FDA Makes Quality the Rule


The new regulation's requirements in the areas of production and process controls (subpart G) represent a significant restructuring of FDA's previous rules. Although the regulation imposes few wholly new requirements, its revised language and structure should help manufacturers more easily understand and comply with FDA's expectations--some of which have previously been expressed only in unofficial interpretations of the 1978 GMP regulation.

Production and Process Controls (820.70). Although this section of the new regulation includes no new requirements, it does offer clarification of the ways that FDA has, officially and unofficially, interpreted the 1978 GMP regulation in past years. The types of process controls that must be implemented when their absence could cause deviations from device specifications are listed at the beginning of the section (820.70(a)(1) through 820.70(a)(5)).

As presented in the new regulation, the section on production and process controls combines several sections that already existed in the 1978 regulation, including those on buildings (subpart C), manufacturing specifications and processes (820.100, excluding 820.100(a)(1) and (a)(2)), personnel health and cleanliness (820.25), and equipment (820.60).

The new regulation's section on automated processes (820.70(i)) combines requirements that existed in the 1978 GMP regulation under the sections on measurement equipment (820.61) and critical devices, automated data processing (820.195). These requirements are essentially the same as contained in the November 1993 proposal and in the 1995 working draft, where they were reworked in order to clarify the requirements for validation of automated processes and software changes.

Inspection, Measuring, and Test Equipment (820.72). Requirements in these areas were covered in the 1978 regulation under the section on measurement equipment (820.61). The only significant change in the new regulation is the addition of provisions for the handling, preservation, and storage of equipment so that its accuracy and fitness for use are maintained. The 1978 regulation included requirements for the validation of computer software programs, which have now been transferred to the section on production and process controls (820.70(i)).

The new regulation's section on calibration was included in the 1978 regulation, except for the new requirement to "reestablish the limits" when remedial action is necessary (820.72(b)). This addition will require manufacturers to restore the limits for accuracy and precision, or establish new ones, whenever remedial action is carried out.

The 1978 GMP regulation did not accommodate the use of international standards for calibration. Allowance to do so was first introduced in the 1995 working draft, and has been retained in the final regulation.

Process Validation (820.75). The 1978 GMP regulation did not use the term process validation. In its "Guideline on General Principles of Process Validation," however, FDA interpreted the regulation's section on manufacturing specifications and processes as requiring process validation.⊂1 The new quality system regulation removes any ambiguity in this matter: it very clearly requires process validation.

The new process validation requirements appear to provide some flexibility to manufacturers by allowing process validation not to be conducted if the results of the process can be fully verified by subsequent inspection and testing. However, the agency has not defined the term fully, and says in the preamble only that the term "has been used in ISO 9001:1987 and 1994 and explained in several guidance documents" (comment 143). Since many manufacturers continue to be concerned that FDA investigators may require them to conduct 100% inspection or testing in order to comply with this requirement, the agency should be more forthcoming with a definition for the term fully.

A similar problem surrounds the agency's use of the phrase "with a high degree of assurance," which also appears in the new regulation's section on process validation (820.75(a)). This phrase was first included in the agency's "Guideline on General Principles of Process Validation," as part of the definition of validation, and its meaning has been questioned ever since. It did not appear in the November 1993 proposal, or in the section of the 1995 working draft dealing with process validation. However, the phrase was included in the definition of validation used in the 1995 working draft (820.3(cc)). To emphasize that a "high degree of assurance" is a requirement, the phrase has now been included in the section on process validation, but the agency has still provided no indication as to its meaning.

Since the publication of the 1995 working draft, a new section has been added to address the requirements for revalidation (820.75(c)). The requirement for "continuous" monitoring proposed in the 1995 working draft has been deleted.

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