Sampling for tests by a drug product manufacturer.
Common sampling plans were discussed, and the assessment was that the practice of collecting (n
0.5 + 1) number of samples for a shipment of excipient batch received is justifiable, in which n is the number of containers received for an excipient lot. When compositing is appropriate, (n
0.5 + 1) can be a valid sampling plan.
An identity test is performed on excipient materials to determine whether the material is what it purports to be and to detect
any mix-up or presence of foreign material before use of the excipient. Current practice in many companies is to perform the
identity test on a composite sample. In contrast, workshop attendees recommended that the material sampled from each individual
container not be composited before identity testing. In other words, the samples should be tested individually for identity.
This practice increases the chance of detecting any incorrect or foreign material. In some situations, there can be a need
for a modified approach, such as when excipients are shipped in bags on pallets, which results in a large number of bags per
lot. A modified approach for sampling can be acceptable if a drug-product manufacturer has procedures in place to conduct
a thorough inspection of the packaging and labeling, including auditing of excipient manufacturers facilities and procedures.
Because each lot must at least be tested for identification, skip-lot testing should not be used by the drug product manufacturer
for the identity test.
Workshop attendees from many drug-product manufacturers stated that they are using skip-test procedures based on CoA qualification
and/or vendor qualification. This means that in lieu of testing samples of each lot to show that an excipient material meets
its specifications, a drug-product manufacturer relies on a CoA from its suppliers of excipient materials (which the drug
product manufacturer has validated for reliability) to ensure that each lot meets its specifications. In effect, no test is
actually being skipped, because the testing to show that each lot meets all of its specifications is being performed either
by the excipient or drug-product manufacturer. Participants did not find any practice that must be changed or modified.
FDA's Guidance for Industry: Testing of Glycerin for Diethylene Glycol.
As a specific exception to the previous discussion, on May 2, 2007 FDA issued Guidance for Industry: Testing of Glycerin for Diethylene Glycol in which FDA recommends that drug-product manufacturers perform a specific identity test that includes a limit test for diethylene
glycol on all containers of all lots of glycerin before glycerin is used in the manufacture or preparation of drug products
(5). This guidance was issued because of past incidences of diethylene glycol contamination in glycerin.
Excipient vendor qualification and periodic or skip testing of excipients.
From the excipient survey answers on vendor qualification, 91% of drug-product manufacturers stated that their vendor qualification
includes CoA qualification. International Pharmaceutical Excipients Council (IPEC) recommends vendor qualification as part
of the CoA qualification. Vendor qualification begins with receipt of a completed questionnaire (e.g., the Excipient Information
Program, IPEC-Americas) and generally followed by an on-site assessment of the excipient manufacturer by a trained auditor.
For 78% of survey respondents, such qualification of CoA means a reduced frequency of complete monograph testing for their
excipients. The reduced testing programs for 89% of drug-product manufacturers included at least five of their excipients.
All five distributor respondents stated that a reduced testing program is applicable to some, most, or all of the products
they distribute. This data suggest that many drug-product manufacturers and excipient distributors do not perform all monograph
tests on their excipients after qualifying their vendors. Every 3rd lot of the excipient a drug product manufacturer receives
is fully tested by 3% of them, every 5th lot by 7%, and every 10th lot by 29%, and the remaining 61% test their excipients
according to "other" frequency. The workshop participants explored practices for skipping tests.
Workshop participants were confused by the terms skip lot and skip test. For this article, skip test or skip testing is the performance of specified tests at release on preselected batches and/or at predetermined intervals, rather than on
a batch-by-batch basis, with the understanding that those batches not being tested still meet all acceptance criteria established
for that product. The use of skip-test strategies should be identified on the CoA.