with recording charts retained as part of the batch record. For example, reactors may require narrow temperature ranges for consistent operation, and when recorders are absent, the manufacturer should justify their absence.
(b) Equipment Cleaning and Use Log
Where multipurpose equipment is in use, it is important to be able to determine previous usage as an aid in investigating cross-contamination or the possibility thereof.
An equipment cleaning and use log, while desirable and even preferable, is not the only method of determining prior use. Generally speaking, any documentation system that clearly identifies the previous batch and shows that the equipment was in fact cleaned is acceptable.
(c) Equipment Located Outdoors
Some fermentation tanks, reaction vessels, and other equipment are not situated within buildings; thus a considerable amount of processing occurs out-of-doors. Such processing is unobjectionable provided that it occurs in a closed system.
(d) Protected Environment
Isolation of intermediates or products may require the use of a protected environment to avoid microbial contamination or degradation caused by exposure to air or light. The degree of protection required may vary depending on the stage of the process. Equipment should be designed to minimize the possibility of contamination when used by the operator. Often, direct contact is involved in the unloading of centrifuge bags, transfer hoses (particularly those used to transfer powders), drying equipment and pumps.
Also, the sanitary design of transfer equipment such as pumps should be evaluated. Those with moving parts should be assessed in regard to the integrity of seals and other packing materials to avoid product contamination.
Processes requiring special environments to assure product quality (inert atmosphere, protection from light, etc.) should be carefully scrutinized for any lapses in the special environment. If any such lapses are found in the production process, adequate evidence and appropriate rationales must be shown that such lapses have not compromised the quality of the BPC. Such environmental concerns become more important after the purification of the BPC has been completed. The area where the BPC may be exposed, and especially those used to manufacture parenteral substances, should have environmental quality similar to that used for the manufacture of dosage forms. For example, controlled areas may need to be established along with appropriate air quality classifications. Such areas should be serviced by suitable air handling systems and there should be adequate environmental monitoring programs. Any manipulation of sterile BPCs post-sterilization must be performed as an aseptic process, including the utilization of Class 100 air and other aseptic controls.
(e) Cleaning of Product Contact Surfaces
Cleaning of multiple use equipment is an area where validation must be carried out. The manufacturer should have determined the degree of effectiveness of the cleaning procedure for each BPC or intermediate used in that particular piece of equipment.
Validation data should verify that the cleaning process will remove residues to an acceptable level. However, it may not be possible to remove absolutely every trace of material, even with a reasonable number of cleaning cycles.
Specific inspectional coverage for cleaning should include:
1. Detailed Cleaning Procedure:
There should be a written equipment cleaning procedure that provides details of what should be done and materials to be utilized. Some manufacturers list the specific solvent for each BPC and intermediate.
For stationary vessels, often clean-in-place (CIP) apparatus may be encountered. For evaluation of these systems, diagrams will be necessary, along with identification of specific valves.
2. Sampling Plan:
After cleaning, there should be some periodic testing to assure that the surface has been cleaned to the validated level. One common method is the analysis of the final rinse water or solvent for the presence of the substance last used in that piece of equipment. There should always be a specific analytical determination for such a residual substance.
3. Analytical Method/Cleaning Limits:
Part of the answer to the question, "how clean is clean?", is, "how good is your analytical system?" The sensitivity of modern analytical apparatus has lowered some detection thresholds past parts per million, down to parts per billion.
The residue limits established for each piece of apparatus should be practical, achievable, and verifiable. When reviewing these limits, ascertain the rationale for establishment at that level. The manufacturer should be able to document, by means of data, that the residual level permitted is scientifically sound.
Another factor to consider is the possible non-uniformity of the residue. If residue is found, it may not necessarily be at the maximum detectable level due to the random sampling, such as taking a swab from a limited area on that piece of equipment.
(a) Raw materials, especially those received in large quantities (hundreds of bags or in bulk), should not be physically moved from a quarantine area to a released area prior to quality control acceptance. However, such raw materials may remain in the quarantine area after release. The important consideration is that an unreleased material should not be used prior to quality control acceptance. Effective quarantine can be established with suitable identifying labels or signs, sound and valid documentation systems, etc. With increasing frequency, it is noted that such quarantine and documentation is widely being accomplished internally with a computer system in lieu of a physical stock control system. This is acceptable provided that system controls are adequate to prevent use of unreleased material.
(b) Film-wrapped palletized bags may not be individually identified by information normally applied to every container in a lot. To insist otherwise would destroy many of the advantages of film wrapped pallets. This is acceptable provided the pallet load itself is adequately identified. If issued individually, bags should be identified with the necessary information at the time of issuance.
