1、GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT AND VALIDATIONJanuary, 1994Note: 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
2、for or on any person(s).I INTRODUCTIONThis inspection guide provides information regarding the inspection and evaluation of the manufacturing and control processes used to manufacture solid oral dosage form pharmaceutical products. This document provides guidance for the FDA investigator and promote
3、s uniformity and consistency during the inspection and evaluation of the validation of the solid oral dosage form manufacturing and control processes. It covers three phases of the validation process; product development, design of the validation protocol, and demonstration runs (validation) of the
4、equipment and process in the manufacture of full scale commercial production batches.Although this document it is not all inclusive, it addresses many of the issues and examples of validation problems of oral solid dosage forms which investigators and analysts may encounter. The inspection team is e
5、xpected to review other agency documents in preparation for these inspectionsThe Validation Guideline issued by the agency in 1987 defines processvalidation as establishing documented evidence which provides a high degreeof assurance that a specific process will consistently produce a productmeeting
6、 its predetermined specifications and quality attributes.The three components of this definition include documented evidence,consistency, and predetermined specifications. Documented evidence includesthe experiments, data and analytical results that support the masterformula, the in-process and fini
7、shed product specifications, and the filedmanufacturing process.With regard to consistency, several batches would have to be manufactured,using the full scale batch size, to demonstrate that a process meets theconsistency test. At least three batches are needed to demonstrateconsistency.The developm
8、ent of a product and its manufacturing process andspecifications, the design of the validation protocol, and the demonstration(validation) runs of the full scale manufacturing process requiresscientific judgement based on good scientific data. We expect thatin-process control and product specificati
9、ons will be established during theproduct development process, with the test batch serving as the criticalbatch used for the establishment of specifications.Specifications, such as hardness and particle size, should be establishedprior to validation of the process; these specifications should be inc
10、ludedin the validation protocol. The use of product development runs of theprocess to establish both specifications and demonstrate that the system isvalidated often causes problems. In these cases, more in-depth inspectionand evaluation will be required; some of these process runs often producefail
11、ing product because the product specifications have not been fullyestablished and tested.The inspection team should observe facilities, equipment and processes toput data review in proper context. It is also important that raw data,including validation and laboratory logbooks be audited or reviewed
12、toverify accuracy and authenticity.II BACKGROUNDTwo common complaints regarding validation issues frequently have beenraised. The first concerns the misconception that the 1987 validation guiderepresents a new requirement. The second concerns the lack of specificity inthe agencys guides. In 1978, th
13、e Current Good Manufacturing PracticeRegulations were revised and provided for process validation. Therefore thisguideline does not represent a new requirement. The regulation is nearly 15years old.Both the agency and the industry have recognized the need to establishgeneral guidance for the validat
14、ion of manufacturing processes, and theagency published a draft guideline in March, 1983. However this draftguideline was a very general document addressing general principles and wasapplicable to sterile and non-sterile drugs and devices. In March, 1984, itwas reissued as a draft guideline, and was
15、 finalized in May, 1987.The 1987 validation guideline merely points out the need to adequatelydevelop and control manufacturing processes. It discusses microbiologicalissues and provides few specific an practical applications for thevalidation of manufacturing processes for a marketed solid oral dos
16、age form.The issue of retrospective validation, and its application to marketedproducts, is frequently encountered. This concept of using historical data(test results), along with process control and process specificity was ofvalue until more scientific methods for demonstrating process validationev
17、olved. It should be pointed out that retrospective validation is notmerely the review of test results. It also requires that the manufacturingprocess be specific and the same each time a batch is manufactured. Thus,specific raw material specifications (including particle size whennecessary), in-proc
18、ess specifications (tablet hardness, etc.), and specificmanufacturing directions are required. Obviously, any failing batchesattributed to the process would necessitate the conclusion that the processis not validated and is inadequate.Prospective process validation is required, particularly for thos
19、e productsintroduced in the last 7 to 8 years, or those for which manufacturingchanges have been made. However, in some cases where older products havebeen on the market without sufficient pre-market process validation, it maybe possible to validate, in some measure, the adequacy of the process byex
20、amination of accumulated test data on the product and records of themanufacturing procedures used.III PRODUCT DEVELOPMENTA. PRODUCT DEVELOPMENT REPORTSThere is no statute or regulation that specifically requires a productdevelopment report, although companies are required to produce scientificdata w
21、hich justifies the formulation and the manufacturing and controlprocesses. Most companies have used product development reports, technologytransfer reports, and others to summarize the scientific data that justifiesthe product and process. The product development report should satisfy theneeds of th
22、e company. Therefore, there is no specific format for thecontents of the report.It is suggested that the company develop a product development SOP whichdescribes the development process, the documentation requirements, and theindividuals responsible for approving the filed process. This SOP can bebr
23、ief and again there is no legal requirement that companies produce such anSOP.Investigators must not list the absence and or the poor quality of a productdevelopment report on the FDA 483. The investigators should list or includethe inadequacy of data to support the filed process and specific Master
24、Formula filed. It is not a GMP deficiency nor is it a filing requirement tohave a formal Development Report. Investigators should review productdevelopment reports since they will reduce the time required to inspect theprocess.The development data found in these reports should include the following:
25、1. Drug Substance CharacterizationCharacterization of the chemical and physical properties of the drugsubstance is one of the most important steps in the development of a soliddosage form. Chemical properties especially the identification of impuritiesare very important. In addition, the physical pr
