10. Finished Product Testing

Guidelines for Manufacturing Homeopathic Medicines

10. Finished Product Testing

1. 21 CFR § 211.165(a) requires each batch of drug product to have laboratory determination of identity and strength of each active ingredient.  However, some Homeopathic Drug Products (HDP) contain such low levels of chemical constituents that the quantitation and detection of these components are unattainable; thus, the required testing for identity and strength is impossible to perform. For this reason, manufacturers and marketers must place a greater emphasis on an overall control strategy for the HDP.
   1. At the same time, as FDA has noted “There may be instances where testing of a homeopathic product for identity and strength of the active ingredients prior to release for distribution would be appropriate and consistent with protection of the public health.”(¹)
2. To address concerns regarding protection of public health, testing of finished HDPs should be designed to ensure:
   1. the absence of chemical impurities;
   2. all components of the HDP are below safety related thresholds; and, 
   3. consideration for the relationship between safety concerns and detectability.
3.  While the FDA requires testing to include the identity and strength of each active ingredient for each batch of drug product (as per 21 CFR 211.165), their concern for homeopathic products is likely only to the level that the Agency considers safe. Detection of single molecules may represent the ultimate goal of ultrasensitive chemical analysis  (e.g., LC/MS, LC/MS/MS); however, it may not be practical, and is not necessary to utilize forHDPs which have been taken through enough attenuation steps that the starting material has been too diluted to pose any safety concern. 
   1. For the purposes of testing HDPs, the HPUS supports modern spectroscopic and chromatographic analysis with results that would be meaningful. Manufacturers should use technologies and systems that are sufficiently sensitive to comply with the 21 CFR GMP requirements without requiring testing that provides no additional useful data.
4. Safety and Detectability Priority Matrix

Group IV Safety Concern High Detectability Low	▲ Increased Safety Concern	Group III Safety Concern High Detectability High
◄ Decreased detectability		Increased detectability  ►
Group I Safety Concern Low Detectability Low	Decreased Safety Concern ▼	Group II Safety Concern Low Detectability High

Moving from Left to Right, one sees increased Detectability. Moving from Bottom to Top, one sees increased Safety Concern. Safety (vertical axis) is a measure of the severity of any potential harm. The Safety and Detectability Priority Matrix helps visualize when testing is justified (risk/assessment). Usual risk assessments place the possibility of a potential risk on the horizontal axis; the probability of manufacturing errors is equally weighted along this axis. Thus, detectability is substituted for likelihood on the horizontal axis. For example, in Group I, detectability of the homeopathic starting material is minimal; in Group IV, any toxicity concerns regarding the homeopathic starting material are insignificant when considering products containing attenuations at or beyond the Lowest Permissible Attenuation (LPA – which has an inherent 100-fold margin of safety) for OTC distribution. 

Using the above Safety and Detectability Priority Matrix and a risk assessment based on starting material and number of attenuations steps performed, the following Table provides a starting point for determining when quantitative testing is meaningful and needed.  [The need for testing is based on the known toxicity of individual constituents of the starting material at attenuations between 1X and the LPA for OTC distribution.]

Group IV Safety Concern High (If OTC LPA is 6X or higher)  [Example: Rauwolfia serpentina] Detectability Low (Target analyte extractable from the dosage form < 1 PPM ) (Target analyte extractable from the dosage form in attenuations up to the LPA is < ppm)   Product Controls  Limit testing & Process Controls	▲ Increased Safety Concern	Group III Safety Concern High (If OTC LPA is 6X or higher)  [Example: Mercurius solubulis] Detectability High (Target analyte extractable from the dosage form ≥ 1 PPM ) (Target analyte extractable from the dosage form in attenuations up to the LPA is ≥ ppm)   Product Controls  Process controls OR  Assay/Limit Testing
◄ Decreased detectability		Increased detectability  ►
Group I Safety Concern Low (If OTC LPA is 5X or Lower) [Example: Passiflora incarnata] Detectability Low (Target analyte extractable from the  dosage form < 1 PPM ) (Target analyte extractable from the dosage form in attenuations up to the LPA is < ppm)   Product Controls  Process Controls	Decreased Safety Concern ▼	Group II Safety Concern Low (If OTC LPA is 5X or Lower) [Example: Coffea tosta] Detectability High (Target analyte extractable from the dosage form ≥ 1 PPM ) (Target analyte extractable from the dosage form in attenuations up to the LPA is ≥ ppm)   Product Controls  Process Controls