(c) Some raw materials are stored in silos or other large containers, making precise separation of lots difficult. Considering that such materials are usually nutrients or are inactive, such storage is acceptable. It should be possible, via inventory or other records, to show usage of such materials with reasonable accuracy.
(d) Solvents used in BPC production are frequently stored in large tanks. Often, fresh and recovered solvents are commingled so that precise lot identity is missing. This is satisfactory provided incoming solvents are identified and tested prior to being mixed with recovered solvents and if the latter are tested for contaminates from the process in which they were used previously. The quality of the solvent mixture must also be monitored at suitable intervals.
(e) Some raw materials are stored out-of-doors; e.g., acids, other corrosive substances, explosive materials, etc. Such storage conditions are satisfactory provided the containers give suitable protection to their contents, identifying labels remain legible, and containers are adequately cleaned prior to opening and use.
(f) Some raw materials may not be acceptance tested by the firm because of the hazards involved; e.g., phosphorus pentachloride, sodium azide, etc. This is acceptable where there is a reason based on safety or other valid considerations. In such a circumstance, assay certification from the vendor should be on file. There should always be some evidence of an attempt by the BPC manufacturer to establish identity even if it is only a visual examination of containers, examination of labels, and recording of lot numbers from the labels.
Containers, Closures, and Packaging
Components
A system for BPC containers, closures, and packaging components should include the following features at a minimum:
(a) Suitable written specifications, examina- tion or testing methods, and cleaning procedures where so indicated.
(b) Determination that the container-closure system is not reactive, additive, or absorptive so as to alter the quality of the BPC beyond its established specifications and that it provides adequate protection against deterioration and contamination.
(c) Storage and handling in a manner to protect containers and closures from contamination and deterioration and to avoid mixups (e.g., between containers that have different specifications but are similar in appearance).
(d) Use of bulk shipping containers in which bulk pharmaceutical components were received should be avoided for BPC storage or shipment unless a suitable polymer lining or inner bag is used.
Production and Process Controls
(a) Mother Liquors
Mother liquors containing recoverable amounts of BPCs are frequently re-used. Such re-use may consist of employing the mother liquor to dissolve the reactants in the next run of that step in the synthesis. Re-use may also consist of a separate reaction to obtain a "second crop" of final product. Finally, since crystallizations are sometimes slow, some second crops are obtained simply by allowing the second crystallization to continue for long periods after the first crop is removed. These secondary recovery procedures are acceptable providing the isolated BPC meets its original, or other suitable, specifications. The recovery procedures should be indicated in batch production records.
Similarly, mother liquors may contain unreacted starting materials or intermediates that are not recoverable. Secondary recovery procedures for these materials are acceptable provided that the materials meet suitable specifications.
(b) In Process Blending/Mixing
Deliberate in-process blending, or mixing, is that blending required in the process for a variety of reasons and is carried out with reasonable reproducibility from run to run during the process. Examples include: 1) Collection of multiple fermentation batches in a single holding tank (with a new batch number); 2) Recycling solution from one batch for further use in a succeeding batch; 3) Repeated crystallizations of the same mother liquor for better yield of crystals; and 4) Collecting several centrifuge loads in a single dryer/blender. Such in-process blending is acceptable provided it is adequately documented in batch production records.
Incidental carryover is another type of in-process mixing that occurs frequently. Examples include: 1) Residue adhering to the wall of a micronizer used for milling the finished BPC; 2) Residual layer of damp crystals remaining in a centrifuge bowl after discharge of the bulk of the crystals from a prior batch; and 3) Incomplete discharge of fluids or crystals from a processing vessel upon transfer of the material to the next step in the process. These practices are usually acceptable since we do not normally require complete cleanup between successive batches of the same drug during a production campaign. However, in the case of non-dedicated production units, complete cleaning procedures designed to prevent contamination that would alter the quality of the substance must be employed when changing from one BPC to another. The effectiveness of these cleaning procedures may require the use of analytical testing for the substances involved.
In contrast to in-process blending and incidental carryover discussed above, the process intent should be directed toward achieving homogeneity of the batch of finished BPC to the maximum extent feasible. Three areas in the processing of finished batches of BPCs should be examined carefully and critically. These are: 1) The final blending operation that will constitute the finished batch; 2) The point in the process at which the lot number is assigned; 3) The sampling procedure used to obtain the sample is intended to be representative of the batch.
Note: Blending of batches or lots that individually do not conform to specifications with other lots that do conform (to salvage adulterated material) is not acceptable practice.
