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11. Process validation

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Guidelines for Manufacturing Homeopathic Medicines

11. Process Validation

  1. Homeopathic Drug Products (HDPs) and their associated homeopathic product intermediates often contain levels of homeopathic starting materials that are orders of magnitude below the limits of detection (LOD) of conventional analytical chemistry. Therefore, manufacturers and marketers of HDPs must rely upon a robust validated process to ensure the final product delivers the labeled attenuation, as there are no practical or feasible tests which can provide that assurance. Further, a well-designed process validation project helps assure quality and safety are designed or built into the manufacturing process of the product, as neither attribute can be adequately assured merely by in-process and finished-product inspection or testing of HDPs that are below limits of detection. Manufacturers and marketers are free to choose a process validation approach which best fits their circumstances, so long as the technical approaches provide sufficient information to substantiate a well-reasoned confirmation of the manufacturing process. Manufacturers are encouraged to reference FDA’s Guidance for Industry Process Validation: General Principles and Practices (1) for more background and information.
  2. One possibility is described below. This technical approach does not propose any HDP manufacturing process change(s).  It provides a data-based framework supporting a reasonable verification of the dilution by providing relevant data to show that the deconcentration effect of the homeopathic dilution process is (or is not) following arithmetic predictions relative to the homeopathic starting material content.  An added benefit to such an approach: it permits the assessment of variability associated with manual techniques , equipment usage, environment, etc. on the accuracy and precision of the attenuation step. All of these help to understand the origin, existence, or extent of variation as well as the potential impact of variance on the ultimate product.
  3. In the many circumstances in which neither intermediate nor final HDP identity testing can be performed due to the extreme de-concentration levels, this technical approach provides a reasonable and attainable alternative based on the scientific principles of Quality by Design. If the observed homeopathic starting material concentration is aligned with the arithmetic prediction (within established acceptance criteria) at measurable attenuations, then there is greater assurance that the labeled attenuation is met when the HDP is at an attenuation too dilute to feasibly measure the homeopathic starting material content.  QbD approaches have been used in the development of approved drug products since at least 2012 (2,3).  One key benefit of QbD: to help to ensure the availability of quality medication by leveraging scientific principles which justify manufacturing flexibility in terms of safety and quality. Further, there is no prohibition against data-based extrapolations as part of a design space based on scientific expectations and which shows no change in mechanism or interaction with other quality parameters over the range(s) actually tested.  A classic example is the extrapolation of available stability data to support expiry periods longer in duration than the actual stability interval tested(4).
  4. The Homeopathic Quality by Design (HQbD) model is constructed and tested per QbD tenets and provides valuable and useful information regarding the accuracy and reproducibility of the attenuation process used in HDP manufacture. It is a scientific approach that better satisfies 21 CFR 211.165a for HDPs, and demonstrates, with data, that the Hahnemannian attenuation (see Guidelines for Manufacturing Homeopathic Medicines [GMHM] §29) process has sufficient accuracy and precision to assure that the labeled concentration of homeopathic starting materials (corresponding to the labeled X or C potency) in the HDPs are appropriate and correct despite containing concentrations too low to measure by conventional means. The concepts of this technical approach may be applied to other attenuation methods described in the GMHM (see also GMHM §30, 31, and 32).
    1. The aliquot method is linked to the Hahnemannian attenuation method. Aliquots for attenuation and for analytical testing from attenuations should be conducted in a manner which ensures that the sample accurately represents the whole uniformly.
    2. Selected diluents should correspond to those used by the manufacturer / brand owner to make HDPs.
  5. The following model described utilizes two attenuation-test substances; one surface active type substance (for example, Benzalkonium chloride (4) (or BAC ); and a well characterized, water soluble single molecule (for example, salicylic acid (8). Whatever substances are chosen by a manufacturer wishing to utilize a HQbD validation process should be adequately stable, readily available at reasonable cost, and have straightforward published conventional analytical methods.
    1. All records and documentation should include the raw data, documentation, and summary documents which clearly capture the procedure, results, and outcome (including statistical analysis) for each study conducted.
    2. Summary of Procedures
