Summaries of the first set of White Papers

Introduction — these are non-technical summaries of three White Papers now out for public comment. The comment period closes on April 20, 2024. The papers in their entirety, along with the process for comment, can be found here.

Before reading these summaries, we suggest that you read the Introduction to the White Paper Project.

(1) Utilizing a Quality by Design Model for Hahnemannian Dilutions in the Manufacture of Homeopathic Drug Products. 

This paper is summarized first because it relates to fundamental issues unique to homeopathic drug products. 

Due to certain unique aspects of homeopathic drug manufacture, some current Good Manufacturing Practices (CGMP) requirements for conventional pharmaceuticals may be inappropriate or impossible with which to comply. These are “gaps” between current regulation and the feasibility of compliance that the White Papers are intended to address. 

This paper “propose[s] science-based methods to achieve compliance… consistent with the spirit of the regulation and the limits of available science”.   The paper further makes recommendations that meet the needs of both regulators and manufacturers while providing assurances for the former and without placing undue burdens on the latter, 

For instance, CGMP requires laboratory determination of the identity and strength of each active ingredient.  Compliance with this requirement is straightforward for the lowest attenuations (serial dilutions and succussions).  But how do we comply when most homeopathic drug products (HDPs) contain levels of homeopathic starting materials that are orders of magnitude below the limits of detection (LOD) of conventional analytical chemistry? 

This paper describes a “reasonable and attainable alternative” called Quality by Design (QbD), based on scientific principles and has been used for over a decade. QbD has also been the subject of prior FDA guidance. Using a QbD approach, one can achieve “science-based and risk-managed manufacture and distribution of drug products.…”  

How? When it is not feasible or practicable to measure the amount of the homeopathic starting material in the HDP, use of a QbD slightly altered for homeopathy (HQbD) can confirm, with reproducible data, that the attenuation process is sufficiently accurate and precise despite containing concentrations too low to measure by conventional means. This is a validation of the attenuation process. 

When identity testing is impossible due to the ultra-low levels of “testable” substance in the attenuation, validation by HQbD is a reasonable alternative. Such validation assures consumers, healthcare providers, and regulatory authorities that the labeled attenuation will be present in the HDP. 

The paper discusses the core principles of QbD and their appropriateness for an HQbD model.  It also proposes using two specific substances to implement the model for testing levels in successive low homeopathic attenuations to validate the process. These were chosen for several reasons: the amounts of each substance are measurable at those attenuation levels, the chemicals are inexpensive, and the test methods are easy to use.   

The two compounds can be considered “stand-ins” for most homeopathic starting materials in terms of validating the attenuation process.  This “surrogate or stand-in” status is enhanced because one has surface active properties (which may adversely impact predictable quantities in subsequent attenuations) while the other does not. Thus, a side-by-side comparison of each result can further assure proper mixing, dispersal, and de-concentration from one attenuation level to the next. 

The paper suggests that through use of such an HQbD (Homeopathic Quality by Design) validation procedure of a company’s attenuation process, the following opportunity is possible: When a supplier provides a buying company with an “untestable” intermediate attenuation (e.g., a 10X which the buying company will then run up to a 12X), the supplier will still need to provide a Certificate of Analysis (C of A), but also must provide proper documentation showing the attenuation process has been validated. The QbD model can be used for that validation.  The acquiring company will then not need to repeat identity tests on the supplied materials, although they are required to assess the seller’s methods to ensure compliance. (Such additional documentation must also be available to regulatory authorities in cases where the product is under investigation.) 

The proposed HQbD approach can obviate the need for a manufacturer to test received intermediate attenuation below the LOD, so long as they are accompanied by documentation of the validation described in the HQbD approach. This will eliminate a heavy (and impossible to comply with) burden for companies. Of course, starting materials must still be properly ID tested, the attenuation process must be vigorously validated, and documentation must clearly show all bases have been covered.  Limit tests will still need to be performed for intermediates prepared from highly toxic substances to confirm they do not exceed any risk or safety assessments; this provides assurance the product is safe for the consumer even if an undetected manufacturing error has occurred. 

