Towards the end of 2007, the FDA issued the proposed rule "Amendment to the Current Good Manufacturing Practice Regulations for Finished Pharmaceuticals".
You can see the proposed rule, comments and subsequent withdrawal notice here.
I commented (as did a number of other companies) in a response to the FDA as follows:
GENERAL COMMENT
The Agency's provision of clarification in this area is to be welcomed, but the proposed ruling has a potential to conflict with current industry practice and curb the development of good practice contrary to ASTM E2500 .
Specifically, we question the approach expressed in the proposed change to 211.103 and 211.188.
These changes are intended to “clarify the agency's longstanding interpretation of, or increase latitude for manufacturers in complying with, preexisting CGMP requirements”. In our opinion they do not achieve this goal, but rather confuse the agency’s intent with respect to the requirements of 211.68.
The agency states in the preamble (Section II. D);
“we are amending Sec. 211.101(c) and (d), 211.103, 211.182, and 211.188(b)(11) to indicate that the use of automated equipment under Sec. 211.68 may eliminate the need for verification by a second individual”
However the proposed changes will still require verification by a second individual, with the first “individual” being an automated system.
Our understanding of this proposed change is that if a calculation of yield is performed by an automated (computer) system, then that calculation must also be verified manually (211.103). The person manually verifying the calculation must then be identified in the batch records for that operation (211.188).
Currently, under direction from predicate rules such as 211.68(b), if an automated (computer) system were employed to calculate yield, that function would be validated. The rationale for appropriately validating the function is that the function can be proven to be accurate and consistent and therefore negate the need for manual verification. In effect, the manual verification is appropriately performed during the validation exercise (using a range of test data and positive and negative test cases), thus ensuring future accurate operation in a controlled system.
Under current good practice this means that a manufacturer will spend time and resource in validating an automated function (such as yield calculation) knowing that during subsequent operation they can be confident of a consistently accurate output given accurate inputs, and therefore that output does not need to be re-checked manually. This has an operational time/cost benefit that is a major incentive for a manufacturer to invest in the initial validation effort.
We believe that although such calculations potentially impact product quality and patient safety, the use of appropriately validated computerized systems is in line with ASTM E2500 which places the emphasis on the appropriate verification of systems.
However, the proposed change subverts this paradigm and puts into question the value of validating such functions. In essence, pharmaceutical manufacturers may question the benefit of validating a function that must additionally be manually verified every time it operates?
Our concern is that pharmaceutical manufacturers are required to expend time and effort in the validation of the automated system but will no longer have the benefit of improved process efficiency and operational cost saving.
Additionally, given that “this proposed rule represents the first increment of modifications to parts 210 and 211”, we are concerned that similar changes might be considered for other sections where an automated system may be used to perform a function.
We believe that a pragmatic approach would encompass validation of the automated system (as required in 211.68(b)) and that other rules such as 211.103 would require a verification of data entry and/or resulting output e.g. the second person should verify that the input data and validated result is included in, for example, the batch record, but would not be required to recalculate the result so long as this has been performed by an appropriately validated system.
We believe this would reflect the current understanding and practices within the industry and the intent by the agency to “encourage innovation and the development of improved manufacturing technologies”.
Most companies who responded presented similar arguments. However, it is worth noting that some companies actually welcomed the proposed ruling as a good thing(!) that clarified the situation. It is not clear if they actually read the proposed rule, or just wanted to get their names on the FDA website as a respondent.
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