By Eric L. Foxman, Pharmacist, AAHP Secretary
Having listened to the speakers at AAHP’s 2021 Summit: Implementing HPUS Guidelines for FDA Compliance, Part 2, I came away with several thoughts that will be important to manufacturers and marketers in the coming months and years. But first a huge thank you to the presenters and the behind-the-scenes organizers of the event. As an attendee, I saw a four-hour series of helpful presentations. But there were also many hours of preparation by each and every person involved – all of which contributed to a rich session providing meaningful information. I’d also like to thank those who submitted questions, as the responses provided supplemental details and information, or reinforced critical points to which the homeopathic industry needs to attend. Plus a thank you to the HPCUS, which has taken on the project of finding solutions to identified technical gaps.
A key thought that struck me again and again: there are existing guidelines and cGMP requirements, yet some of them can be impractical to apply directly to homeopathic manufacturing. However, with careful and creative thinking, we can find alternative ways to harmonize existing homeopathic manufacturing experience with regulatory expectations for drug products – especially as we consider the primary objective of safety for OTC products. The presented white paper, and the four in the pipeline, are examples of this creative thinking.
Active Pharmaceutical Ingredients
While I had already seen Adam Grobin’s draft white paper on Active Pharmaceutical Ingredients (APIs), I appreciated his overview and emphasis on essential factors that need consideration. Adam noted an especially important point: for each lot of incoming material that may be too dilute to perform specific ID tests, we must have data showing that it is below any practical limits of measurement as well as a comparison between the limits of detection and any safety thresholds. Dr. Grobin also pointed to some interesting cGMP corollaries in other segments of the market; it may be possible to explore how those ideas might be formalized and implemented for the homeopathic industry.
While companies may use risk analysis to establish supplier qualification, we received a strong reminder that our industry may too often assume received starting materials are in compliance with our expectations and specifications. If we don’t perform the necessary tests, how do we know that our assumptions are correct? The conundrum is especially challenging when using an outside vendor to supply intermediate attenuations that become starting materials for additional in-house attenuation steps; these intermediate attenuations can’t be tested, so how can we know? A robust vendor qualification program, including review of their production SOP’s, their incoming materials release criteria, and their test results, etc., all become a part of our work to assure our customers they are getting what they expect. As Adam clearly stated: we can have others perform the work for us, but we cannot delegate our responsibility for the end results.
Validation of the Hahnemannian Liquid Attenuation Process
The presentation on Validation of the Hahnemannian Liquid Attenuation Process highlighted wide-ranging aspects that each manufacturer must consider when validating their own processes. For instance, how does one validate the process with a large number of different starting materials and with different methods of dilution? This might seem overwhelming at first, but Isabelle Chanel brought our attention to validating the “deconcentration” process. A key parameter to focus upon is homogeneity.
A possible approach incorporates the following thoughts: the homeopathic dilution process is simple and traditional; and the first steps are clearly laid out in the HPUS to produce a homogeneous solution.
- If subsequent attenuations in the product have starting material concentrations within the limits of detection, one can depend on an assay of a specific component (or, possibly, a surrogate compound) plus a risk analysis if there are toxicological safety concerns.
- If the attenuations involved in the product have starting material concentrations beyond the limits of detection, one can depend on an assay of an appropriate surrogate compound for the process validation.
For these two routes, a validation protocol would take into account batch size, dilution scale, vehicle, personnel, equipment, surrogate choice (solubility and ease of analysis considerations), number of batches, and sampling protocol. (For the first group, the risk analysis includes the lowest safe attenuation and the route of administration. A pharmacovigilance program is also helpful, and since this is required in the U.S. It needs few extra resources.)
