By Eric L. Foxman, R.Ph., senior scientist, HPCUS
June 1, 2017
Before proceeding to review the major areas of updates in the HPUS, two specific items are of timely interest:
- The Guidelines for Manufacturing Homeopathic Medicines became official on March 31, 2017. The older General Pharmacy section and the Classes of Manufacture are no longer official documents of the HPUS. The newly official document expands upon the now-obsolete webpages and provides additional — and clarifying — details and information.
- However the implementation of the Expanded Labeling Guidelines has been postponed until March 31, 2018. This is due to the recently announced FTC policy and the steps the AAHP is taking in light of the FTC announcement.
- The obsolete pages mentioned above are archived and available for informational purposes only. These can be accessed from the last link of the left hand menu on the subscriber side of the HPUS website.
- In 2016, seven monographs were reviewed by the Monograph Review and Pharmacopeia Revision Committees and approved for inclusion in the HPUS by the Board of Directors, bringing the total number of official homeopathic starting materials to 1,304.
- During the course of 2016, the Standards and Controls Committee added quality control specifications to 52 monographs. This brings the total to approximately 580 of the 1,304 monographs that now have QC specifications. These 580 include almost all commonly used homeopathic substances.
- The Council on Pharmacy determined that it was appropriate to make slight changes in the HPUS alcohol coefficients to bring them into harmony with the USP values. The change in the HPUS alcohol coefficients is very slight and will not appreciably affect existing tincture production methods.
- The Council on Pharmacy also discussed the impact of California’s Proposition 65 on the HPUS and its OTC attenuation levels. Since California’s Proposition 65 impacts only one aspect of labeling, but not the legal marketing of products, and since it’s a one-state issue, the HPUS has simply added a reminder to encourage manufacturers, marketers and labelers, when preparing labeling for homeopathic drug products, to review specific state-by-state requirements for all locales in which they offer their products.
Two Revised/New Guidelines
The first of two new documents is the revised Homeopathic Good Manufacturing Practices. These Homeopathic GMPs are not all that manufacturers and marketers need to comply with. The foundation for GMPs that pertain to all drug products, homeopathic ones included, is 21 CFR 210–211.
Although the present revision was first posted in 2016, it is the result of deliberations that began 5 years before and has gone through more than a dozen iterations and stages of improvement. The revision is about four times more detailed than the prior version. More important, the revised version touches on many more details and subjects that were not mentioned previously.
The first four sections cover Introductory Information, Personnel, Faculties and Documentation, and Equipment. They contain little that will be new to those familiar with pharmaceutical GMPs. But there are some subjects not previously addressed, such as the management of suppliers and vendors, equipment reuse, and measurement equipment, amongst others.
The other four longer sections deal with starting materials and address many specifics that had not been mentioned in the previous version. Some are related directly to 21 CR 210–211. Examples include comparisons of specifications and the use of compendial standards.
Identity and Purity testing are noted in relation to HPUS monograph specifications, as well as test methodologies, especially when QC specifications have not yet been adopted by the Pharmacopeia Convention.
The section on Raw Materials of Chemical Origin addresses expiration and retest intervals, as well as storage. As an example of some of the new information in the revised version:
The HPUS allows for chemical substances that might be kept beyond the manufacturer or vendor’s expiration date, but they need to be retested prior to any use beyond that expiration date. However, in those instances in which the manufacturer/vendor has provided no expiration date, the material should be retested, prior to any use. This is a subtle but critical difference in production planning.
The section Raw Materials of Botanical Origin addresses subjects on which the previous version was silent, such as Good Cultivation Practices for cultivated plants, including issues of site selection and propagation, and Good Collection Practices for wild crafted plants. This includes an adherence to CITES (Convention on International Trade in Endangered Species of Wild Fauna and Flora) requirements.
Similarly the sections on Raw Materials of Biological Origin have corresponding information regarding Good Breeding Practices, including feed and medication use, as well as wild collection with, again, adherence to CITES requirements.
Storage and shipment are addressed. This includes guidelines for potentially acceptable methods for preservation between harvest/collection and processing when the time interval exceeds 72 hours. Some methods are noted that do not have long track records of use; the HPUS requires the manufacturer to determine and document the effectiveness and the maximum (or appropriate) time interval between harvest/collection and processing when using such preservation methods.
The revised guidelines provide a handy checklist of information necessary for verification, for identification and for labeling to prevent mix-ups and/or adulteration of materials shipped or stored together.
Rather than require designated tests for Pesticide exposure, Heavy metals exposure and Radioactive contamination, the HPUS recognizes that a risk analysis might be appropriate depending on the source location, documented history and analysis of prior collections, vendor audits, etc. The responsibility still rests on the manufacturer/ marketer of the product to ensure that the raw materials and finished products are not contaminated or compromised. But the HPUS allows for latitude in how this is done depending on individual circumstances.