      1. The homeopathic starting material is used in three dilution trials. Each attenuation step will be given adequate mixing to ensure uniform distribution and then allowed to come to rest before being sampled. Multiple samples are taken at each dilution step for each trial: after the contents have come to rest, representative samples are taken from multiple locations (for example near the top of the container, a second near the middle, and a third sample from near the bottom).  [The number of samples may vary depending upon the size of the vessel / container. The manufacturer is responsible to ensure the number of units is based on rational criteria intended to satisfy that the samples accurately portray the contents of the vessel / container. Manufacturers are encouraged to reference 21 CFR 210.3  (b)(21) and 211.110).]  If the results of top, middle and bottom are tracked, it allows for a comparison of sampling location which would highlight any nonuniformity of the dilution process resulting from surface activity, innate handling difficulties (e.g., resinous material), or incomplete mixing.
    3. Using the Model
      1. Calculate the mean (M1) and standard deviation (SD1) for the 9 concentration values at Dilution 1 (all three trials). Do this for Dilution 2 to get M2 and SD2 and for Dilution 3 to get M3 and SD3.  [For a surface active substance like BAC, this is the total measured concentration of all BAC related species (i.e., homologues)].  Some minor serial accumulation of variability may occur with successive attenuations; this is normal and unavoidable. Table 1 below provides workable estimates for the mean (M) and standard deviation (SD) that may reasonably describe limits of acceptability for the attenuation process for each homeopathic starting material studied.
      2. Table 1: An example of Hypothetical Upper Limits for Attenuation (Dilution) Accuracy and Precision as Mean (M) and Standard Deviation (SD) reported as %RSD (where RSD is the relative standard deviation expressed as a percentage value of the mean value) for the single molecule entity (for example salicylic acid) and for a surface active type substance (for example, BAC)  .
      3. If there are homologues present in the surface active substance, they are also assessed together (as the sum of the peak areas) to assess how a mixture of related substances with potentially different surface activities behaves during the de-concentration step of the attenuation process. The order of the homologue peak areas should remain the same throughout the attenuation steps and there should be no apparent trend of concern indicating that dilution results are affected by the surface activity of the constituent homologues.
    4. Managing Substantive Deviations from Near Ideal Attenuation Behavior.
      1. If the dilution test results within the statistical limits of M and SD as described in Table 1, and the homologue ratios follow the same order with no adverse trends, this is strong evidence that further attenuations conducted in the same manner should yield corresponding results. Documented manufacturing adherence to the HQbD process will provide assurance of proper manufacturing whenever the actual amount of the homeopathic starting material in the HDP is anticipated to be non-feasible or impracticable to measure directly.
      2. However, several possible scenarios where this is not the case are worth exploring. If the M and SD criteria are not met at some attenuation number, or if there are apparent trends in the ratios of the three main homologues the data should be examined at that dilution and evaluated to see if position (top, middle, or bottom per Fig. 1) plays a role.  If values in one location are trending higher or lower, or the BAC ratio changes substantively, this provides useful information on how to correct and ultimately prevent the non-ideal mixing outcome. Once the root cause is determined (e.g., human error, incomplete mixing, analytical method problem(s), surface activity, etc.) it can be corrected, and the study repeated.
  6. Applicability to HDP Intermediates in Commerce 
    1. If a manufacturer purchases homeopathic attenuations below thresholds of measurement for identity and strength, the seller (i.e., the intermediate manufacturing entity) should perform similar attenuation verification exercises as described above and provide that information as part of a certificate of analysis (C of A) so the product owner has written documentation that the product contains the labeled attenuation.
    2. Greater assurance is provided for the seller and buyer via viable and detailed C of A documentation along with correspondingly healthy buyer / seller relationships (see also HPUS Homeopathic Good Manufacturing Guidelines §3.8).  It is a pillar of FDA inspectional activities to have access to the entirety of data and information involved in the drug manufacturing process. The seller’s robustly informative C of A may help to address important inspectional CGMP requirements.  In cases where the C of A cannot include proprietary information, a drug master file (DMF) may be submitted to the FDA.  The information in the DMF is available to FDA staff as necessary and as authorized by letter from the DMF Holder (i.e., the seller) via a Letter of Authorization (LOA) from the DMF Holder. 
  7. Alternative validation approaches may be utilized so long as a chosen alternative provides at least an equivalent measurable level of assurance of proper manufacturing. Companies choosing to use an alternative validation protocol are responsible for justifying the chosen alternative.

(1 https://www.fda.gov/files/drugs/published/Process-Validation–General-Principles-and-Practices.pdf)

(2 FDA Guidance Document Q8, Q9, & Q10 Questions and Answers — Appendix: Q&As from Training Sessions (Q8, Q9, & Q10 Points to Consider) August 2012 accessed 01042024 online at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q8-q9-q10-questions-and-answers-appendix-qas-training-sessions-q8-q9-q10-points-consider)

(3 FDA Guidance for Industry Q8(R2) Pharmaceutical Development; November 2009 ICH Revision 2 accessed 01042024 at  https://www.fda.gov/media/71535/download)

(4 see ICH Q1E Evaluation of Stability Data, Section II.C; accessible at https://www.fda.gov/media/71722/download)

10. Finished Product Testing