Current Questions on Validation of Blend Uniformity - Stratified Sampling

Validating blend uniformity is a decisive factor for the validation of solid dosage forms. In Europe, there are no regulatory provisions for this. This is different in the USA: according to 21 Code of Federal Regulation (CFR) 211.110, the adequacy of mixing has to be regularly assessed. Until 2013, there was a FDA Draft Guidance which described how to realise this assessment. The FDA withdrew it in 2013 though.

Now, what is today's state of the art with regard to the validation of blend uniformity? To provide guidance on that topic, the ISPE started a Blend Uniformity and Content Uniformity (BUCU) initiative. This initiative was the topic of a webinar organised last year. In the following, please find a few questions and the answers provided by the speaker Dr Gerrit Hauck, today at Basilea Pharmaceutica International AG.

Question Answer
Is an assessment of blend uniformity via the acceptance value (AV) according to USP 905 generally still tolerated? In particular with regard to the batch release?

USP 905 exclusively refers to the Uniformity of Dosage Units. The Stratified Sampling scheme from the DRAFT Guidance dated 2003 was based on the former, non-harmonised USP Content Uniformity (CU) monograph. Strictly speaking, the use of the harmonised CU monograph in conjunction with the scheme for routine production had never been formally accepted. Moreover, the FDA clearly positioned itself in 2013: a batch release only on the basis of <905> is rejected by the Agency, testing in accordance with ASTME2810 is rather expected.
The AV doesn't play any role in the framework of the revised ISPE's BU/CU Guideline.

In our process of validation, the tolerated standard deviation is derived as acceptance criterion depending on the sample size and mean in accordance with the label claim from the ASTM. Is this procedure acceptable? As long as you refer to the tables laid down in ASTME2810, this procedure is - as far as I am concerned - correct, however only insofar as you consider a pure random sample.  Stratified Samples require other statistics.
Does the assessment include reviews for normal distribution and trend test? Testing the normal distribution is not performed. The submission of a normal distribution is - to my knowledge - accepted.
Does the approach of validation of mixing remain the same for more than one API? Usually yes, unless one of the drug substances would be present in very high concentration so that one could argue that a determination of the mixing homogeneity shouldn't be required.
Is it acceptable for revalidating established processes to validate according to USP <905> or is there a risk of getting a finding in case of an inspection? Basically, the FDA has adopted a clear position and rejects the use of USP 905 for batch release. According to me, this also excludes the use of USP 905 for revalidation. Insofar, there is some risk that a US inspector would criticise the procedure you described.
Do you apply sampling already in the routine? How will you ensure in practice that samples are taken at 30 sampling locations? Will the samples be combined and should I take more in case that a pill falls off?  Yes, sampling at 20 or 40 sampling locations has to be exactly planned. We usually set the sampling times on the basis of significant events and then distribute the remaining samples according to the period between e.g. the beginning of the batch, change of template and batch end. It is quite not unusual to take more than e.g. 3 samples per locations so that for example a pill that fell off can be replaced. We usually take reserve samples.
Will the ISPE recommendation be soon implemented in a guideline? To my knowledge, the implementation in a guideline is not being planned. Through the publication of the ISPE recommendation, a method aligned with the state of the art is now available so that there is no actually need for a FDA Guideline.
Is the ISPE table provided validated? If yes, can the validation documents be made available? The table as such is - to my knowledge - not validated. This should be caught up for in operation.
Should the acceptance value be taken into consideration for BU and CU? The acceptance value only applies to the CU testing in accordance with USP 905. Within the scope of ISPE's testing it is not applicable.

Why is the USP provision far less strict than the expectations of the FDA & Co?


In my opinion, many tests traditionally used in the pharmaceutical industry are not particularly demanding. Especially considerations about the risks for consumers are often excluded from the test criteria. Especially in the USA, the scientific debate is moving to more demanding tests.

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