Representative batches? [Regulatives / Guidelines]

posted by Helmut Homepage – Vienna, Austria, 2010-08-05 12:30  – Posting: # 5725
Views: 9,674

Dear ElMaestro!

» I also occasionally wondered what representative batch actually means, […]
» […] I imagine it would be OK to think of a repr. batch as one that has some in vitro properties that are close to the means/medians from the distribution of said properties.
» The distributions (let's say of dissolution aspects, content) though are never well known at the time of batch selection and if regulators tried to force selection of 'average batches' (pardon my French) as a means of ensuring repr. batches I would imagine many companies would have to give up.

I love your French. Think about Section 4.1.2 (my emphases):

Reference product

The selection of the reference product used in a bioequivalence study should be based on assay content and dissolution data and is the responsibility of the Applicant. Unless otherwise justified, the assayed content of the batch used as test product should not differ more than 5% from that of the batch used as reference product determined with the test procedure proposed for routine quality testing of the test product. The Applicant should document how a representative batch of the reference product with regards to dissolution and assay content has been selected. It is advisable to investigate more than one single batch of the reference product when selecting reference product batch for the bioequivalence study.


Test product

The test product* used in the study should be representative of the product to be marketed and this should be discussed and justified by the applicant.
  1. The test product should usually originate from a batch of at least 1/10 of production scale or 100,000 units, whichever is greater, unless otherwise justified.
  2. The production of batches used should provide a high level of assurance that the product and process will be feasible on an industrial scale.
    In case of a production batch smaller than 100,000 units, a full production batch will be required.
  3. The characterisation and specification of critical quality attributes of the drug product, such as dissolution, should be established from the test batch, i.e. the clinical batch for which bioequivalence has been demonstrated.
* Test product - not batch of the test product!

Note the subtle difference: representative batch of the reference product vs.(test) study product representative of the to be marketed test product. The requirement to select from a least three reference batches in the draft was dropped (almost impossible for non-blockbusters) and replaced by ‘advisable to investigate more than one single batch’.

» Real life, as I know it works like this: We have X batches of Ref, and Y batches of Test. Now we measure whatever property we consider most likely to correlate with in vivo results and pick the pair that provide the closest match of Test and Ref for that property without in any way having regard to what's typical.

Exactly. I would replace ‘consider’ by ‘hope’. The GL calls for content and dissolution.
Content: OK. Dissolution? Well… :ponder:
Look at c): ‘critical quality attributes’ - side batches tested in vivo beforehand?

Even if we would know ‘critical quality attributes’ from pilot studies, we can only get this data of the test. Representative in a statistical sense – forget it. What about the reference? No way at all, IMHO.

Cheers,
Helmut Schütz
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