26、operties of the BPC such assolubility, polymorphism, hygroscopicity, particle size, density, etc. mustbe addressed.The literature, and actual experience demonstrates, that the physicalquality, e.g., particle size of raw materials, can sometimes produce asignificant impact on the availability and cli
27、nical effect of a dosage formdrug. Therefore, it is appropriate that the physical characteristics of adrug substance be characterized, that the impact of the physicalcharacteristics be determined and that a specification for the bulk drugproduct be established if necessary.Development data will vary
28、 between new drugs and generics. Characterizationand establishment of specifications for the drug substance is one example.In most cases the manufacturing process for a new drug substance (newchemical entity) is developed and scaled-up before the dosage form. In earlydevelopment stages very little i
29、nformation is available regardingpolymorphic forms, solubility, etc. Consequently, changes to themanufacturing process for the drug substance may change the purity profileor physical characteristics and thus cause problems with the finished dosageform. Although these types of problems are expected,
30、the firm mustinvestigate and document batch failures for the BPC and dosage form product.On the other hand the generic manufacturer usually purchases the drugsubstance from a BPC manufacturer who may not be willing to supplyinformation regarding the synthesis or analysis of the drug substance.Theref
31、ore, the finished dosage form manufacturer must perform theappropriate test to characterize the drug substance chemically andphysically and establish appropriate specifications. This may requiredeveloping analytical methods to identify impurities. In some cases thisinformation can be obtained from l
32、iterature searches.In either case it is important that the firm compare the drug substance usedto manufacturer the bio-batch or clinical batch(es) and the drug substanceused for the commercial batches. Therefore, review the specifications,analytical methods, and test results for the lots of the drug
33、 substance usedto manufacture these batches. Remember that the safety of the drug may bebased upon the type and level of impurities and different physicalcharacteristics may affect dissolution or content uniformity.Inspectional coverage should be given to the physical characteristics of rawmaterials
34、, especially bulk drug substances, since they frequently affect theperformance of the dosage form in which they are incorporated. This isparticularly important for those drug substances that are poorly soluble inwater.For those products on which biostudies were conducted, the physicalcharacteristics
35、 of the drug substance used for the study should serve as thebasis for the physical specifications.It is widely recognized that when discussing in-vivo release rates and drugabsorption rates, fast, immediate release is not always best. For some“immediate“ release drug products, such as carbamazepine
36、 tablets, a slowerrelease is desired. Therefore, it is frequently desirable to have minimumand maximum particle size specifications to control the release rate. Forexample, micronizing or milling a drug substance and providing greatersurface area of the substance may also result in faster dissolutio
37、n andpossibly faster absorption and higher blood levels. Such changes to“improve“ the dissolution may not always be desired.In addition to release or dissolution, variation in particle size, particleshape, and/or bulk density can also have an effect on the uniformity ofdosage forms, particularly tho
38、se manufactured by direct compression ordirect encapsulation.Particulate solids, once mixed, have a tendency to segregate by virtue of differences in the shape, size and density (other variables are also important) of the particles of which they are composed. This process of separation occurs during
39、 mixing, as well as during subsequent handling of the completed mix. Generally, large differences in particle size, density or shape within the mixture result in instability in the mixture. The segregation process normally requires energy input and can be reduced following mixing by careful handling
40、.Some manufacturers have established wide ranges for specifications.Investigators should review these specifications from a GMP and validationperspective. Even though a wide range for a physical specification, such asparticle size or surface area may be established in a filing, it is expectedthat su
41、ch ranges be verified in the validation of the process. In a recentcourt decision the judge ruled that companies cannot hide behind theapproval of processes listed in an application when these processes do notwork. In other words the approval of the filing has no impact on processesthat do not perfo
42、rm consistently.For example, in a filed process it was determined that particle size wouldhave no effect on drug absorption and dissolution and a wide range particlesize specification was established. However, in the GMP review, it was foundthat variation in particle size had a major effect on conte
43、nt uniformity.Therefore, a tighter particle size specification had to be established.Control of the physical characteristics of the excipient is also importantbecause variations in such characteristics may also affect the performanceof the dosage form. Changes in particle size of some excipients, fo
44、rexample, may affect content uniformity. In other cases, a change in thesupplier of an excipient or lubricant may affect dissolution orbioavailability. In fact, the release of the active ingredients in someproducts is “timed“ by varying lubricant blending time and concentration.The literature contai
45、ns many examples of lubricant processing causing majorchanges. Such changes in excipients illustrate the deficiencies with theutilization of retrospective validation because, for such validation to beContinued to next message This message is part 2 of a previous message satisfactory, control of all
46、parameters and key steps in the process arenecessary.The control of mixing times and physical characteristics of all ingredientsis critical to successful validation of all formulations and processes. Amajor question that must be addressed is the need for testing physicalcharacteristics (particle siz
47、e) for each batch of excipient. For many singlesource excipients, particle size is a supplier specification and is usuallytightly controlled. Having established a specification and not testing eachlot of excipient upon receipt may be satisfactory in such cases. However,for some multi-source excipien
48、ts and where the dosage formulator expects toshift sources of supply, there may be differences in physicalcharacteristics (particle size) that may have an effect on dose uniformityand dissolution. Examine the practices with respect to the source of supplyof the key excipients and determine if there
49、is justification for the lackof testing lots of excipient for physical characteristics.2. Manufacturing ProceduresProcedures used to manufacture development batches must be specific and welldocumented. This is necessary for scale-up and subsequent comparison to thecommercial process.This is another area where you will see differences between NDA/NADA andANDA/ANADA products. In the case of the NDA/NADA you will see severalclinical and/or test batches manufactured over a period of time and youwould expect to see changes in the process as more is learned about the drugand the process.
