Stability Testing

By Mark Land, M.S., RAC-US, AAHP President 

When I think back to my early days in homeopathy, I recall that in the manufacturing facility there was a paper copy of the Code of Federal Regulations (CFR) Title 21. Under Section 211, someone had highlighted every appearance of “homeopathy” or “homeopathic.” Two areas in which it appeared frequently was 211.137 on expiration dating and 211.166 on stability testing. At that time, it was just curious and unexplained to me. 

Subsequently during inspections, FDA inspectors spoke about the specific requirements for homeopathic drug products: 

211.166 Stability Testing 

(c) For homeopathic drug products, the requirements of this section are as follows: 

1. There shall be a written assessment of stability based at least on testing or examination of the drug product for compatibility of the ingredients, and based on marketing experience with the drug product to indicate that there is no degradation of the product for the normal or expected period of use. 
2. Evaluation of stability shall be based on the same container-closure system in which the drug product is being marketed. 

Still curious, I took a look back at what motivated the Commissioner of the Food and Drugs Administration to establish this framework for the stability of homeopathic drug products. 

In response to a request for exemption from both expiration dating and stability testing of homeopathic drug products from the American Homeopathic Medical Association in 1978, the Commissioner said: 

The Commissioner notes that homeopathic medicine and drugs used for homeotherapeutics are unique and differ substantially from other forms of pharmaceutical products. Previously, the Commissioner has exempted homeopathic drugs from the Over-the-Counter Drug Review (see the FEDERAL REGISTER of May 11,1972 (37 FR 9464)). Further, homeopathic drugs were excluded from review under the NAS/NRC Drug Efficacy Study Review (DESI) and distributors of homeopathic drugs have not been required to list such drugs under the Drug Listing provision of the act. (Manufacturers, however, are required to register as drug establishments.) 

Because of the unique nature of homeopathic drugs, the Commissioner has reconsidered the value of stability testing and expiration dating for this small class of drug products and concludes the need for expiration dating and complete stability testing, as proposed, are unnecessary in this group. The imprecise nature of determining extremely low levels of active ingredients for each of a large number of attenuations (dilutions) that may be prepared for each drug substance, and the fact that factors such as potency, absorption, bioavailability and other measures of effectiveness do not appear to be applicable to homeopathic drugs, have convinced the Commissioner that requiring an expiration date for such products would be a burdensome requirement that would not result in any added assurance of drug quality to the user. 

Certain provisions of the proposed stability testing requirements, especially those relating to determining an expiration date, are also inappropriate. On the other hand, some stability information. such as the compatibility of ingredients based on testing or examination and marketing experience, is necessary for this class of drug products. The final regulations are amended in § 211.166 by modifying the stability testing requirements for homeopathic drugs. (See FEDERAL REGISTER, VOL. 43, NO. 190 - FRIDAY, SEPTEMBER 29, 1978 Page 45058). 

The Commissioner, among other things, spoke about the small size of homeopathy in those days and the added value to quality. Over the years, many within homeopathy took this as a full exemption of homeopathic drugs from stability testing. This was never the case, and the regulations reflected that point, stating that a stability program that at least reviewed the compatibility of ingredients was appropriated for homeopathic drug products. 

Over the years homeopathic drug products, specifically dosage forms increased in complexity and compatibility of ingredients took on more importance. In her articles on stability testing, former AAHP Board Member Mary Beth Watkins highlights the minimum stability testing requirements by dosage form. Mary Beth was a major contributor to the HPUS’ stability guidelines first published around the time of her articles on stability. 

The Commissioner exempted homeopathic drug products from characterizing the stability of homeopathic dilutions but not the stability of the dosage form itself. Also, the regulations require that the stability testing be conducted in the same container closure system in which the product is marketed. This implies that the compatibility of the container closure system must be established both at the design of the package and over the shelf life of the product. These points are not negotiable. 

Along with Mary Beth’s articles, a few good references are the HPUS stability guidelines and the range of stability guidances from FDA and the ICH.