(c) Validation of Process and Control
Procedures
An important factor in the assurance of product quality includes the adequate design and control of the manufacturing process. Routine end product testing alone is not necessarily sufficient because of limited sensitivity of such testing to reveal all variations that may occur and affect the chemical, physical, and microbial characteristics of the product. Each step of the manufacturing process must be controlled to the extent necessary to assure that the product meets established specifications. The concept of process validation is a key element in assuring that these quality assurance goals are met.
Process validation is required in general and specific terms by the CGMP regulations for finished dosage forms (21 CFR Parts 210 and 211). More specific guidance on process validation is provided in guidelines (See References). Many of these concepts are applicable to BPCs to assure that such BPCs are manufacturered in accordance with CGMPs as required by the Act under Section 501 (a)(2)(B).
BPC manufacturers are expected to adequately determine and document that significant manufacturing processes perform consistently. The type of BPC, the range of specifications and other factors determine the extent of the process development and documentation required. However, most bulk manufacturing processes and control procedures can be validated with less arduous procedures than would be required for finished dosage forms.
Many firms already possess the data necessary to prepare an evaluation of the process and demonstrate that it works consistently. For example, limitations of a reaction and/or purification steps are usually identified in the development phase. Impurities with acceptable levels and tests used to determine them are established at this phase. The report describing the process reactions and purifications, impurities, and key tests needed for process control provide the basis for validation. Thus, when the process is scaled up to production batch sizes, a comparison can be made with development batches. Scale-up and development reports, along with purity profiles would constitute such a validation report.
While validation can be applied to any process, greater emphasis should be placed on validation of the BPC production at the stage(s) in the synthesis and purification steps used for the bulk substance and/or the removal of impurities.
(d) Reprocessing
Where reprocessing occurs during the synthesis of a BPC, there should be written documentation covering the reason for the failure, the procedures involved in the reprocessing, and changes made to eliminate a recurrence of the problem. Merely relying on final testing of the reprocessed BPC as a means of demonstrating compliance with specifications, and neglecting the investigation and evaluation of the manufacturing process, is unacceptable.
Equivalence of the quality of reworked material to the original material must also be evaluated and documented to insure that the reprocessed batches will conform with all established standards, specifications, and characteristics. Obviously, if the product failure results from a human error, it will not reflect on the process, but may reflect on other aspects such as adequacy of training. However, there should be sufficient investigation, evaluation, and documentation to show that reprocessed product is at least equivalent to other acceptable product and that the failure did not result from an inadequate process.
(e) Process Change
Manufacturers should have a formal process change system in place with standard operating procedures covering such changes. Management of the change system should be assigned to an independent quality unit having responsibility and authority for final approval of process changes.
(f) Impurities
Characterization and control of impurities in a BPC are important because of the adverse effects that such impurities may have on dosage form stability, safety and efficacy. Consequently, it is important that manufacturers identify and set appropriate limits for impurities and adequately control manufacturing processes so that the impurities consistently meet established specifications.
The attached Appendix A (Impurities) includes a more detailed discussion of impurities and should be reviewed prior to conducting inspections.
BPCs are normally subjected to various in-process tests to show that a synthesis or fermentation is proceeding satisfactorily. Such tests are often performed by production personnel in production laboratory facilities. Approval to continue with the synthesis (process) is often issued within the production department. The important considerations are that specified tests are performed, recorded, and results are within specified limits. In addition, instruments should be calibrated at appropriate intervals.
It is important that a firm utilize a quality control unit independent from production that has the responsibility and authority to reject in-process materials not meeting specifications. Such responsibility and authority should also extend beyond testing to include overall quality assurance activities such as procedure approvals, investigation of product failures, process change approvals, and product record reviews.
Packaging and Labeling of Finished BPC
(a) Sound procedures must be employed to protect the quality and purity of the BPC when it is packaged and to assure that the correct label is applied to containers. A good system of packaging and labeling should have the following features at a minimum:
(1) A file of master labels. A responsible individual reviews incoming labels against the appropriate master labels.
(2) Storage of labels in separate containers, or compartments, to prevent mixups.
(3) Formal issuance by requisition or other document.
(4) Issuance of an exact number of labels sufficient for the number of containers to be labeled, retention copies, and calculated excesses, if any.
(5) The employment of a lot number from which the complete batch history can be determined.
(6) Avoidance of labeling more than one batch at a time without adequate separation and controls.
(7) Reconciliation of the number of labels issued with the number of units packaged, together with the destruction of excess labels bearing lot numbers.
(b) If returnable BPC containers are re-used, all previous labeling should be removed or defaced. If the containers are repetitively used solely for the same BPC, all previous lot numbers, or the entire label, should be removed or completely obliterated.
