Identity testing should be performed on all raw material ingredients in a formulation, as well as the finished product. As part of release testing, there should be 2 identity tests performed, one of which is a definitive fundamental test. This fundamental test is most frequently an infra-red spectroscopy technique (FTIR or nIR), because of the ease of collecting the spectra (with a number of different sampling techniques) and the ability to perform a quantitative comparison to a library of IR spectra. This library can either be one commercially available or one that is compiled in-house. Near IR (nIR) will require development of a learning set of a significant number of samples (typically 20 or more) in order to provide a positive confirmation of the material in question. Ultraviolet (UV) spectroscopy or HPLC retention time are frequently used for the secondary identification technique.
For an Active Pharmaceutical Ingredient (API), FTIR and HPLC retention time are very frequently used. The acceptance criteria for these tests will often be a short list of specific peaks in the FTIR spectrum that must match the reference spectrum within a few (to be specified) wave-numbers (cm-1). From a qualitative perspective, it is also advisable to inspect the entire spectrum in comparison to the reference. HPLC retention times are usually specified within 5% difference from the reference peak in the chromatogram of a reference standard, although 2% should be easily achievable. It should be noted here that the reference standard needs to be injected in the same chromatographic run as the sample of interest. This is usually done during system suitability testing of the chromatographic system.
The USP spectroscopy testing for identity <197> specifies obtaining a spectrum of the reference standard at the same time as that of the sample. This is a somewhat outdated notion with today's modern FTIR spectrophotometers, where all the data are digital and there would be no significant peak shift occurring from a spectrum taken today versus one taken months or even years earlier and stored in the digital library. Therefore, it is my opinion that it is acceptable to compare the sample spectrum with one in the spectral library to confirm identity.
There are, of course, other identity tests that can be conducted, spectroscopic, wet chemical, and chromatographic to name a few. If the compound of interest is a salt, ICH Q6A requires that an identity test be conducted for the salt. If the material is compendial, the compendial identity test(s) should be performed. ICH Q6A also says that if a drug substance is developed "as a single enantiomer, the identity test(s) should be capable of distinguishing both enantiomers and the racemic mixture."
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Mark--What is your opinion on performing complete compendial testing on all incoming lots of excipients coming from a qualified supplier who certifies the materials as meeting the compendial requirements? In one of my previous jobs, this was a hotly contested topic--my contention was that you do full testing on every X lots (X=3, 5, or whatever # you're comfortable with), particularly if the excipient wasn't critical to function, e.g. for a pH adjustment or filler. My commercial colleagues never bought into this, and did lots of testing that I felt was wasteful and useless. What do you think?
ReplyDeleteSteve Rabin
Ultimately, it is the product manufacturer's responsibility that the excipient meets the specs. Each company has to decide how they are going to qualify the supplier. This may also depend on the criticality of the excipient. My experience has been to fully test the excipients upon receipt to verify they meet the specifications and the suppliers' COA's. Once you gain enough experience and confidence with a supplier, you can go to reduced testing performing only some of the tests or reducing the number of lots tested.
ReplyDeleteThanks for your question, Steve.
Ahh.. Identity testing definitely needs to have a quality result. Identity testing is important for both the purchaser and supplier of the ingredient. It is a very clear rule for both to have the specifications for “identity, purity, strength and composition” of the ingredient. Whereas, it is part of the Food and Drug Administration’s final rule to have a Certificate of Analysis containing the latter to secure the identity of a certain ingredient. In conclusion, having an infra-red spectroscopy technique is an aid for the industry in ensuring the product quality that will be later used for manufacturing our various everyday items.
ReplyDeleteGeorge Melcher