Acceptable Analytical Practices for Justification of Specifications - Pharmaceutical Technology

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Acceptable Analytical Practices for Justification of Specifications
The concept of Acceptable Analytical Practices (AAPs) was developed by the Analytical Technical Group of the Pharmaceutical Research and Manufacturers of America to share information about how the pharmaceutical industry has implemented chemistry, manufacturing, and controls and quality guidances of the International Conference on Harmonization and worldwide regulatory authorities. The AAP process identifies and addresses critical issues in which guidance is lacking, ambiguous, or contradictory. AAPs were..

Pharmaceutical Technology

The industry advocates that statistical evaluation is of value in establishing acceptance criteria for impurities, including degradation products and residual solvents. Although the mean can be reasonably estimated from relatively small datasets, estimating variability inherently requires more data. To illustrate and expand on this point, a hypothetical case (see sidebar "Ruggedness of acceptance criteria") was used to consider the ruggedness of acceptance criteria derived from three general approaches: mean 3 standard deviations, tolerance limits, and maximum value. The general industry consensus is that on the order of 15–30 relevant batches are required to estimate statistically meaningful and robust acceptance criteria for a given test. Concerning the analysis of data to estimate appropriate acceptance criteria, the industry preference was to use a tolerance limit approach, which is considered an appropriate statistical approach to making inference about individual values and is therefore relevant for establishing statistically justified limits based on process capability.

Shelf-life considerations

Tests to consider for potential skip testing*
As noted previously, the situation is more complex for specifications in which a parameter is expected to change over time. The amount of change with time must be estimated, and specifications will need to accommodate this change. This is often the case for degradation products, for active ingredient assays or potency estimations, and for other important quality parameters. It then becomes important to distinguish between those specifications that apply throughout the expiry period and those that should apply only at the time of batch release. Where use-related limits are specified in advance (i.e., there is already a range linked to safety and efficacy concerns), appropriate allowances must be calculated to take the change with time into consideration. Requirements may need to be more stringent at the time of release, and manufacturing capability to this requirement would need to be scrutinized. Where limits cannot be specified in advance, and the process capability paradigm described above is used to set release specifications, the effect of the change with time needs to be accommodated in developing the appropriate shelf life specifications (3).

During stability studies, many batches are tested on many occasions. Even without any change with time, this additional testing may carry with it additional risk through the simple compounding of the probability of an out-of-specification (OOS) result. The design of the shelf life specification must appropriately accommodate such risks to avoid unexpected and unintended consequences.

Specifying impurities

Justification of the specifications established for impurities and degradation products is an area that has received considerable attention. ICH guidances Q3A(R) and Q3B(R) address the regulatory filing requirements for the reporting, identification, and qualification of impurities and degradants, together with a general outline of the impurity specifications (4, 5). The guidelines further indicate that the rationale for specifying an impurity (or not) should be explained on the basis of process understanding, data from development batches, stability studies, and batches made by the commercial process.

During development, it is common for impurities to be reported and tracked as processes are modified, optimized, and then scaled up. Impurities initially observed in development batches may be minimized or no longer be present in material prepared by the final commercial process. The industry agrees that potential impurities not observed in the commercial process should generally not be specified. Nonetheless, when there is limited manufacturing experience or outsourced materials or intermediates are used with limited experience, it may be appropriate to include an impurity specification for a potential impurity, possibly as an interim or sunset specification, until additional data are available.

Interim specifications

An interim acceptance criteria (specification) for a specific test generally involves setting a provisional limit on a quality characteristic of the drug substance or drug product at the time of approval. This provisional limit usually involves a postapproval commitment to review the limit as more data become available and is made by prior agreement with FDA. In general, there is strong industry support for this concept of interim specifications, but some reservations exist about how this would be specifically implemented. There is a need for additional clarity from the regulators regarding implementation of this concept.


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