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Forced degradation, analytical methods, qualification, and new guidance from ANVISA

The requirements by ANVISA for conducting forced degradation studies and developing a stability-indicating analytical method are described in RDC 58 (recently revised to RDC 53/15), and the guidelines for meeting these requirements are published in the revised CP68. The intent is to use forced degradation to discover and identify the “potential” degradation profile under a broad set of pharmaceutically relevant conditions to develop a valid stability-indicating analytical method capable of detecting and quantifying all potential degradation products and to use that method to determine the “actual” profile of degradation products that will appear on long-term stability. As described by ANVISA, the forced degradation study involves two parts: (1) the Critical Part and (2) the Experimental Part.  

The Critical Part (or “critical analysis”) of the forced degradation study that must be carried out prior to conducting the Experimental Part. The Critical Part involves bibliographic research (including the drug master file, scientific literature, and official compendia) and an assessment of theoretically possible degradation pathways based on the chemical principles. The bibliographic research is intended to obtain information about known degradation products and pathways. The assessment of theoretically possible degradation pathways requires knowledge of functional group chemistry of the API, degradation chemistry, and the potential interactions with common excipients. “This work is intended to help guide the design of the Experimental Part (including the analytical method development) to aid in the development of a stable formulation and to uncover the possibility of forming degradation products of unusual toxicity (e.g., mutagenicity or genotoxicity),” according to Steven W. Baertschi, a renowned degradation chemistry expert.

Developing the Critical Part of the forced degradation study can be a labor-intensive undertaking, requiring significant time for the bibliographic research and significant expertise to apply chemical principles that may be involved in degradation chemistry specific to the API.

Mutagenic impurities (MIs) and/or potentially mutagenic impurities (PMIs) formation is a concern during forced degradation studies and strategies for mapping these impurities can be adopted after theoretical studies of degradation and stress studies using in silico models and extensive literature review. This point is not specifically covered by Brazilian legislation, but for product safety, it is necessary to consider international guidelines (for example, ICH M7) to establish acceptable levels of these MIs and PMIs within the drug dosage.

After the stability evaluation process, there may be a need for qualification of impurities. Qualification is the process of acquiring and evaluating data that establish the biological safety of an individual degradation product or a given degradation profile at the level(s) specified. The applicant should provide a rationale for establishing degradation product acceptance criteria that includes safety considerations. “Qualification strategy is another important point for decision and usually requires a case-by-case analysis to avoid high testing costs,” according to Carlos E. Matos, project manager at Intertox Ltda.

The level of any degradation product present in an existing drug that has been adequately tested in safety and/or clinical studies, metabolites, and some known substances would be considered qualified. Sometimes there are gaps in information to search for and fill by testing.

Success case

To support Brazilian laboratories, Intertox Ltda (Brazil) has developed a partnership with Steven W. Baertschi, PhD (Baertschi Consulting LLC, USA), a renowned degradation chemistry expert, to provide services related to developing the Critical Part of the forced degradation studies as described in CP68.

The following services related to developing the Critical Part of the forced degradation studies as described in CP68:

  • Theoretical degradation studies and excipient reactions
  • Scientific literature searching
  • Assessing and drawing theoretical degradation pathways based on:
  • Chemical principles/degradation chemistry
  • Predictions from Zeneth, a chemical degradation prediction software program
  • Discussion of the implications for analytical method development

In addition, the following services are offered for the Experimental Part:

  • Help with the elucidation of structures for degradation products discovered during forced degradation studies that were not predicted in the Critical Part
  • Developing a mechanistic proposal for the degradation pathway
  • Creating a discussion of the mass balance observed
  • Establishing a discussion to tie together the Critical Part with the experimental results

Founded some years ago, Altox Ltda is a Brazilian company specializing in toxicology and regulatory affairs. It has provided consultancy services to several national and international clients for the qualification of impurities.

Services include (but are not limited to):

  • Impurities qualification and report validation
  • Testing strategies for risk assessments
  • Genotoxicity assessments
  • In silico modeling

Scientific advice liaison with regulatory authorities

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