In recent years, the Brazilian human health regulatory authority ANVISA, has issued a number of documents describing in detail what is expected to be presented in a Regulatory submission in Brazil for Forced Degradation Studies (FDS), i.e., how FDS should be designed and managed, and how relevant data should be evaluated (Ref. 1-3).
The target of this blog is to summarize, following the FDS process flow in an easy and schematic way, the key elements to be considered when designing and assessing data from an FDS intended for ANVISA submission.
Part 1 of this blog (Ref. 4) has covered background and basic information on FDS according to the ICH and WHO stability guidelines as well as on ANVISA.
The present blog, (Part 2 of 3) will cover how ANVISA views FDS in a larger, overall context, and will outline the preliminary steps to practical FDS, i.e., preparing an FDS protocol and choosing the appropriate batch of drug substance or drug product to be tested in the study.
FDS design in overall context of an ANVISA ‘Degradation Profile Study’
Among world-wide Regulatory Authorities, ANVISA is on the cutting edge in regard to FDS. As mentioned, ANVISA has issued three official documents, covering between them all main details of how these studies should be designed, managed, and interpreted (Ref. 1-3).
All three documents are well written, structured, and detailed. Their sole limitation being that they are only available in official Portuguese, leaving the rest of the world to rely on online translation tools.
To go through the ANVISA approach to FDS, we have first to introduce the ANVISA concept of the ‘potential degradation profile’ study.
A ‘degradation profile’ (‘perfil de degradação’, DP) is defined by ANVISA as a “list of all relevant degradation products of an API or of a drug product when exposed to a certain condition.” (Ref. 2 – Sect 4.5). A more complete ANVISA definition is “a description of results and of analytical activities used for detection, identification, structure elucidation, and quantitative determination of degradation products present in the active pharmaceutical ingredient and the drug product” (Ref. 1 – Art. 3.VI).
Therefore, for a certain API or drug product, there will be a degradation profile at the long-term storage condition (also called by ANVISA the ‘real’ degradation profile), a degradation profile at the accelerated storage condition, and finally a degradation profile under the FDS conditions, also called by ANVISA the ‘potential’ degradation profile (Ref.2 – Sect 2).
These degradation profiles may be qualitatively and quantitatively different. Generally, the FDS degradation profile is broader than the accelerated one, which in turn is generally broader than the long-term one, that as mentioned, is considered the ‘real’ degradation profile by ANVISA (Ref. 2 – Sect 2 and Figure 1).
The FDS conditions being harsher than the accelerated and long term conditions, may result in degradation products that will be never observed at long-term and accelerated conditions (Ref. 5 – Sect 2.1.2.) . Regardless, they must predict (possibly in excess) the accelerated and long-term degradation products.
A ‘Degradation Profile Study’ (DPS) is defined by ANVISA as “a study composed of a critical part and, when necessary, an experimental part, which has the purpose of evaluating the degradation profile of a specific API and/or medication, in order to conclude whether a method is stability indicating.” (Ref.2 – Sect 4.1)
Therefore, in the ANVISA’s view and approach, an FDS is just the experimental part of a higher level DPS. So, all the main ANVISA requirements and expectations for FDS are targeted in the overall context of clarifying the product degradation profile, in a DPS context.
Preliminary bibliographic search
As a preliminary step of the DPS and therefore before any experimental FDS, ANVISA recommends to perform a well-structured bibliographic search on the compound (Ref. 2 – Sect.7), including official compendia (i.e., Pharmacopeias) and the Drug Master File.
This search, as indicated in the ANVISA guideline, should focus on the functional groups of the active molecule(s) most susceptible to degradation or interaction with excipients and potential degradation products, considering the most common potential degradations of the functional groups of the active(s).
The information gathered in the bibliographic search should help the company scientists in (Ref. 2 – Sect.7):
- choosing and focusing on the potentially more critical FDS conditions vs. the most likely molecular degradation routes
- selecting the more suitable analytical methods for the potential degradation products
- predicting possible analytical methods limitations in the FDS, such as due to potential degradation products chromophores
- predicting any potential degradation product derived by drug-excipient interaction
- highlighting possible degradation product toxicity
A study protocol is explicitly required by ANVISA for an FDS of the Active Pharmaceutical Ingredient (API) in the stability study RDC 318/2019 (Ref. 6 – Art. 73). However, a protocol may be very important in best managing an FDS for both API and a drug product.
The information to be included in the protocol mentioned in the above RDC Regulation mainly refers to the complete, primary stability study for the API (Ref. 6 – Art. 69) and the drug product (Ref. 6 – Art. 87) and not only for the FDS, but it can give an idea of what is expected by ANVISA to be present in the protocol, as follows.