The HPUS gives microbiological limits of various categories of common problematic organisms with a bifurcation of some limits depending upon alcohol concentration. And for certain classes of raw materials, the GMP addresses viral safety and / or sterility.
To ensure that raw materials obtained from Cell Culturing and microorganism culture are the proper materials, the HPUS requires these raw materials for sarcodes to be clearly identified by a national reference center or someone with proper training and equipment.
Some of the information from the obsolete GMP document is now in the newly official Guidelines for Manufacturing Homeopathic Medicines; it appears there in a much expanded and clarified form. Some of the information is also better covered by the more complete information in 21 CR 210–211.
The other document is entirely new for the pharmacopeia: the Homeopathic Drug Stability Guidelines. Drug product stability is an integral part of product quality and assures that homeopathic products will perform as intended throughout their period of use. This document is the result of more than 3 years of discussions, deliberations and iterations.
There are six sections in this guideline. The first section covers introductory points. Homeopathic drugs are exempt from expiration dating; however market forces and GMPs generally dictate the necessity and practicality of providing shelf life information for homeopathic drugs. The responsibility for assessing the stability falls on both manufacturers of homeopathic drugs and contract marketers. Marketing companies share an equal responsibility with their contract manufacturers for assuring that stability is properly assessed.
Risk analysis or product matrixing may be appropriate in instances of a) small scale production, b) a wide variety of active ingredients with similar physicochemical characteristics and prepared in similar attenuations, or c) products with active ingredient attenuations beyond the limits of analytical detection.
The HPUS gives some guidelines for Expiration Dating and Retesting specifications; manufacturers and marketers can use these guidelines in their internal deliberations regarding substance specific or cross product applicability of stability data.
The second section pertains to starting materials. Some of this information is also addressed in the Homeopathic GMPs revision. Here, general time frame guidelines are given for fresh plants and dried plant materials as well as sarcode and nosode starting materials. The time frame for chemical starting materials is a reiteration of the information in the Homeopathic GMP revision.
The third section addresses tinctures and low attenuations, for which analytical methods can be adopted fairly easily and utilized along with time frame guidelines. The fourth section, which is similar, addresses triturations. Both sections have provisions for potentially appropriate retest intervals.
The fifth section addresses intermediate products and attenuations. Of prime importance is the HPUS position that homeopathic intermediates, attenuations and triiturations are to be considered as separate entities from tinctures and starting materials. Thus they should be tested or assessed for stability and assigned appropriate shelf lives that are independent of those for starting materials or tinctures.
Secondarily is the HPUS position that the stability of attenuations and triturations beyond the limits of current quantitative analytical methodologies, should be established based on the stability of the vehicles and the specifications of the dosage form.
The sixth section addresses finished products. Not surprisingly, finished products need to have specifications for the product’s physical, microbiological and chemical characteristics as applicable. Of course any assessment must be performed in the same container and closure system in which the product is marketed. As a corollary to the primary statement in the prior section, any established shelf life is independent of the use life of the starting material or tincture.
What’s to Come?
(All of the following is subject to change depending on progress of the various committee deliberations.)
We can probably expect a few new monographs to complete their review process in 2017. Discussions are underway that will lead to (minor) revisions to the Guidelines for Manufacturing Homeopathic Medicines and to the Homeopathic Good Manufacturing Practices. Both sets of minor revisions will be based on a recently issued FDA Guidance regarding Active Pharmaceutical Ingredients.
The Toxicity and Safety Committee is continuing its ongoing review, which might lead to attenuation changes for various monographs. Side by side with this, the Council on Pharmacy will be discussing the definition of “External Use Attenuations,” which might lead to new wording and a corresponding impact on monographs.
This past winter, the HPCUS signed a Memorandum of Understanding with the Indian Ministry of AYUSH (Ayurveda, Yoga and Naturopathy, Urani, Siddha and Homeopathy) to work collaboratively on Pharmacopeial development. While the actual work is only beginning, it represents a potential for the HPCUS to have access to additional sources of QC methodologies, specifications and other information that may be appropriate to incorporate into the HPUS; at the same time, it also makes possible changes in the Indian Pharmacopeia to harmonize with what is already official here in the USA.
Need More Information?
The HPCUS is about to implement an email announcement mechanism for upcoming changes as well as points under discussion to solicit more input from the homeopathic industry. Details are still being worked on. If you want to be on the recipient list for these emails, contact email@example.com requesting to be put on the distribution list to receive these announcements and updates.
The landing page of the HPUS (www.hpus.com) has links to annual announcements of the years’ updates. The HPUS 2016 update has the above information in abbreviated form, but does include the lists of new and changed monographs.
In May 2016, the AAHP presented a Compliance Thru Education webinar on the HPUS 2016 updates. An archive recording (in both audio-only and audio/video formats) of the webinar is available from the AAHP office, which also includes the Q&A session and the handouts distributed during the webinar. To order copies of the archive, contact the AAHP Office directly.