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


One example of a case in which skip testing is routinely used is for the monitoring of microbial attributes for certain low-risk solid oral-dosage forms. Generally, this practice is widely accepted in many European Union countries. Other examples of tests that the industry considers candidates for skip testing are provided in the sidebar "Tests to consider for potential skip testing."

The industry strongly supports the application of skip testing when appropriate. Because only limited data are usually available at the time of filing, skip testing typically would be implemented as a postapproval change, requiring justification and preapproval by a regulatory agency before use. Nonetheless, conditions and criteria for the introduction of skip testing can be specified in the original registration applications.

Sunset specifications

The concept of sunset testing involves establishing a predetermined time interval or number of batches as a postmarketing commitment after which testing of certain attributes would be discontinued if specific criteria were met. It differs from skip testing insofar as after the commitment is met, the test would no longer be part of the product specifications. This strategy is particularly useful when only limited data are available at the time of submission and there is low risk to the patient. In some cases, a sunset-testing approach could be used in conjunction with skip testing (i.e., skip-testing intervals are gradually increased until finally the test is retired from routine testing). Many of the same considerations discussed for skip testing apply to sunset testing. Examples of tests the industry considers candidates for sunset testing are listed in the sidebar "Tests to consider for potential sunset testing."

Parametric release

The concept of parametric release involves making release decisions by measuring critical operational parameters for a given process in lieu of direct measurement of the quality attribute itself (1, 6). A typical example of a parametric release is sterility testing for terminally sterilized products. In this case, the release of each batch is based on satisfactory results from monitoring specific parameters such as temperature, pressure, and time during the sterilization process instead of conducting actual sterility testing. Parametric release is also commonly used to release in-process materials. For example, solids mixed in a V-blender are essentially released for further processing by the measurement of operational parameters, including the mixing time and the rotation speed of the blender, provided that the parametric endpoints have been validated to ensure adequate mixing. In some cases, blend uniformity is verified by off-line chemical testing of the powder blend or stratified testing of the finished product (7). In principal, the concept can be extended to other types of testing.

Building on parametric release, the FDA has proposed a concept of real-time release (8) in which quality attributes are measured either directly or indirectly in real time during processing using techniques of PAT. Thus, in the blending example given above, parametric confirmation of the blending operation would be replaced with data from real-time sensors that would establish when satisfactory blending had been achieved.

Through the use of in-process testing and process analytical technology (PAT) controls, there is a potential to substantially decrease or eliminate end-product testing while improving compliance and reducing rework or rejection. The implementation of PAT would either eliminate the need for conducting finished-product testing of particular attributes or would support skip-testing or sunset-testing protocols by greatly reducing the risk of failure and risk to the patient. Using a "science and risk-based approach to good manufacturing practices" in conjunction with strategies to reduce testing costs will provide benefits to both the industry and the patient (9).

Conclusion

Fundamental questions about setting specifications for pharmaceutical products are currently receiving much attention for both traditional therapeutic agents and biopharmaceuticals. Through its initiatives on PAT and CGMPs for the 21st Century, the US Food and Drug Administration has provided the pharmaceutical industry with a clear mandate to take a new look at the way product quality is defined and controlled (8, 9). These initiatives are stimulating considerable discussion with regard to better ways to set standards that ensure the safety and efficacy of pharmaceutical products. The process of establishing and maintaining meaningful product specifications throughout the product life cycle is an important part of that process. Moreover, traditional concepts of demonstrating that processes are robust and operated in a state of control using process validation and end-product testing are being challenged by the concept of real-time process monitoring, which will potentially lead to increased process robustness, enhanced in-process controls, and presumably less of a need for verification through end-product testing.


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