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2008-08-22 15:58:18|  分类: FDA&EDQM Inspect |  标签: |举报 |字号 订阅

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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.


Buildings and Facilities


(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.

任何情况下都不容许交叉污染。然而,事实是,原料药工厂是,或可是是用于制造多种药品,甚至是同时生产地,极少数情况是可以接受的。对于青霉素的生产,必须有单独的设施和完整的分离空气处理系统,因为CGMP法规对制剂要求。对于某些甾体,生物碱, 头雹菌素类,某些环境污染或毒性药物,杀冲剂, 化学物质,和/或起始物料,鼓励使用单独的设备和空气处理系统。

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.

无菌药工艺审查程序(CP 7356.002A)提供了详细的审查指南用于制造无菌原料药。同时,无菌工艺指南,尽管旨在用于制剂,包括也适用于无菌原料药的无菌操作。文件应根据无菌原料药制造审查相关内容审查。



(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.


Raw Materials


(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.

一些原料储存在室外,如,酸,其它的腐蚀性物质,爆炸 物质,等。这些储存条件是令人满意的,假若容器对内含物有合适的保护,确认标签仍然清晰,在开启和使用前,容器是充分清洗了的。

(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




A system for BPC containers, closures, and packaging components should include the following features at a minimum:


(a) Suitable written specifications, examination 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




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).

工艺验证在制剂CGMP法规的一般和具体范围中都有要求(21CFR Parts 210 和211)。关于工艺验证的更多的具体的指南提供在指南中(见参考文献)。这其中的许多概念是适用于原料药的以确认这些原料药的制造是根据CGMP的要求的,如501(a)(2)(B)章中所要求的。

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.


In-process Testing


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.


Laboratory Controls


(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.


(e)   Appropriate analytical methods should be validated.


Stability Testing


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


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.


Batch Production Records


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:

两者的情况,常规的硬副本批生产记录可能会遗失。换句话说,表明组分增加的记录,实际操作,常规记录中看到的其它信息可能会缺失。实际存在的,当计算机和其它成熟的设备被使用,重点应由常规的, 手写记录变为:

(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.



附录 A



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

 USP 章467- 有机挥发杂质

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.



附录 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.


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