Editor’s Note: This is another installment in a series of articles on the need to update ICH guidances. For the first article in the series, Ciurczak’s analysis of Q2 (R1), click here.
The ICH Q7A Guidance was intended as a showpiece for multi-jurisdictional cooperation in establishing methodology and standards for API inspections. It was the first internationally harmonized tripartite GMP guidance developed jointly by industry and regulators under the ICH umbrella. It establishes one global GMP standard for APIs and is intended to provide mutual recognition of GMPs in API production. (Note: Q7A does not apply to steps prior to the introduction of the defined API starting material.)
However, in light of recent problems with outsourced APIs and the growing number of small pharma houses, the ability of ICH Guidances to protect consumers is under question. The 2001 document assumes use of cGMPs by manufacturers, primarily in the signatory countries.
Definition of “API”
From the intended use clause: “Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product.”
From the pharmacological activity clause: “Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.”
From the FD&C Act: “Section 501(a)(2)(B) of the Act requires that all drugs be manufactured, processed, packed, and held in accordance with current good manufacturing practice.” [Note: CGMP regulations (21 CFR 210 and 211) apply only to preparation of drug products. These CGMP regulations apply to finished dosage form drugs (under CFR 210.3(b)(4) and 211.1) and are not binding requirements for chemical manufacturing.]
The current Q7A Guidance was approved in August of 2001, several months before the U.S. FDA’s subcommittee on PAT was even convened by Ajaz Hussain of CDER/FDA. That alone indicates that PAT was not a concern of the ICH committee working out the details of this Guidance. There is no mention of process measurements in the Guidance, only GMPs, which, according to most QA personnel, do not cover PAT/QbD directly.
The guidance was intended to facilitate API inspections by supplying uniform guidelines to inspectors in all participating countries. It impacts any manufacturer that markets APIs in ICH regions and addresses the uniqueness of API processes (that is, drug “products” are physical mixtures, while APIs are the result of chemical synthesis).
The suggestions and methodologies in this Guidance are based on:
- laboratory analyses of, usually, a statistical sample of the API lot; or
- the Certificate of Analysis from the manufacturer.
Both approaches are based on experience with “Western” suppliers in the U.S., Europe, Canada, or Japan. Since the legal systems within these countries had jurisdiction over the supplier, there was little illegality involved. In-house tests, used by QC, are mainly to identify the product possibly caused by mislabeling problems. These confirm the grade (polymorphic form, particle size, hydrous or anhydrous) and purity (testing for potential break-down products—e.g., % salicylic acid in aspirin). They were not designed to detect deliberate fraud: e.g., melamine in gluten or sulfated chondroitin in heparin.
Adulterants were apparently chosen to fool the tests run on the materials mentioned. For instance, melamine polymer was used by some agro-businesses a quarter century or so ago to fool the Kjeldahl nitrogen test, making the protein content seem higher, garnering more profit. The melamine monomer, quite toxic, was added to the milk in China to cover up the watering-down of the product, covering up fraud. Companies using simple, chemical spot tests (in compendia such as EP, USP, and ASTM) did so under the assumption of a scrupulous supplier with a possibility of “known” and reasonable contaminants, well documented in the normal production of a material. They were designed for safety and potential breakdown of the API, not chemicals deliberately added to fool them.
The diligence of the FDA and USP in the heparin scandal is noteworthy. The speed with which the contaminants were identified and new procedures instituted is remarkable and should be congratulated as well as noted. However, considering the effort of so many researchers and the costs involved, can this be done for all imported APIs, raw materials, finished drug products, and intermediates every batch ad infinitum? And, if this was to become protocol, what effects will it have on the industry and cost to consumers?
If a material is imported to save 30-40% of its cost, but several weeks of testing, using sophisticated instrumentation, are needed to pass the imported lots, what will happen to the final cost of goods? QC departments will have enormous pressure to expand and add equipment not usually associated with routine analyses: capillary electrophoresis, multi-dimensional NMR and numerous other techniques. [For further details, see the “Tools” section below.]
The time involved will diminish the profit margin and/or increase the cost of goods to the patients. Smaller, independent generic Pharma companies do not routinely have the ability to perform 2-D NMR and capillary electrophoresis; in fact, few larger firms supply their QC departments with such equipment, either. The cost of either purchasing the equipment (plus hiring people to run it) or paying someone else to run the tests would be quite a hardship. I can envision a number of small houses closing in short order.