The stated aim of this guidance is to provide "recommendations on how you, the applicant, can submit analytical procedures and methods validation data to support the documentations of the identity, strength, quality, purity, and potency of drug substances and drug products. It will help you to assemble information and present data to support your analytical methodologies."
To assist you in an assessment of the new guidance I have summarised the content under the following headings: What's new, what's stayed (nearly) the same, and what's gone?
Section III on 'Analytical Methods Development' consists of three paragraphs focused on the importance of getting the method right at the beginning. To quote: "the choice of analytical instrumentation and methodology should be selected based on the intended purpose and scope of the analytical method." It goes on to list the validation characteristics which may be evaluated during method development: "specificity, linearity, limits of detection (LOD) and quantitation limits (LOQ), range, accuracy, and precision." The next two paragraphs are about method robustness and how this "should be evaluated because this characteristic can help you decide which method you will submit for approval."
I think that this emphasis on methods development and robustness of methods is a great idea. It seems so obvious that you might think it's not necessary in regulatory guidance. However, I am constantly surprised during my work, whether it is in training, auditing or consulting, by how little attention is paid to method robustness until it is too late, resulting in problematic method validation and transfer. No doubt FDA comes across this regularly. However, in the third paragraph it says that "To fully understand the effect of changes in method parameters on an analytical procedure, you should adopt a systematic approach for method robustness study (e.g., a design of experiments with method parameters)." I've no problem with that, it makes sense, but it goes on to say: "You should begin with an initial risk assessment and follow with multivariate experiments." In my opinion, multivariate experiments may be very useful for some methodologies, but are not always the best approach.
Under section VI, Part C on 'Compendial Analytical Procedures', the section on method verification has been updated to make it clear that the verification should be generated under a verification protocol and the results should be included in the submission. Information required in the protocol is detailed but the actual choice of which validation characteristics to investigate is left to the applicant, it is implied (rather than stated) that the approach taken should be justified.
The new Section VIII on 'Life Cycle Management of Analytical Procedures' begins with four paragraphs on the concept of method life cycle management and how it relates to product life cycle. It says that "Trend analysis on method performance should be performed at regular intervals to evaluate the need to optimize the analytical procedure or to revalidate all or a part of the analytical procedure. If an analytical procedure can only meet the established system suitability requirements with repeated adjustments to the operating conditions stated in the analytical procedure, the analytical procedure should be reevaluated, revalidated, or amended, as appropriate." I like these sentences very much since it is advice that I regularly give to customers when they ask me that rather unscientific question - "How often should I revalidate my methods?"
Further on in this section, under Part B, 'Analytical Method Comparability Studies', the section from the previous draft guidance on 'Alternative Analytical Procedures' has been updated to include additional information on biological products and also more detail on the requirements for the comparability study, in particular with respect to stability indicating methods. There is a new section on 'Analytical Methods Transfer Studies' which consists of a brief paragraph containing a lot of information. A comparative approach is suggested where: "The comparative studies are performed to evaluate accuracy and precision, especially with regard to assessment of interlaboratory variability." The importance of using suitable materials for the transfer of stability indicating methods is stressed.
Finally, in part C of this section, 'Reporting Postmarketing Changes to an Approved NDA, ANDA or BLA' is discussed.
You may also notice that the language used in the revision is different to the previous draft in that it addresses 'you' throughout, rather than 'the applicant'.
What's stayed (nearly) the same?
The 'Introduction' and 'Background' sections are similar to the previous version although there are new references to some of the content discussed above.
The section IV on 'Content of Analytical Procedures' is also quite similar although it has been rewritten and in my opinion is much improved with greater clarity. Of particular note:
- The number of replicates in sample preparation for quantitative tests is mentioned. I think this is important since my opinion is that the required number of replicates should be considered for each individual method, based on the data obtained during validation.
- Information on the stability of solutions and storage conditions is advised.
- ASTM E29 is referenced with respect to use of significant figures.
- The information provided is very focused on HPLC methods.
The new draft document is 14 pages long and the previous draft is 33 pages long so it follows that quite a lot of content has been removed. The sections in question are (all referenced by the section number in the year 2000 draft):
- III. 'Types of Analytical Procedures'.
- IV. 'Reference Standards' - sections on characterisation have been removed.
- VII. 'Methods Validation for NDAs, ANDAs, BLAs, and PLAs - Validation characteristics are listed in the new version but the details on the required methods validation information has been removed. Also the table defining recommended validation characteristics is gone.
- X. 'Methods Validation Package: Contents and Processing' - replaced by a short section which directs that necessary information will be provided by FDA if required.
- XI. 'Methodology' - details on particular methodologies such as HPLC, GC, etc. has been removed.