1. Safety
   1. Some homeopathic starting materials have inherent safety concerns. Thus, the homeopathic starting material as well as the 1X and 2X attenuations (and possibly a few subsequent attenuations) would present a safety concern if there was a manufacturing error or mix-up.
   2. In such a case, the manufacturer should ensure known potentially toxic components of the HDP are below any safety related thresholds by utilizing limit tests or other control strategies which assure the safety of the HDP with regards to its homeopathic starting material. An assay to determine concentration (content of target analyte) should be included when there are concerns regarding safety and an assay is technically feasible and reasonably achievable.  Further assurance is provided through a homeopathic Quality By Design (HQbD) approach which is the subject of the White Paper, Utilizing a Quality by Design Model for Hahnemannian Dilutions in the Manufacture of Homeopathic Drug Products. (See also Sec. §12)
2. Control Strategy
   1. A written control strategy should be in place. This consists of a planned set of controls that assuresprocess performance and product quality.  This incorporates product specifications, which include tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the tests described. Finished HDPs must have established (i.e. pre-approved) specifications for the product’s physical, microbiological, and chemical characteristics. . Established specifications also include those applicable to the finished HDP’s packaging which must be qualified to protect the product from degradation, microbial contamination, absence of leachable components, etc.
3. Identification
   1. A specific identity test should be included when technically feasible and reasonably achievable. For some homeopathic starting materials, identity testing is performed for a target analyte(s) that is uniquely characteristic of the natural substance. If it is impractical to extend the limits of measurement for identity testing through sample pre-concentration and/or application of conventional analytical technology (e.g., HPLC), product identity may be demonstrated through the totality of CGMP compliant documentation of the homeopathic starting material identity, batch manufacturing records, in-process test results and/or process validation. Owing to the unique nature of many HDPs, testing to demonstrate that homeopathic starting materials are not present above levels of safety concern may be the only current feasible approach in such cases. When multiple compounds of concern are associated with a given compendial article, only one compound needs to be tested, provided its control also assures the control of the untested compounds. Test methods must be validated to assure detection at concentrations relevant to the applicable safety thresholds. 
      1. HDPs attenuated below levels of detectability for homeopathic starting material(s) should remain exempt from finished product testing. Owing to the unique nature of many HDPs, testing to demonstrate that homeopathic starting materials are not present above levels of safety concern may be the only current feasible approach in such cases. Limit testing to demonstrate that constituents of toxicological interest are below levels of safety concern is a feasible and appropriate approach to ensure safety.  (See also §10.4 Safety and Detectability Priority Matrix.)
      2. When specific identity testing is not technically feasible nor reasonably achievable, a process validation program may be used to assure the manufacturing process delivers the intended attenuation step. One possibility is the homeopathic Quality by Design (HQbD) approach, which is discussed at length in the HPCUS White Paper titled Utilizing a Quality by Design Model for Hahnemannian Dilutions in the Manufacture of Homeopathic Drug Products. (see also Sec. §11)
4. Impurities
   1. Comprehensive control of homeopathic starting materials typically obviates the need for testing of the final HDP for organic impurities, solvent impurities, and elemental impurities, provided similar controls are in place for all other components of the HDP (e.g., excipients, primary packaging).
   2. Organic Impurities: For homeopathic starting materials that are not obtained directly from natural sources, impurity specifications for the HDP would not be more restrictive than those applied to the homeopathic starting material itself.
   3. Solvent impurities: Testing should be performed for residual solvents when production or purification processes are known to result in the presence of such solvents. A cumulative method may be used to calculate the residual solvent levels in the HDP from the levels in the ingredients used to produce the HDP following a risk management approach. The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk.
5. Other Characteristics
   1. Finished homeopathic dosage forms/routes of administration should be tested for relevant characteristics that should be stated in the product specifications. These may include, among others: tablet dissolution/disintegration times, alcohol content, tablet hardness/friability, microbial limits(²), pH, uniformity of dosage units, apparent viscosity.

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(¹ FEDERAL REGISTER of November 26, 2004, 69 FED. REG. 68831)

(² There may be a need to specify the total count of aerobic microorganisms, the total count of yeasts and molds, and the absence of specific objectionable bacteria. These should conform to HPUS requirements. Justification for not including testing of microbiological attributes may be developed following the decision tree (#6) of ICH Q6A.)