A ANVISA tornou público através do Edital 3/2016, publicado nesta segunda-feira (19/12) no Diário Oficial da União, chamamento para as empresas e cidadãos interessados em contribuir para as Perguntas e Respostas do Guia de Desenvolvimento e Manufatura de Insumos Farmacêuticos Ativos (Q11). O documento descreve conceitos e abordagens a serem aplicados no desenvolvimento e entendimento do processo de fabricação de insumos farmacêuticos ativos (IFA), sintéticos e biológicos.
A prévia do guia apresenta pelo menos 4 perguntas envolvendo avaliação de impurezas mutagênicas e o impacto de etapas específicas do processo de fabricação no perfil de impurezas (as perguntas são apresentadas abaixo).
O perfil de segurança de impurezas em Ingredientes Farmacêuticos Ativos (IFAs) e medicamentos é uma preocupação não muito recente da comunidade científica, indústria e órgãos reguladores. Já coberta pela legislação vigente, a formação de impurezas mutagênicas (IM) e/ou impurezas potencialmente mutagênicas (IPM) é um dos pontos a serem considerados na avaliação da degradação de IFAs, demandando estratégias de gestão do risco que envolvem o mapeamento destas impurezas após estudos teóricos, estudos de estresse e de estabilidade. Nesta nova consulta, no entanto, o foco é o processo de fabricação e especificações.
Devido ao fato das diretrizes ICH Q3A(R2), ICH Q3B(R2), ICH Q3C(R3) não contemplarem a avaliação de impurezas genotóxicas, em 2014 foi publicada a diretriz M7—Assessment and Control of DNA reactive (mutagenic) Impurities in Pharmaceuticals to limit Potential Carcinogenic Risk pela Conferência Internacional de Harmonização (ICH), que define critérios para o estabelecimento de níveis de impurezas mutagênicas ou produtos de degradação que resultem em um risco aceitável. Segundo a diretriz ICH M7, a Avaliação de Segurança envolve uma análise das impurezas para classificação através da busca de dados na literatura e bases de dados em relação à carcinogenicidade e mutagenicidade. Se não há dados disponíveis, a diretriz M7 orienta para a realização de uma avaliação in silico, envolvendo estudos de Relação Estrutura-atividade (Q)SAR para classificação da impureza nas classes 3, 4 ou 5; através duas metodologias complementares entre si (uma baseada em regras de sistema especialista e outra em estatística).
A recente inclusão da Anvisa na condição de membro do ICH permite sua participação efetiva nas discussões para elaboração dos guias e documentos do ICH. Tal participação deve ser precedida de consulta pública no país para a coleta de contribuições e avaliações dos impactos sobre as propostas de guias e documentos em elaboração.
Perguntas e respostas sobre impurezas mutagênicas:
Question 5.2 – ICH Q11 recommends that “manufacturing steps that impact the impurity profile of the drug substance should normally be included in the manufacturing process described in Section 3.2.S.2.2 of the application.” At what level would a related substance or mutagenic impurity be considered to impact the impurity profile of the drug substance?
For non-mutagenic related substances, an impurity that is likely to be present in the drug substance at a level above the ICH Q3A Identification Threshold is considered to have an impact on the impurity profile of the drug substance.
A mutagenic impurity that is likely to be present in the drug substance above 30% of the ICH M7 acceptable intake is usually considered to impact the impurity profile of the drug substance. Any of the approaches described in ICH M7 can be used to determine which impurities are likely to be present above the 30% threshold. The 30% threshold serves an analogous function in ICH M7 to the Identification Threshold in ICH Q3A.
In line with ICH M7 and ICH S9, there are situations (e.g., when the drug substance is itself genotoxic, and other circumstances as described in these guidelines) when the selection of the starting material for a drug substance does not need to specifically consider the mutagenic impurity profile at the levels described above. In such cases, mutagenic impurities are not considered to impact the impurity profile of the drug substance unless they are above the ICH Q3A Identification Threshold.
Impurities that persist through multiple steps of manufacture should be considered in conjunction with Q&A 5.3.
Question 5.4 – How should an applicant determine which manufacturing steps impact the profile of mutagenic impurities in the drug substance as part of the selection and justification of starting materials?
As part of determining which manufacturing steps impact the impurity profile of the drug substance, the applicant should first identify mutagenic materials that are likely to be formed or are introduced in the manufacturing process. The applicant can then determine which steps contribute mutagenic impurities to the drug substance at a level considered to impact the impurity profile (see Q&A 5.2).