(c) Labeling for containers of BPCs is subject to all applicable provisions of 21 CFR, Parts 200 and 201. In case questionable labeling is encountered, collect samples of the labeling for submission to the appropriate Center(s) for review.
Expiration Dating or Re-evaluation Dating
(a) With few exceptions, expiration dates are not presently considered to be a general requirement for all BPCs. Thus the absence of an expiration date may not be objectionable. The chief exception is antibiotic BPCs where expiration dates are required by the antibiotics regulations.
(b) Where expiration or re-evaluation dates are used on BPCs either because of a regulatory requirement or voluntarily, they must be derived from appropriate stability testing.
(c) Where stability testing reveals a limited shelf life, e.g., less than two years, the label should declare a supportable expiration date or indicate the need for re-evaluation testing at an appropriate interval to assure quality at time of use.
(a) Raw materials are usually subjected to an identity test and additional testing to determine if they meet appropriate specifications. Such specifications will vary in depth, sophistication, and the amount of testing required to show conformance. This in turn will depend on various factors such as the critical nature of the raw material, its function in the process, the stage of the synthesis, etc. Raw material specifications should be written documents, even if only minimal requirements are required/requested. The specifications should be organized to separate those tests that are routine from those that are performed infrequently or for new suppliers.
(b) Laboratory controls should include a comprehensive set of meaningful analytical procedures designed to substantiate that each batch of finished BPC meets established specifications for quality, purity, identity, and assay. Data derived from manufacturing processes and from in-process controls also provide some assurance that a batch may be acceptable.
(c) Many BPCs are extracted from, or purified by, the use of organic solvents in the later (final) stages of recovery. The solvents are normally removed by drying the moist BPC. In view of the varying (and sometimes unknown) toxicity of solvents, it is important that BPC specifications include tests and limits for residues of solvents and other reactants. Refer to the attached Appendix A for further information about impurities, including volatile organic impurities.
(d) Appropriate analytical methods should be validated.
Most BPC manufacturers conduct stability testing programs for their products; however, such programs may be less comprehensive than the programs now required for finished pharmaceuticals.
Undetected changes in raw materials specifications, or subtle changes in manufacturing procedures, may affect the stability of BPCs. This, together with the generally widespread existence of stability testing programs, make it reasonable to require such programs for BPCs.
(a) A stability testing program for BPCs should contain the following features:
(1) The program should be formalized in writing.
(2) Stability samples should be stored in containers that approximate the market container. For example, where the product is marketed in polylined drums, it is acceptable to keep stability samples in the same container material/closure system within mini-fiber drums. Such samples may be stored in glass or other suitable containers only if there are data developed by the firm or others to show that results are comparable.
(3) The program should include samples from the first three commercial size batches.
(4) Thereafter, a minimum of one batch a year, if there is one, should be entered in the program.
NOTE: Lower levels of sampling may be acceptable if previous stability studies have shown the BPC to be stable for extended periods and the normal period between production and ultimate use of the BPC is relatively short.
(5) The samples should be stored under conditions specified on the label for the marketed product.
(6) It is recommended that additional samples be stored under stressful conditions (e.g., elevated temperature, light, humidity or freezing) if such conditions can be reasonably anticipated.
(7) Stability indicating methods should be used.
(b) Conducting a stability testing program does not usually lead to a requirement to employ expiration dates. If testing does not indicate a reasonable shelf life, e.g., two years or more, under anticipated storage conditions, then the BPC can be labeled with an expiration date or should be re-evaluated at appropriate intervals. If the need for special storage conditions exists, e.g., protection from light, such restrictions should be placed on the labeling.
Reserve samples of the released BPCs should be retained for one year after distribution is complete or for one year after expiration or re-evaluation date.
Documentation of the BPC manufacturing process should include a written description of the process and production records similar to those required for dosage form production. However, it is likely that computer systems will be associated with BPC production. Computer systems are increasingly used to initiate, monitor, adjust, and otherwise control both fermentations and syntheses. These operations may be accompanied by recording charts that show key parameters (e.g., temperature) at suitable intervals, or even continuously throughout the process. In other cases, key measurements (e.g., pH) may be displayed on a television screen for that moment in time but are not available in hard copy.
In both cases, conventional hard-copy batch production records may be missing. In other words, records showing addition of ingredients, actual performance of operations by identifiable individuals, and other information usually seen in conventional records may be missing. As a practical matter, when computers and other sophisticated equipment are employed, the emphasis must change from conventional, hand-written records to:
(a) Systems and procedures that show the equipment is in fact performing as intended;
(b) Checking and calibration of the equipment at appropriate intervals;
(c) Retention of suitable backup systems such as copies of the program, duplicate tapes, or microfilm;
(d) Assurance that changes in the program are made only by authorized personnel and that they are clearly documented.
