Current Interpretation of the FDA Requirements on Sampling

GMP News
6 August 2008

Current Interpretation of the FDA Requirements on Sampling

In October 2007, in the "Questions and Answers on Current Good Manufacturing Practices", the successor document to the human Drug CGMP Notes, there was an interesting question on sampling and on identity testing of starting materials (active pharmaceutical ingredients (APIs) and excipients):

"How many containers of each component from each shipment must a firm sample and test to comply with the CGMP requirements for identity testing? Do the CGMPs permit the identity test on a pooled, or composite, sample of multiple containers?"

Brian Hasselbalch and Dr Steven Wolfgang from FDA (CDER) gave a very detailed answer to that, which can be summarised as follows:

The CGMP regulations do not specify the number of containers from which samples should be taken. However, the requirements laid down in 21 CFR 211.84(b) can be summarised as a programme for sampling of APIs and excipients as follows:

  • The samples must be representative.
  • With regard to variability of starting materials, the confidence intervals and the level of necessary precision, the number of containers from which samples are taken as well as the amount of material sampled must be based on statistical criteria
  • The sampling plan must take account of the past quality history of the supplier.
  • The sample quantity must be big enough to perform analysis and to keep reserve samples

The pharmaceutical company is required to develop an approach that guarantees a high level of certainty that each container contains exactly the material indicated on the label.

The CGMP regulations allow the pharmaceutical company to make its own decision on how many samples are necessary for identity testing. If starting materials are bought from traders, it is considered advisable to take a sample from each container for identity testing.

What is surprising is the statement that "pre-shipment samples or so-called 'piggyback' samples are generally not acceptable".

Pooling, or compositing, samples from several containers is viewed as quite possible, since the preamble for 21 CFR 211.84(c)(4) of 1978 declares that there is no general prohibition on compositing samples from single containers.

The statements made here now comply in many points with the regulations laid down in the EC GMP Guide and the European Annex 8 on the sampling of starting materials.

We have linked the complete original text at the end of this news for your reference.

Dr Günter Brendelberger
On behalf of the European Compliance Academy (ECA)

Source: FDAs "Question and Answers on current Good Manufacturing Practices

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