Method Development and Validation

Supply chain lapses highlighted: Every so often, a high profile case will raise serious questions the pharmaceutical industry's control over its supply chain.

In recent times, the most prominent of these have included the incidents of diethylene glycol contamination of glycerine and the problem of heparin being contaminated with oversulfated chondroitin sulfate (OSCS).

Supply Chain Control

Although these examples are quite different in terms of the type of contamination (deliberate in the first cases, accidental in the second) both demonstrate that modern supply chains are very complex. They often start in countries where quality standards are not strictly enforced, so that it can be hard for the pharmaceutical manufacturer at the end of the chain to keep tabs on all of its suppliers.

Whilst auditing of suppliers provides a useful check, it is still important to test supplies routinely in order to verify that quality standards are being maintained. And it is important to ensure that the test methods being used are suitable and accurate in actual conditions of use.

Learning the lessons

The heparin contamination incident referred to above provides some useful background detail, and the possibility to learn useful lessons, because the FDA has made its warning letters public. They serve as a useful reminder to all pharmaceutical manufacturers of the need to have better control over their wider supply chain.

Identifying and Testing for Impurities

Specific breaches

Four main breaches of cGMP were highlighted in the FDA's warning letter to Changzhou SPL of April 21^st 2008. Essentially, these were as follows;

1. There was no assurance that processing steps were capable of removing impurities.
2. Systems for evaluating the suppliers of heparin crude materials, and the crude materials themselves, were inadequate.
3. The test methods had not been verified to ensure suitability under actual conditions of use.
4. Equipment used to manufacture heparin sodium USP was unsuitable for its intended use.

The issue of identifying and testing for impurities is governed by the ICH Q7A Guidance (Laboratory Controls, Testing of Intermediates and APIs). Whilst ICH Q7A does contain a statement that "Impurity profiles are normally not necessary for APIs from herbal or animal tissue origin." The FDA has subsequently stated that "a full impurity profile may not be necessary as part of the batch-to-batch testing of certain APIs, it is necessary that specifications for impurities be established for the production of all API and that each API batch be tested for conformance to these specifications."

In fact, ICH Q7A requires appropriate specifications to be established for APIs, including for control of impurities. It is also the case that the complexity of isolating and identifying impurities does not negate the responsibility to establish appropriate specifications for, and routine monitoring of, possible impurities arising from production.

Further to the testing issue, point three of the FDA's warning letter highlights that the heparin supplier had failed to ensure that certain USP compendial test methods were verified under actual conditions of use. In short, there was no evidence that test methods could reliably detect and quantify the presence of contaminants in the finished API.

Method Development and Validation

In accordance with cGMP, analytical methods have to be validated unless the methods are already included in a relevant pharmacopoeia or other recognized standard reference. If the method is already a compendial method, a laboratory needs to verify that the method is suitable for its intended use under actual conditions.

ICH Q7A guidance makes a further requirement that all testing methods should be verified under actual conditions of use and documented. In practice, this means that even USP methods need to be shown to be suitable for the specific conditions of use.

Interestingly, in respect of the specific contaminant identified by the FDA in the heparin case, there are two published methods that might be used for screening. One is based on capillary electrophoresis, the other on proton NMR spectroscopy. Both methods are available from RSSL Pharma, and both are relatively easy to carry out. The FDA now insists they be used for all Heparin Sodium API prior to batch release.

Other contaminants

RSSL Pharma is experienced in method development and validation for dealing with all kinds of contaminants and quality control issues, be they chemical, bio-chemical or biological.

Our scientists can start from scratch if necessary, but are equally comfortable in working with clients to transfer technology, and to adapt or adopt existing methods.