By Mark Land, AAHP President

In light of recent warning letters to homeopathic manufacturers, I have received several questions regarding procurement of homeopathic active pharmaceutical ingredients (API). Usually the conversations begin something like this: since I can’t test for the active ingredient how do I comply with FDA’s expectations for control of components? Code of Federal Regulation (21 CFR 211.84(d)(1)) states: At least one test shall be conducted to verify the identity of each component of a drug product. Specific identity tests, if they exist, shall be used.

Hearing this question, my mind immediately goes to 211.84(d)(2) which says: Each component shall be tested for conformity with all appropriate written specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals.

Paragraph 2 allows for acceptance of the supplier’s purity, strength, and quality test results if the manufacturer conducts at least one specific identity test. The final clause requires that the manufacturer establishes the reliability of the supplier’s analyses through validation. You might say that is obvious and it is. The implications however are not so obvious.

The globalization of the API supply chain in general has removed the arms-length relationship between supplier and recipients. This means that knowing your supplier is not nearly as easy now as it once was. Recognizing this, FDA established the guidance: Contract Manufacturing Arrangements for Drugs: Quality Agreements Guidance for Industry. The contracting guidance speaks at length about quality agreements. Quality agreements are excellent tools for establishing the working relationship between supplier and client, including the responsibilities of each party. That too may seem obvious from the title of the guidance alone. While that is true, what is important is the maintenance of the agreement.

For example, the reliability of a quality agreement must be maintained through an effective auditing program. Routine audits ensure not only compliance with GMP but tether the promises made within the agreement to in-person knowledge of practices at the supplier’s facility. Often minor changes effected without notice to the client can accumulate and lead to a gradual distancing from expectations. If geography is a problem, third-party auditing firms are available to provide on-ground support.

Back to the problem of identity tests for homeopathic APIs, modern laboratory instrumentation yield limits of detection around the parts per million (ppm) range. This is often insufficient for homeopathic APIs. So what do we do? This question is under intense discussion at the Homeopathic Pharmacopoeia of the United States at this moment. One likely result of their deliberations is: if you can test then test. One interpretation of this phrase could refer to the API. Other interpretations could include adjacent attributes of the product: alcohol percentage, sugar content if it is a solid, preservatives if the exist, etc.

In short, procurement begins with vendor qualification but is maintained by auditing and reinforced by acceptance testing employing as many objective measurements of identity and quality as possible.

 

We hope you will join us for a deeper dive on complying with FDA’s expectations for API testing at the AAHP 2020 (virtual) Summit, “Implementing HPUS Guidelines for FDA Compliance,” Sept. 23, 11 a.m. to 5 p.m. via Zoom (with scheduled breaks).