(2) Best Practices for Testing and Control of Homeopathic Starting Materials in Batch Manufacturing

This White Paper addresses important differences (gaps) in Good Manufacturing Practices between the FDA and those of the HPUS.  The White Paper’s scope includes GMPs relevant for manufacturing batch-processed (in large quantities) commercially distributed products and where the starting materials (see below for definition) are of chemical, botanical, or mineral origin.  

Excluded from this White Paper’s scope are:  

• extemporaneously compounded drug products (e.g., medicines made according to a physician’s order for a specific patient) 
• Pharmaceutical compounding of non-sterile or sterile preparations 

• Substances of zoological (animal) origin. 
   

The paper seeks to clarify specific definitions that do not match those for allopathic drugs: 

1. Raw Materials vs. Starting Materials and “Intermediates” — Homeopathic medicines made from plant sources (whole plant or part) are both raw materials and homeopathic starting materials as the harvested plant is not fundamentally altered before it begins to be made into a homeopathic preparation.   
    

2. But some homeopathic medicines are made using materials that have already been processed.  One example is Ferrum phosphoricum, where the conversion into a homeopathic attenuation begins with four distinct salts of iron mixed (a “process”) in specific proportions. 
    

3. This White Paper clarifies these and other terms appropriate to homeopathic drug products, which have different meanings than those for conventional pharmaceutical products.  These definitions are essential to understanding the proper manufacturing of homeopathic drugs, which CGMP applies to which manufacturing stages, and all the documentation and testing for the appropriate stage.   

The paper goes on to discuss other issues: 

1. Intermediate Products — A manufacturer of homeopathic products may begin the process from the homeopathic starting material, provided they have the capability and capacity to prepare the first attenuation.  Or, as in many cases, an “intermediate” potency (attenuation) is purchased from a “contract manufacturer” (supplier).  The purchaser then runs the intermediate up to the potency intended for the finished product.   
    
   Such intermediates are themselves subject to regulation.  The Contract Manufacturer sends the purchaser a Certificate of Analysis (C of A). Still, for that Certificate to comply with FDA CGMP (citation to 21 CFR 211.84***), the supplier’s test results must be appropriately validated at appropriate intervals. This requirement applies to all drugs, not just homeopathic drug products.  
    
   Such testing covers many aspects (control of residual solvents such as alcohol, elemental impurities such as minerals, microbial contaminants, etc.) already covered in the HPUS. 
    

2. Identity testing of ALL incoming components is a fundamental requirement, which may be impossible.  Say, for example, that a contract manufacturer has supplied a 10C of Arnica montana to another manufacturer who will then run it up to a 12C.  At that attenuation, any marker substance specific to Arnica montana is way below any detection limits by currently available technology. 
    
   Because there is presently no exemption or alternative process to meet the identity testing requirement, the regulatory requirement of 21 CFR 211.84 confronts the manufacture and marketing of homeopathic drugs with a conundrum:  Congress recognizes drugs in the HPUS, but full (and impossible) compliance with FDA’s CGMP (current Good Manufacturing Practices) regulation can be seen as making their sale impossible. 
   
   Specific Identity testing is possible at the first few attenuations but rarely beyond 6X (3C).  This White Paper proposes a science-based solution to this problem based on currently accepted concepts in pharmaceutical quality systems. 
   
3. Expiration dating of Intermediate Products — FDA exempted homeopathic drug products from bearing an expiration date on the label and complete stability testing ( 21 CFR 211.137 and 21 CFR 211.166).  It did so owing to the “unique nature” of homeopathic drugs (Federal Register, Vol.43, No. 190, September 29, 1978, p. 45058 left column under 211.137(e)).  In 2004, the agency partially withdrew that exemption (Federal Register November 26, 2004, 69 FED. REG. 68831 — search on [[Page 68834]]), saying that there “may be certain situations” where expiration dating and strength testing for intermediates would be necessary.  It has never specified what those situations might be.
   
   Such exemptions are, however, not an exemption from another regulation, 21 CFR 211.87, which requires that approved components (including drug product containers and closures) be retested or reexamined, as appropriate, for identity, strength, quality, and purity (alcohol, for example).   
   
   For Containers, This White Paper recommends a “risk-based approach” to assessing the likelihood of packaging-component and dosage form interactions.  Such interactions are possible with liquid and solid dosage forms.
    

