Experts Susan J. Schniepp, distinguished fellow for Regulatory Compliance Associates® (RCA), and Steven J. Lynn, executive vice-president of Pharmaceuticals for RCA, discuss the verification of compendial methods.
Q. Are compendial methods considered validated?
A. According to the pharmacopoeias, compendial methods are validated—that’s about as simple as it gets. The United States of Pharmacopeia National Formulary (USP–NF) states,
“…users of analytical methods described in USP–NF are not required to validate the accuracy and reliability of these methods but merely verify their suitability under actual conditions of use”
The European Pharmacopoeia (Ph.Eur.) and the (JP) also consider their methods validated. Ph.Eur. states:
“The analytical procedures given in an individual monograph have been validated in accordance with accepted scientific practice and recommendations on analytical validation. Unless otherwise stated in individual monograph or in the corresponding general chapter, validation of these procedures by the user is not required”
The Japanese Pharmacopoeia says:
“when an analytical procedure is to be newly carried in the Japanese Pharmacopoeia, when a test carried in the Japanese Pharmacopoeia is to be revised, and when the test carried in the Japanese Pharmacopoeia is to be replaced with a new test according to regulations in General Notices, analytical procedures employed for these tests should be validated according to this document”.
Supporting validation information for pharmacopeia methods is retained by the compendial authorities and not by the users of the methods. However, this does not change the fact that the official methods in these publications are supported by validation information.
The USP–NF and Ph.Eur. explicitly require that compendial procedures demonstrate suitability under actual conditions of use. This information can be found in General Chapter, Verification of Compendial Procedures <1226> in the USP–NF, and General Notices in the Ph.Eur. (1,2).
On the other hand, the European Directorate for the Quality of Medicines (EDQM) stipulates on their website:
“When implementing a Ph.Eur. analytical procedure, the user must assess whether and to what extent its suitability under the actual conditions of use needs to be demonstrated according to relevant monographs, general chapters, and quality systems.”
In other words, it is the user’s responsibility to transfer the procedure correctly”
Once a monograph has been established and it is accepted that the published method is validated, users of the monograph need to verify that the method is suitable for determining the product quality. Moreover, the purpose of verification is to establish that the official method is reproducible when used by others.
The monograph sponsor proves the method works for its product with the manufacturer’s analysts using the firm’s laboratory equipment. They have already met the basic International Council for Harmonisation (ICH) requirements for reproducibility, repeatability, and intermediate precision.
The task for the user of the USP monograph is to prove the published method is reproducible. Additionally, any analyst for their company’s product should be capable of testing using the lab equipment.
There is no absolute guidance for verification requirements. Companies must decide for themselves how they will establish the method is verified and suitable for their product. Lastly, the test methodology verification will depend and fluctuate based on complexity of the test method.
Chromatographic methods should, at a minimum, meet the system suitability requirements defined in the official method. Conversely, other method parameters, such as accuracy and precision, may be considered.
Method performance can be accomplished by using performance characteristics such as blanks in chemistry or un-inoculated media in microbiology. Finally, laboratory control samples and spiked samples for chemistry, or positive culture controls for microbiology to assess accuracy.
Technique-dependent methodologies should not require verification. These methods include but are not limited to loss on drying, pH, residue on ignition, etc. Technicians should be trained, and their training records maintained, demonstrating their ability to perform the method regardless of the material being tested.
To simplify activities for their analysts, many companies translate monograph instructions into laboratory procedures. Although this practice has its benefits, it can also lead to compliance concerns.
Nevertheless, the author recommends that a baseline comparison be made between the standards and the internal testing documents to minimize this risk. Further, the comparison does not need to elaborate, but should focus on critical parameters for test methods.
Equally important, the reader may also want to consider reference standard usage, system suitability requirements, or other parameters that may help establish equivalency to the compendial methods.
Critical to Quality (CTQ)
Finally, the criteria listed above should not be considered all-inclusive. Establishing an internal method that complies with the official pharmacopeial method is critical to quality (CTQ). After all, many different users may have other requirements to consider for their specific laboratory usage.
Volume 46, Number 4
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