Cleaning Validation Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality. For example, in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed by subsequent purification steps. Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability. The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples to be obtained and how they are collected and labelled. Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers). Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The methodâ€™s attainable recovery level should be established. Residue limits should be practical, achievable, verifiable and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component. Equipment cleaning/sanitization studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products). Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these procedures are effective when used during routine production. Equipment cleanliness can be monitored by analytical testing and visual examination, where feasible. Visual inspection can allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling and/or analysis. Inglês > Português Tradutor Online, Tradutor Inglês-Português

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Cleaning Validation Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality. For example, in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed by subsequent purification steps. Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability. The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples to be obtained and how they are collected and labelled. Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers). Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The methodâ€™s attainable recovery level should be established. Residue limits should be practical, achievable, verifiable and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component. Equipment cleaning/sanitization studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products). Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these procedures are effective when used during routine production. Equipment cleanliness can be monitored by analytical testing and visual examination, where feasible. Visual inspection can allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling and/or analysis.

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Os procedimentos de validaÃ§Ã£o de limpeza de limpeza normalmente devem ser validado. Em geral, a validaÃ§Ã£o de limpeza deve ser direcionado para situaÃ§Ãµes ou etapas do processo onde contaminaÃ§Ã£o ou reporte de materiais constitui o maior risco para a qualidade de API. Por exemplo, na produÃ§Ã£o antecipada pode ser desnecessÃ¡rio validar os procedimentos de limpeza de equipamentos onde os resÃduos sÃ£o removidos por etapas de purificaÃ§Ã£o subseqÃ¼ente.ValidaÃ§Ã£o de procedimentos de limpeza deve refletir os padrÃµes de uso do equipamento real. Se vÃ¡rias APIs ou intermediÃ¡rios sÃ£o fabricados no mesmo equipamento e o equipamento estÃ¡ limpo pelo mesmo processo, um representante intermediÃ¡rio ou API pode ser selecionado para a validaÃ§Ã£o de limpeza. Esta selecÃ§Ã£o deve basear-se a solubilidade e a dificuldade de limpeza e o cÃ¡lculo dos limites mÃ¡ximos de resÃduos com base na potÃªncia, toxicidade e estabilidade.Protocolo de validaÃ§Ã£o de limpeza deve descrever o equipamento a ser limpo, procedimentos, materiais, nÃveis aceitÃ¡veis de limpeza, parÃ¢metros para ser monitorado e controlado e mÃ©todos analÃticos. O protocolo tambÃ©m deve indicar o tipo de amostras a serem obtidos e como eles sÃ£o coletados e rotulados.Amostragem deve incluir mÃ©todos de limpeza, lavagem ou alternativos (por exemplo, extraÃ§Ã£o direta), conforme apropriado, para detectar resÃduos insolÃºveis e solÃºveis. Os mÃ©todos de amostragem utilizados devem ser capazes de medir quantitativamente os nÃveis de resÃduos restantes sobre as superfÃcies do equipamento apÃ³s a limpeza. Cotonete de amostragem pode ser impraticÃ¡vel quando as superfÃcies de contato de produto nÃ£o sÃ£o facilmente acessÃveis devido a limitaÃ§Ãµes de projeto e/ou processo de equipamento (por exemplo, superfÃcies internas das mangueiras, tubulaÃ§Ãµes de transferÃªncia, os tanques de reator com pequenos portos ou manipulaÃ§Ã£o de materiais tÃ³xicos e pequeno equipamento intrincado como micronizadores e microfluidizers).MÃ©todos analÃticos validados tendo sensibilidade para detectar resÃduos ou contaminantes devem ser usados. Limite de detecÃ§Ã£o para cada mÃ©todo analÃtico deve ser suficientemente sensÃvel para detectar o nÃvel aceitÃ¡vel estabelecido dos resÃduos ou contaminantes. NÃvel de recuperaÃ§Ã£o atingÃveis do mÃ©todo deve ser estabelecido. Limites mÃ¡ximos de resÃduos devem ser prÃ¡tico, realizÃ¡vel, verificÃ¡veis e baseia o resÃduo mais deletÃ©rio. Limites podem ser estabelecidos com base na conhecida atividade farmacolÃ³gica, toxicolÃ³gica ou fisiolÃ³gica da API ou seu componente mais deletÃ©rio o mÃnimo.Estudos de equipamentos de limpeza/sanitizaÃ§Ã£o devem abordar microbiolÃ³gicos e contaminaÃ§Ã£o de endotoxina para aqueles processos onde hÃ¡ uma necessidade de reduzir a contagem microbiolÃ³gica total ou endotoxinas na API, ou outros processos onde tal contaminaÃ§Ã£o possa ser de interesse (por exemplo, nÃ£o-estÃ©ril APIs utilizados na fabricaÃ§Ã£o de produtos estÃ©reis).Os procedimentos de limpeza devem ser monitorizados a intervalos adequados apÃ³s a validaÃ§Ã£o, para garantir que esses procedimentos sÃ£o eficazes quando utilizados durante a produÃ§Ã£o de rotina. Limpeza de equipamentos pode ser monitorada por testes analÃticos e exame visual, sempre que possÃvel. InspeÃ§Ã£o visual pode permitir a detecÃ§Ã£o de contaminaÃ§Ã£o grosseira concentrada em pequenas Ã¡reas que poderiam, caso contrÃ¡rio, passam despercebidas por amostragem e/ou anÃ¡lise.

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