- Identification of the API (Brazilian Nonproprietary (DCB), International Nonproprietary Name (INN), or Chemical Abstract Service (CAS) name
- Name and address of API/Drug product manufacturer
- Batch size
- Tests to be performed (including the acceptance criteria)
- Study protocol & conditions
- Packaging material used
- Analytical methods used in all tests
It must be emphasized that protocol presentation to ANVISA is optional if the study report (that will be described in part 3 of this blog) includes all the information required for the protocol (Ref. 6 – Art. 73.2).
Choice of the batch(es) to be tested
An FDS should be performed on one drug substance and one drug product batch according to ANVISA, in line with ICH Q1A(R2) expectations.
The batch may be at laboratory, pilot or industrial scale (Ref. 1 – Art. 4.I). The batch used for an FDS must be representative of the product to be registered, regarding the degradation profile (Ref. 3 – Question 4.2.16).
If there is any difference of the batch tested in the FDS vs. the product to be registered (as exemplified by ANVISA; difference in batch size, manufacturing site and process, etc.), this difference should be discussed and justified. The discussion should clarify whether there is a possibility that this difference may qualitatively alter the product degradation profile, i.e., whether there is a possibility of forming new degradation products with the differences. The company must also provide justification for not carrying out the tests on the product manufactured as the commercial one (Ref. 3 – Question 4.2.16).
FDS should be performed, on all concentrations of a drug product (Ref. 1 – Art. 4. §1), unless it is justified that the data can be extrapolated from the other concentrations, as it will be detailed in next blog part.
Lorena Pereira and Milena Barrozo are co-founders and consultants at Vita Regulatory Affairs Consulting, a company based in Portugal and Brazil. Piero De Filippis is the StabilityHub EU Regional Contributor, based in Italy.
Comments and Information Requests
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References (Part 2)
- ANVISA Resolução De Diretoria Colegiada [Collegiate Board of Directors Resolution] RDC – Nº 53. ‘Estabelece parâmetros para a notificação, identificação e qualificação de produtos de degradação em medicamentos com substâncias ativas sintéticas e semissintéticas, classificados como novos, genéricos e similares, e dá outras providências’ [‘Establishes parameters for the notification, identification and qualification of degradation products in medicines with synthetic and semi-synthetic active substances, classified as new, generic and similar, and takes other measures’] (4 December 2015 – in Portuguese) Direct link: http://antigo.anvisa.gov.br/documents/10181/3295768/%281%29RDC_53_2015_COMP.pdf/d38f507d-745c-4f6b-a0a6-bd250f2e9892 (last accessed 03 May 2021)
- ANVISA Guia N° 04/2015 – Versão 1 ‘Guia para obtenção do perfil de degradação, e identificação e qualificação de produtos de degradação em medicamentos’ [‘Guide for obtaining the degradation profile, and identification and qualification of degradation products in medicines ’] (December 2015 – in Portuguese) – Direct link: http://antigo.anvisa.gov.br/documents/10181/2738062/Perfil+e+produtos+de+degrada%C3%A7%C3%A3o+em+medicamentos.pdf/c18a4857-9a5c-4292-a1bf-07af6cad6902 (last accessed 03 May 2021)
- ANVISA ‘Perguntas & Respostas – Assunto: RDC 53/2015 e Guia 4/2015’ [Questions & Answers – Subject: RDC 53/2015 and Guide 4/2015] Ed. 2.1. (October 2017 – in Portuguese) – Direct link https://www.gov.br/anvisa/pt-br/centraisdeconteudo/publicacoes/medicamentos/publicacoes-sobre-medicamentos/perguntas-e-respostas-rdc-53-2015-e-guia-04-2015.pdf (last accessed 03 May 2021)
- Lorena Pereira et al. ANVISA’s Guidance on Forced Degradation Studies Explained (Part 1). stabilityhub.com. Published on April 21, 2021
- International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guideline Q1A(R2) ‘Stability Testing of New Drug Substances and Products’ (6 February 2003)
- ANVISA Resolução de Diretoria Colegiada (Collegiate Board of Directors Resolution) RDC No. 318/2019. ‘Estabelece os critérios para a realização de Estudos de Estabilidade de insumos farmacêuticos ativos e medicamentos, exceto biológicos, e dá outras providências’ [‘Establishes the criteria for conducting Stability Studies for active pharmaceutical ingredients and drug products, except for biological, and provides other arrangements’] (Published in DOU No. 216, November 7, 2019 – in Portuguese) – direct link: https://www.in.gov.br/web/dou/-/resolucao-rdc-n-318-de-6-de-novembro-de-2019-226513805 (last accessed 03 May 2021)