Dilution Process Validation Is Complex and Data Driven
By Mark Land, AAHP President
There are more than 1,300 substances currently approved for inclusion within the Homeopathic Pharmacopoeia of the United States (HPUS). Based on discussions with homeopathic manufacturers, many companies work with 300 and 500 different substances. Because each manufacturer works with a different list of substances, most of the 1,300 substances are in commercial production. That’s a lot of substances.
Process validation seeks to prove that a process reliably produces the intended product. Process validation study designs generally include one or very few active substances. For the homeopathic manufacturer, that could mean hundreds of validation studies times the number of dosage forms produced. That is not practical, and manufactures therefore seek study designs with application across a range of substances.
What are the challenges in designing a study model with broad applicability? When asked this question, FDA spokesman Dr. Rik Lostritto told our recent Summit audience that we must address the challenges of adsorption, surface activity, and colloid formation of the active ingredients. Because these properties may vary by HPUS substance, one might again think of species-specific validation studies. So, are we working on an unworkable solution here?
Probably not. First, HPUS has established 11 liquid manufacturing classes for starting materials. The classes are based on the actual manufacturing process used, which derives from the physical and chemical properties of the starting materials. This presents a starting point for segmenting the long list of substances into shorter lists of groups for purposes of dilution process validation. To evaluate the grouping concept, examining the principle chemical constituents by substance for risks of adsorption, surface activity, and colloid formation is necessary. This is daunting but achievable work under consideration at HPUS right now.
Second, a challenge arises due to the concentration and nature of the ingredients with which we work. This is specifically true for botanical species. The target analytes in botanical species are often in concentrations below 1% of the botanical tincture. At such low concentrations, often the analyte is below detectable levels in one or two dilution steps. To overcome this problem, we often look to surrogate analytes, starting with stronger concentrations. In this way the study model is more predictable and yields data from a greater number of dilution steps.
FDA reminds us, however, that surrogates must have the same physical and chemical properties of the substance under study. From this perspective, the work turns toward looking for patterns within physical and chemical properties of the list of HPUS substances that can be exploited for purposes of developing a list of surrogate analytes.
The confounding problems of adsorption, surface activity, and colloid formation have a strong theoretical basis and present difficult problems for drug manufacturers and analytical laboratories. Not all apply to homeopathic drug products, however, and that is why we are approaching this problem in a data-driven manner.