Isabel provided an example of such a validation study using a surrogate compound that is readily soluble and can be detected in low concentrations using a very specific methodology. That validation study of the Hahnemannian liquid attenuation process included multiple batches, multiple operators, and multiple dilution ratios. With a goal of less than five percent variation from theoretical concentration results at the various attenuations tested, the results of the study clearly validated her company’s process, showing that it yields homogeneity of batches, exceedingly small relative standard deviations, and deviations from expected results ranging from only 0.8% to 1.2%. This study clearly shows a path forward. Isabelle also shared her company’s considerations regarding choice of surrogate. The surrogate must have some relation to the target solute in both physical and chemical terms, such as batch sizes, sampling, and other parameters that should be taken into account. If nothing else, this portion of the 2021 Summit provided attendees with a huge step in the right direction. I look forward to reviewing in detail the draft white paper that will come out of this initial work.
A Word from the FDA
Over the years, I have had a few opportunities to speak with Dr. Lostritto of FDA’s Office of Pharmaceutical Quality, who was the Summit’s final speaker. It is clear he appreciates there are many challenges that face our industry, and he seems personally interested in finding solutions to the conundrums that we encounter when confronted with the difficulty of strict application of cGMPs to the higher attenuations found in many homeopathic drug products. I found his overall presentation to be very positive. It is clear that he is pleased with the steps the HPCUS is taking to address the identified technical gaps in a thorough and scientific manner.
The potential for dilution deviation seems to be of major concern to the agency. Isabelle’s presentation helped provide a focus that can put that concern into context and demonstrate it is a theoretical issue that has little, if any, impact on the therapeutic utility of homeopathic drug products. On the other hand, one should pay attention to Dr. Lostritto’s emphasis on the factors that need to be considered when addressing dilution deviation or lack thereof. For instance, if adsorption were really an issue, it would appear in solutions that are nearly saturated and which “want to become” less saturated. For homeopathically prepared drugs, this might be an issue only at the first attenuation step. There may be more to consider, such as microstructures or suspensions that might be formed and which could result in uneven solute distribution within attenuations. Additionally, surface activity may be impacted by the size of the container versus the volume processed in the container. At the same time, both Dr. Lostritto and Chanel were clear that other factors need to be considered for validation of the Korsakovian Liquid Attenuation Process. This was not the subject of this Summit’s presentation.
Dr. Lostritto also provided useful comments when addressing stability and expiration considerations. When dealing with attenuations that are too dilute to measure concentration (beyond limits of detection), one can’t just assume all will be stable “because there’s nothing to measure.” Stability data need to address potential physical and chemical changes of inactives and containers. This rang so true for me. In my own consulting work, I have seen far too many examples of dosage-form breakdown, container deformation, and labeling that became illegible – all of which happened “over time.” One should consider stability measurement as a “package deal” – it’s not just the stability of the active homeopathic drug product.
It was very worthwhile listening to the presenters, who provided lots of information and details during the four-hour event. The 2021 Summit was the third that AAHP hosted on technical gaps. This event presented the first results of the HPCUS’ efforts to develop white papers addressing the technical gaps and therefore was the most meaningful Summit so far. I look forward to the next sessions that will further this project.
I urge everyone to watch (or re-watch!) the presentations and the Q&A portions of the recordings. This will provide you with an important start towards meeting cGMP requirements in a meaningful way. Summit attendees were emailed a link to access the recordings and to download the presentation slides. Attendees can re-receive this complimentary link by contacting the AAHP office. Anyone who missed the 2021 Summit can still access the entire set of recordings and download the presentations for review. The presentation deck and video archive are $249; the deck alone (without the important speakers’ words, comments, and additional verbal information) is $99. Contact the AAHP office for method of payment, after which the link and password will be provided.
It is also important to often revisit the Homeopathic Pharmacopeia’s landing page for links to the actual white papers as they become available. Comments and feedback from all involved in the homeopathic industry are critical and will improve the final implementation into the HPUS of the ideas presented in the white papers. This 2021 Summit is another step in our industry’s evolving cGMP compliance. I foresee that unprepared companies will find themselves forced to leave the market. Don’t let that be your company’s fate.