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, 1994

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).

I INTRODUCTION

This 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 inspections

The Validation Guideline issued by the agency in 1987 defines process
validation as establishing documented evidence which provides a high degree
of assurance that a specific process will consistently produce a product
meeting its predetermined specifications and quality attributes.

The three components of this definition include documented evidence,
consistency, and predetermined specifications. Documented evidence includes
the experiments, data and analytical results that support the master
formula, the in-process and finished product specifications, and the filed
manufacturing process.

With regard to consistency, several batches would have to be manufactured,
using the full scale batch size, to demonstrate that a process meets the
consistency test. At least three batches are needed to demonstrate
consistency.

The development of a product and its manufacturing process and
specifications, the design of the validation protocol, and the demonstration
(validation) runs of the full scale manufacturing process requires
scientific judgement based on good scientific data. We expect that
in-process control and product specifications will be established during the
product development process, with the test batch serving as the critical
batch used for the establishment of specifications.

Specifications, such as hardness and particle size, should be established
prior to validation of the process; these specifications should be included
in the validation protocol. The use of product development runs of the
process to establish both specifications and demonstrate that the system is
validated often causes problems. In these cases, more in-depth inspection
and evaluation will be required; some of these process runs often produce
failing product because the product specifications have not been fully
established and tested.

The inspection team should observe facilities, equipment and processes to
put data review in proper context. It is also important that raw data,
including validation and laboratory logbooks be audited or reviewed to
verify accuracy and authenticity.

II BACKGROUND

Two common complaints regarding validation issues frequently have been
raised. The first concerns the misconception that the 1987 validation guide
represents a new requirement. The second concerns the lack of specificity in
the agency's guides. In 1978, the Current Good Manufacturing Practice
Regulations were revised and provided for process validation. Therefore this
guideline does not represent a new requirement. The regulation is nearly 15
years old.

Both the agency and the industry have recognized the need to establish
general guidance for the validation of manufacturing processes, and the
agency published a draft guideline in March, 1983. However this draft
guideline was a very general document addressing general principles and was
applicable to sterile and non-sterile drugs and devices. In March, 1984, it
was reissued as a draft guideline, and was finalized in May, 1987.

The 1987 validation guideline merely points out the need to adequately
develop and control manufacturing processes. It discusses microbiological
issues and provides few specific an practical applications for the
validation of manufacturing processes for a marketed solid oral dosage form.

The issue of retrospective validation, and its application to marketed
products, is frequently encountered. This concept of using historical data
(test results), along with process control and process specificity was of
value until more scientific methods for demonstrating process validation
evolved. It should be pointed out that retrospective validation is not
merely the review of test results. It also requires that the manufacturing
process be specific and the same each time a batch is manufactured. Thus,
specific raw material specifications (including particle size when
necessary), in-process specifications (tablet hardness, etc.), and specific
manufacturing directions are required. Obviously, any failing batches
attributed to the process would necessitate the conclusion that the process
is not validated and is inadequate.

Prospective process validation is required, particularly for those products
introduced in the last 7 to 8 years, or those for which manufacturing
changes have been made. However, in some cases where older products have
been on the market without sufficient pre-market process validation, it may
be possible to validate, in some measure, the adequacy of the process by
examination of accumulated test data on the product and records of the
manufacturing procedures used.

III PRODUCT DEVELOPMENT

A. PRODUCT DEVELOPMENT REPORTS

There is no statute or regulation that specifically requires a product
development report, although companies are required to produce scientific
data which justifies the formulation and the manufacturing and control
processes. Most companies have used product development reports, technology
transfer reports, and others to summarize the scientific data that justifies
the product and process. The product development report should satisfy the
needs of the company. Therefore, there is no specific format for the
contents of the report.

It is suggested that the company develop a product development SOP which
describes the development process, the documentation requirements, and the
individuals responsible for approving the filed process. This SOP can be
brief and again there is no legal requirement that companies produce such an
SOP.

Investigators must not list the absence and or the poor quality of a product
development report on the FDA 483. The investigators should list or include
the inadequacy of data to support the filed process and specific Master
Formula filed. It is not a GMP deficiency nor is it a filing requirement to
have a formal Development Report. Investigators should review product
development reports since they will reduce the time required to inspect the
process.

The development data found in these reports should include the following:

1. Drug Substance Characterization

Characterization of the chemical and physical properties of the drug
substance is one of the most important steps in the development of a solid
dosage form. Chemical properties especially the identification of impurities
are very important. In addition, the physical properties of the BPC such as
solubility, polymorphism, hygroscopicity, particle size, density, etc. must
be addressed.