The United States Pharmacopeia (USP) defines an impurity as any component of a drug substance (excluding water) that is not the chemical entity defined as the drug substance.
It has been demonstrated that impurities in a finished drug product can cause degradation and lead to stability problems. Further, some adverse reactions in patients have been traced to impurities in the active ingredient. Therefore, the presence or absence of impurities at the time of clinical trial and stability testing is a very important element of drug testing and development, and the appearance of an impurity in scaled up product that was not present during test stages presents serious questions about the stability of the product and its impact on safety and efficacy.
We expect the manufacturer to establish an appropriate impurity profile for each BPC based on adequate consideration of the process and test results. Because different manufacturers synthesize drug substances by different processes and, therefore, will probably have different impurities, the USP has developed the Ordinary Impurities Test in an effort to establish some specification. Also, in order to protect proprietary information, tests for specific impurities and even solvents are typically not listed in the compendia.
The USP also notes that the impurity profile of a drug substance is a description of the impurities present in a typical lot of drug substance produced by a given manufacturing process. Such impurities should not only be detected and quanitated, but should also be identified and characterized when this is possible with reasonable effort. Individual limits should be established for all major impurities.
During the inspection, compare the impurity profile for the pilot batch material to that of the commercial size BPC batches to determine if the profile has significant changes. In some cases, drug manufacturers have submitted purity profiles in filings. Yet, when covered in some detail in an inspection, it became apparent that additional impurity data obtained by other methods (gradient HPLC) had become available but not yet filed. Thus, manufacturers should be asked specifically for current complete purity profiles, and these profiles should include the levels of solvents normally found in the purified drug substance along with acceptable specifications. Determine if the current impurity profile is reported to dose form manufacturers, especially if it has changed. Also, determine if the DMF (or AADA for bulk antibiotics) is current.
The USP provides extensive coverage of impurities in the following three sections:
(a) USP Section 1086 - Impurities In Official Articles
This section defines five different types of impurities, both known and unknown including foreign substances, toxic impurities, con- comitant components (such as isomers or racemates), signal impurities (which are process related), and ordinary impurities. The USP notes that when a specific test and limit is specified for a known impurity, generally a reference standard for that impurity is required.
Two of the impurities are singled out for in-depth coverage, ordinary impurities and organic or volatile impurities.
(b) USP Section 466 - Ordinary Impurities
These are generally specified for each BPC in the individual monograph. The method of detection involves comparison with a USP reference standard, on a thin layer chromatographic (TLC) plate, with a review for spots other than the principal spot. The ordinary impurity total should not exceed 2% as a general limit.
Be sure to review the extensive USP coverage of 8 factors that should be considered in setting limits for impurity levels.
Related substances are defined as those structurally related to a drug substance such as a degradation product or impurities arising from a manufacturing process or during storage of the BPC.
Process contaminants are substances including reagents, inorganics (e.g., heavy metals, chloride, or sulfate), raw materials, and solvents. The USP notes that these substances may be introduced during manufacturing or handling procedures.
The third and most recent USP section regarding impurities is one that appears in the USP-NF XXII third supplement:
(c) USP Section 467 - Organic Volative
Impurities
Several gas chromatography (GC) methods are given for the detection of specific toxic solvents and the determination involves use of a standard solution of solvents. There are limits for specified organic volatile impurities present in the BPC unless otherwise noted in the individual monograph.
As the USP notes, the setting of limits on impurities in a BPC for use in an approved new drug may be much lower than those levels encountered when the substance was initially synthesized.
Further, additional purity data may be obtained by other methods such as gradient high performance liquid chromatography (HPLC). Be sure to ask for complete impurity profiles.
In preparation for a BPC inspection, these sections of the USP should be given a detailed review.
APPENDIX B
1. CP 7356.002A - Sterile Drug Process Inspections.
2. CP 7356.002F - Bulk Pharmaceutical Chemicals (BPCs).
3. Guideline on General Principles of Process Validation, May, 1987.
4. Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacturer of Drug Substances, Feb. 1987.
5. Guideline on Sterile Drug Products Produced by Aseptic Processing, June 1987.
6. Code of Federal Regulations, Title 21 Part 210 and 211, Drugs: Current Good Manufacturing Practice
314.420 - Drug Master Files
201.122 - Drugs for Processing, Repacking, or Manufacturing (bulk labeling requirements)
7. United States Pharmacopeia, Current Revision, and Supplements.
