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Each of the following topics will be discussed in this article exploring Drug Product Contaminants:
A drug product contaminant is a material, compound or organism that is found in a drug product, which was not intentionally added to that product. Drug product contaminants are generally viewed as being undesirable and objectionable.
** Chemical Contaminants shall be the focus of this article.
There have been growing concerns over the increasing number of chemical contaminants being found in today’s drug products. A recent example was the discovery of benzene in aerosol OTC Sunscreen products which resulted in high-profile product recalls in 2021. One might argue that chemical contaminants have always been present in drug products and that the ever-increasing sensitivity of analytical instrumentation now allows for their detection and quantitation.
Many consider the “modern era” of analytical chemistry to have begun in the 1970s with the introduction of new technology (e.g., HPLC and microprocessors) and the development of more sensitive modes of detection. The discovery of Nitrosamines and 1,4-Dioxane in cosmetic products during the late 1970s were a direct result of “modern era” advances in analytical chemistry and we can expect technological progress to continue along these lines which could lead to the discovery of even more chemical contaminants in our drug products.
API Impurities may be divided into the following three categories of chemical contaminants:
Definition of “Extractables”
Organic and Inorganic chemical entities that are released from plastic container/closure/ delivery systems and primary container labeling systems, and into an extraction solvent under laboratory conditions.
In simple terms, “extractables” are substances which can be “pulled out” from a packaging or labeling system under laboratory conditions using “stressing conditions” such as strong solvents and elevated temperatures. (This is a “forced” process.)
Definition of “Leachables”
Foreign organic and inorganic chemical entities that are present in a packaged drug product because they have leached into that packaged drug product from plastic container/closure/ delivery systems and primary container labeling systems under normal conditions of storage and usage or during accelerated drug product stability studies.
In simple terms, “leachables” are substances which “simply migrate” from a packaging or labeling system into a product under “normal conditions” of exposure over the natural lifespan of that product or during accelerated stability testing.
Important to Note: The current United States Pharmacopeia (USP) includes General Chapter <665> entitled “Standardized Approach to Extractables Testing Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products” to address extractables from contact surfaces of drug product processing equipment and components. Compliance with <665> is not required until 2026.
The raw materials and processing aids that are used to manufacture drug products are themselves, manufactured from bulk chemical starting materials. Since GMP does not apply to the bulk chemical industry, the ingredients that are used and the processing details employed may not be fully documented during the production of bulk chemicals; additionally, equipment cleaning may only be an occasional event. This can result in the presence of unexpected ingredients (e.g., antioxidants, preservatives, flowing agents and cross-contaminants) and residual processing contaminants (e.g., solvents and elemental impurities) in the bulk chemicals which become starting materials for manufacturing the raw materials and processing aids used for making drug products. This is how many chemical contaminants are introduced into drug product raw materials which is why they should be screened for chemical contaminants.
API Impurities
API Manufacturers typically provide an impurity profile to their clients that is specific to that API’s synthetic process and degradative pathway(s). They also provide analytical methods for determination of the profiled impurities which may be present in the API. Such API methods provide an excellent starting point for developing methods for determining the level of impurities in drug product formulations containing that API. Additionally, APIs should be screened for residual solvents and elemental impurities.
Extractables & Leachables – Plastic Packaging and Drug Product Processing Systems
The United States Pharmacopeia (USP) provides specifications and methods for conducting E&L testing of plastic container/closure/delivery systems and proposed testing scenarios for plastic/polymeric contact surfaces of drug product processing equipment and components. USP references for E&L testing include the following:
The testing procedures identified in the USP for plastic packaging materials/systems may also be adapted for primary container labeling material E&Ls which may be present in printing inks, varnishes and adhesives.
Supply Chain Contaminants
Many of the common raw materials which serve as drug product inactive ingredients (“excipients”) and processing aids have USP/NF Monographs which include testing requirements for either Elemental Impurities, Residual Solvents or both. Some Monographs also include purity tests that are specific to that material. That being said, many other raw materials that are used in drug products are either not commercially available as USP/NF grade or are deliberately purchased as non-USP/NF grades since they are less expensive. In either case, testing should be conducted for Elemental Impurities and Residual Solvents to screen for potential chemical contaminants. Additionally, if a non-USP/NF Grade material is purchased instead of the USP/NF grade, any ‘purity’ testing requirements which appear in the Monograph should be conducted on the non-USP/NF grade material being purchased. (NOTE: Often times, the reason why a specific manufacturer’s raw material cannot be sold as USP/NF grade is because it fails to meet the purity requirements found in the Monograph for that material.)
When assembling a profile of all chemical contaminants which might possibly be present in a packaged drug product, one must look to all sources as previously described in this article. This includes:
Once a complete Chemical Contaminant Profile has been assembled, packaged drug product batches that are suitably aged should be tested for the presence of the chemical contaminants listed in the profile for that product. Suitably aged product batches are those at the endpoint of accelerated stability conditioning or batch retention samples which have reached their expiration date.
NOTE: If Supply Chain chemical contaminants have been identified and either eliminated, mitigated or suitably controlled in any specific raw material, it may no longer be necessary to test for their presence in the packaged drug product.
CPT’s Analytical Chemistry Lab is equipped with state-of-the-art instrumentation and staffed by a team of seasoned chemists having a wealth of experience testing for low-level chemical contaminants. Why not give us a call today so that we can begin to assist you in the testing of your raw materials and packaged drug products for expected, suspected and even unexpected chemical contaminants?
Please Note: CPT℠ only performs testing for companies. We do not perform product testing for the general public.