The literature, and actual experience demonstrates, that the physical
quality, e.g., particle size of raw materials, can sometimes produce a
significant impact on the availability and clinical effect of a dosage form
drug. Therefore, it is appropriate that the physical characteristics of a
drug substance be characterized, that the impact of the physical
characteristics be determined and that a specification for the bulk drug
product be established if necessary.

Development data will vary between new drugs and generics. Characterization
and establishment of specifications for the drug substance is one example.
In most cases the manufacturing process for a new drug substance (new
chemical entity) is developed and scaled-up before the dosage form. In early
development stages very little information is available regarding
polymorphic forms, solubility, etc. Consequently, changes to the
manufacturing process for the drug substance may change the purity profile
or physical characteristics and thus cause problems with the finished dosage
form. Although these types of problems are expected, the firm must
investigate and document batch failures for the BPC and dosage form product.

On the other hand the generic manufacturer usually purchases the drug
substance from a BPC manufacturer who may not be willing to supply
information regarding the synthesis or analysis of the drug substance.
Therefore, the finished dosage form manufacturer must perform the
appropriate test to characterize the drug substance chemically and
physically and establish appropriate specifications. This may require
developing analytical methods to identify impurities. In some cases this
information can be obtained from literature searches.

In either case it is important that the firm compare the drug substance used
to manufacturer the bio-batch or clinical batch(es) and the drug substance
used for the commercial batches. Therefore, review the specifications,
analytical methods, and test results for the lots of the drug substance used
to manufacture these batches. Remember that the safety of the drug may be
based upon the type and level of impurities and different physical
characteristics may affect dissolution or content uniformity.

Inspectional coverage should be given to the physical characteristics of raw
materials, especially bulk drug substances, since they frequently affect the
performance of the dosage form in which they are incorporated. This is
particularly important for those drug substances that are poorly soluble in
water.

For those products on which biostudies were conducted, the physical
characteristics of the drug substance used for the study should serve as the
basis for the physical specifications.

It is widely recognized that when discussing in-vivo release rates and drug
absorption rates, fast, immediate release is not always best. For some
"immediate" release drug products, such as carbamazepine tablets, a slower
release is desired. Therefore, it is frequently desirable to have minimum
and maximum particle size specifications to control the release rate. For
example, micronizing or milling a drug substance and providing greater
surface area of the substance may also result in faster dissolution and
possibly 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, particle
shape, and/or bulk density can also have an effect on the uniformity of
dosage forms, particularly those manufactured by direct compression or
direct 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 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.

Some manufacturers have established wide ranges for specifications.
Investigators should review these specifications from a GMP and validation
perspective. Even though a wide range for a physical specification, such as
particle size or surface area may be established in a filing, it is expected
that such ranges be verified in the validation of the process. In a recent
court decision the judge ruled that companies cannot hide behind the
approval of processes listed in an application when these processes do not
work. In other words the approval of the filing has no impact on processes
that do not perform consistently.

For example, in a filed process it was determined that particle size would
have no effect on drug absorption and dissolution and a wide range particle
size specification was established. However, in the GMP review, it was found
that variation in particle size had a major effect on content uniformity.
Therefore, a tighter particle size specification had to be established.

Control of the physical characteristics of the excipient is also important
because variations in such characteristics may also affect the performance
of the dosage form. Changes in particle size of some excipients, for
example, may affect content uniformity. In other cases, a change in the
supplier of an excipient or lubricant may affect dissolution or
bioavailability. In fact, the release of the active ingredients in some
products is "timed" by varying lubricant blending time and concentration.
The literature contains many examples of lubricant processing causing major
changes. Such changes in excipients illustrate the deficiencies with the
utilization of retrospective validation because, for such validation to be

Continued to next message >>>
This message is part 2 of a previous message >>>

satisfactory, control of all parameters and key steps in the process are
necessary.

The control of mixing times and physical characteristics of all ingredients
is critical to successful validation of all formulations and processes. A
major question that must be addressed is the need for testing physical
characteristics (particle size) for each batch of excipient. For many single
source excipients, particle size is a supplier specification and is usually
tightly controlled. Having established a specification and not testing each
lot of excipient upon receipt may be satisfactory in such cases. However,
for some multi-source excipients and where the dosage formulator expects to
shift sources of supply, there may be differences in physical
characteristics (particle size) that may have an effect on dose uniformity
and dissolution. Examine the practices with respect to the source of supply
of the key excipients and determine if there is justification for the lack
of testing lots of excipient for ph