The Hazard Assessment Elements from ICH M7 can be used to determine which of the actual and potential impurities are considered to be mutagenic. For the selection and justification of starting materials, the following approaches are recommended:
• Impurities that have been identified in the drug substance (“actual impurities”) should be assessed for mutagenicity.
• Reagents, solvents, and chemicals used in the synthesis from commercially available chemicals to the drug substance should be assessed for mutagenicity. Note that this will likely include assessment of the mutagenicity of some reagents, solvents, and chemicals that are used in steps before the starting material that is eventually proposed.
• Mutagenic substances that are impurities in commercially available precursors or synthetic intermediates, or that are formed as the result of side reactions during the synthesis, could also be present in the drug substance at levels relevant to safety. However, such mutagenic impurities and by-products are usually present at much lower concentrations than reagents, solvents, and intermediates. Therefore, the risk that such impurities will carry over significantly into the drug substance from early reaction steps is lower than for reagents, solvents, or intermediates from the same steps. The applicant should use risk-based reasoning to determine which steps to include in the hazard assessment for this category of potential impurities, and include a discussion of the risk assessment when identifying the point in the synthesis where these impurities and by-products are included in the assessment of mutagenic impurities.
• For a starting material that is a commercially available chemical that is introduced late in the synthesis of the drug substance (and where its synthetic route is known) the final steps of that chemical’s synthesis should be assessed for potential mutagenic impurities. In this case, because the starting material has already been selected based on its commercial availability, the mutagenicity assessment should be used to ensure that the controls on the starting material are adequate.
Information collected during the evaluation of potential mutagenic impurities can be submitted in an application and could be valuable for multiple purposes. For example, the justification for a proposed starting material should include information demonstrating that none of the steps immediately upstream (i.e., earlier in the synthesis) of the proposed starting material impact the impurity profile of the drug substance. Also, the suitability of the proposed control strategy can be supported with information about any mutagenic impurities formed or purged in the manufacturing steps between the proposed starting material and the drug substance, or that are controlled in the specification of the proposed starting material. The ICH Q11 exception for impurities that “persist” is also applicable to mutagenic impurities (see Q&A 5.3). In addition, steps involving mutagenic reagents or impurities may be before the starting material if they do not impact the impurity profile of the drug substance (see Q&A 5.5).
The approaches outlined in this Q&A are considered to be consistent with the principles in ICH M7, concerning hazard assessment, risk characterisation of mutagenic impurities, and their control. Additionally, this Q&A is not intended for the types of drug substances and indications for which ICH M7 does not apply (e.g., genotoxic drug substances; advanced cancer indications per ICH S9). However, ICH M7 does not provide specific guidance on how mutagenic impurity assessment can be used to justify selection of appropriate starting materials. This Q&A addresses the application of the principles in ICH M7 to the selection and justification of starting materials, based on the ICH Q11 concept of impact to the impurity profile of the drug substance.
5.5 – Do all steps that involve mutagenic reagents, impurities, or establish regio- or stereochemical configurations, need to be included in the process description in Section 3.2.S.2.2?
No. The ICH Q11 general principles for selection of starting materials do not include a recommendation that all steps involving mutagenic reagents or impurities should be included in the process description in Section 3.2.S.2.2. Similarly, the general principles do not include a recommendation that all steps that establish regio- or stereochemical configurations (which can therefore result in regio- or stereoisomerism) should be included in Section 3.2.S.2.2. However, it is expected that the other ICH Q11 principles on impurities (Q&As 5.2, 5.3 and 5.4) and inclusion of enough of the manufacturing process (Q&A 5.6) be applied when deciding whether steps that involve mutagenic reagents, impurities, or establish regio- or stereochemical configurations, need to be included. As an example, a mutagenic compound could be introduced prior to the starting material or be the starting material itself provided the ICH Q11 general principles are addressed.
5.10 – What considerations are important for starting material specifications?
Applicants should provide and justify a specification (which includes a list of tests, references to analytical procedures, and appropriate acceptance criteria) for all proposed starting materials as part of the control strategy.
The specification of a starting material should include tests for identity and purity (e.g., controls on impurities), and could include acceptance criteria for assay, specified, unspecified and total impurities, residual solvents, reagents, elemental impurities and mutagenic impurities. Tests and acceptance criteria should be based on process knowledge and control strategy. The analytical procedures used should be suitably validated. The justification of the specification should include evaluation of the risks and the ability of the subsequent steps to purge impurities.
Fonte:
ANVISA – Agência Nacional de Vigilância Sanitária.