(3) BEST PRACTICES FOR UNIQUE ASPECTS OF FINISHED PRODUCT TESTING FOR HOMEOPATHIC DRUG PRODUCTS 

This paper addresses mismatches between conventionally accepted quality practices for the identity and strength of the product in its final form before release into the marketplace.  The relevant section of the Code of Federal Regulation (CFR) is 21 CFR 211.165(a).  Other requirements in 21 CFR 211.165 are also addressed, some of which were previously exempted for Homeopathic Drug Products (HDPs), including potency, absorption, bioavailability, and other measures of effectiveness (Federal Register VOL. 43, No. 190 – Friday September 29, 1978, p. 45058 (Comment 357 in left column)) 

Because HDPs generally have extremely low levels of active ingredients, finished product testing poses challenges.  FDA’s regulations on finished product testing were part of their 1979 revamping of the original Current Good Manufacturing Practices (CGMP).  In response to comments filed by the American Association of Homeopathic Pharmacists (AAHP), the FDA exempted HDPs from the new finished product regulations.  However, the FDA used language that left open the possibility of reinstating it for HDPs.  Four years later, this exemption and other never-finalized rules were withdrawn.  By so doing, HDPs would have to fulfill finished product testing requirements.   

Once again, the AAHP commented, arguing that the mere passage of time had done nothing to change the correctness of the AAHP’s and FDA’s earlier position.  FDA rejected those comments and withdrew the proposed exemption (citation *** Federal Register November 26.2004, 69 FED. REG. 68831).  FDA stated that: 

“There may be instances where testing of a homeopathic product for identity and strength of the active ingredient prior to release for distribution would be appropriate and consistent with protection of the public health.” (Emphasis added.) 

The scope of this White Paper is limited to homeopathic drug products with the following parameters: 

1. Only Homeopathic Drug Products (HDPs) that may appropriately be sold over-the-counter, 

2. Only HDPs that are available as oral and topical products and 

3. Only HDPs prepared from chemical, mineral, and botanical substances. 

The White Paper suggests that final product testing is not limited to active ingredients and that to help ensure potency, quality, and safety, the testing of finished HDPs is designed to ensure the following: 

1. the absence of chemical impurities; 

2. all components of the HDP are below safety-related thresholds and 

3. Consideration of the relationship between safety concerns and detectability. 

A “Safety and Detectability Priority Matrix” is suggested.  At one end of the spectrum are HDPs with low safety concerns and high detectability.  At the other end are HDPs with high safety concerns and low detectability (i.e., hard to detect).  The White Paper notes that the HPCUS adds a 100-fold increase in safety margin. 

The White Paper discusses the “Control Strategy” defined by international agreement (citation **** International Council for Harmonization – ICH Q10).  Such a strategy is a “planned set of controls, derived from current product and process understanding, that assures process performance and product quality.”  It is noted that a “well-designed control strategy is of primary importance as it lowers the probability of risk-related events occurring in the first place.” 

It is noted that some of the testing specified in ICH Q10 is universally applicable for finished HDPs; alternatives based on Quality by Design (QbD) frameworks are available when those tests are not possible.  

The paper ends with a set of five recommendations that note (in summary): 

1. Effective regulation of HDPs must consider that they contain components that are magnitudes more dilute than current levels of detectability. 
    

2. Medical professionals experienced in this area consider that the effectiveness of HDPs is highly dependent upon factors such as identity, purity, and attenuation rather than on measurable amounts of homeopathic starting materials in the finished product.  
    

3. Adopting the Safety and Detectability Matrix (or an equivalent tool) will permit manufacturers and regulators to evaluate safety assurance programs for different HDPs. 
    

4. Manufacturers and regulators should ensure that comprehensive risk management systems include a robust control strategy as the critical element due to challenges with detectability for many HDPs. 
    

5. For substances that are highly toxic, poorly detectable, or with unusual physicochemical properties that challenge the assumptions of the attenuation process, or the dosage form and route of administration pose a higher toxicological safety risk from the homeopathic starting material(s) present, limit testing to demonstrate that constituents of toxicological interest are below levels of safety concern is the only feasible and appropriate approach to ensure safety.