(精品)FDA口服制剂检查指南.doc

GUIDE TO INSPECTIONS OF ORAL SOLID DOSAGE FORMS PRE/POST APPROVAL ISSUES FOR DEVELOPMENT AND VALIDATION January, 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 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 promotes 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 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 expected 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 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 finished 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 development 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 specifications 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 includedin 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 producefailing 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 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 agency's guides. In 1978, the 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 validation 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 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 dosage 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 validation。