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What are the best practices for documenting the rationale and justification for the worst-case configuration?

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Cleaning validation is a critical process to ensure the safety and quality of pharmaceutical products. It involves verifying that the cleaning procedures and agents can effectively remove any residues, contaminants, or microorganisms from the equipment and surfaces used in the manufacturing process. One of the key steps in cleaning validation is to identify and justify the worst-case configuration, which is the combination of equipment, product, and cleaning method that represents the most challenging and representative scenario for cleaning. In this article, we will discuss the best practices for documenting the rationale and justification for the worst-case configuration, and how to avoid common pitfalls and errors.

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1 Define the worst-case criteria

The first step is to define the criteria that will be used to determine the worst-case configuration. These criteria should be based on scientific and risk-based principles, and should consider factors such as the solubility, toxicity, potency, bioburden, and detectability of the residues, the complexity, size, and design of the equipment, the sequence and frequency of the product and cleaning cycles, and the type and effectiveness of the cleaning agents and methods. The criteria should be clear, consistent, and objective, and should be aligned with the regulatory and industry standards and expectations.

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Sumit Pipaliya

Validation Engineer | CQV | QA | CSV | GxP | QMS | Regulatory Compliance
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The most important parameter for cleaning validation is worst-case consideration. Health-based and Dose-based calculations are performed to determine the worst-case criteria. Most recently, the PDE (Permitted Daily Exposure) limit has been used for calculating the MACO and ultimately worst case product derivation for cleaning validation.

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?? Javier Rodriguez Paradelo

Founder en REGALSA Y VALDECONSA Innovando en el Sector de la Limpieza Industrial ?? con Regalsa Facility Services Y en Energías Renovables? con Valdeconsa Renewable O&M Services
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En el contexto empresarial de limpieza industrial, documentar la justificación para la configuración del peor caso implica: Base Científica: Justificar los criterios con datos sobre solubilidad y toxicidad de residuos. Claridad: Asegurar que la metodología sea clara y objetiva, con fundamentos en estándares de limpieza. Normativas: Alinear procedimientos con regulaciones del sector, mostrando conformidad. Registro Riguroso: Documentar metodologías, decisiones y hallazgos, incluyendo pruebas que validen la eficacia en escenarios extremos. Actualización Continua: Revisar y actualizar la documentación regularmente para reflejar cambios en prácticas o normativas.

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2 Identify the worst-case equipment train

The next step is to identify the worst-case equipment train, which is the sequence of equipment that is used to manufacture the product and that is subject to the same cleaning procedure. The worst-case equipment train should include all the equipment that has direct or indirect contact with the product, and that may harbor residues or contaminants. The worst-case equipment train should also reflect the longest and most complex equipment train that is routinely used in the production process, and that poses the highest risk of cross-contamination or carryover. The worst-case equipment train should be documented with diagrams, schematics, or photographs, and should indicate the locations of the sampling points and the rationale for their selection.

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Sumit Pipaliya

Validation Engineer | CQV | QA | CSV | GxP | QMS | Regulatory Compliance
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If the same product is manufactured in a different manufacturing line in the same manufacturing plant then only the Equipment train concept will be considered. The manufacturing line having the largest surface area will be considered as a worst-case equipment train.

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3 Identify the worst-case product

The third step is to identify the worst-case product, which is the product that is manufactured in the worst-case equipment train and that has the most difficult or challenging residues to remove. The worst-case product should be based on the worst-case criteria defined earlier, and should consider the properties and characteristics of the product, such as its solubility, toxicity, potency, bioburden, and detectability. The worst-case product should also consider the amount and duration of exposure of the product to the equipment, and the potential for degradation or interaction with the cleaning agents or other products. The worst-case product should be documented with data, specifications, or references that support its selection.

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4 Identify the worst-case cleaning method

The fourth step is to identify the worst-case cleaning method, which is the cleaning procedure and agent that is applied to the worst-case equipment train after the worst-case product is manufactured. The worst-case cleaning method should be based on the worst-case criteria defined earlier, and should consider the type and effectiveness of the cleaning agent, such as its concentration, pH, temperature, contact time, and rinse volume. The worst-case cleaning method should also consider the mode and frequency of application, such as manual or automated, single or multiple, and intermittent or continuous. The worst-case cleaning method should be documented with protocols, procedures, or instructions that describe its execution.

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Sumit Pipaliya

Validation Engineer | CQV | QA | CSV | GxP | QMS | Regulatory Compliance
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It should be scientifically justified based on the product's characteristics. In Injectable facilities, mostly WFI is used as a cleaning agent. If the product is not soluble in WFI, then different solvent or cleaning agent can be used.

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5 Justify the worst-case configuration

The final step is to justify the worst-case configuration, which is the combination of the worst-case equipment train, product, and cleaning method. The justification should demonstrate that the worst-case configuration represents the most challenging and representative scenario for cleaning validation, and that it covers all the possible variations and combinations of equipment, product, and cleaning method that are used in the production process. The justification should also show that the worst-case configuration is consistent with the regulatory and industry standards and expectations, and that it meets the predefined acceptance criteria for cleaning validation. The justification should be documented with evidence, data, or references that support its validity and reliability.

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?? Javier Rodriguez Paradelo

Founder en REGALSA Y VALDECONSA Innovando en el Sector de la Limpieza Industrial ?? con Regalsa Facility Services Y en Energías Renovables? con Valdeconsa Renewable O&M Services
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Para documentar la justificación de la configuración del peor de los casos eficazmente, es clave seguir prácticas que eviten errores comunes, asegurando una validación de limpieza sólida y confiable. Incluye criterios objetivos y basados en datos para determinar esta configuración, considerando todas las variables relevantes. Evita seleccionar configuraciones extremas que desvíen la validez del proceso. Cualquier ajuste en la configuración debe estar bien justificado y verificado. Documenta todo de manera clara, concisa y coherente, manteniendo la credibilidad y la rigurosidad científica.

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6 Avoid common pitfalls and errors

When documenting the rationale and justification for the worst-case configuration, it is important to avoid some common errors that could compromise the quality and credibility of the cleaning validation. This includes using subjective or arbitrary criteria to determine the worst-case configuration, failing to consider all relevant factors and variables that affect the cleaning process, selecting a worst-case configuration that is too easy or too difficult to clean, changing the worst-case configuration without adequate justification or verification, and not documenting the rationale and justification for the worst-case configuration in a clear, concise, and consistent manner. By following these best practices, you can ensure that your cleaning validation is professional, scientific, robust, and compliant.

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7 Here’s what else to consider

This is a space to share examples, stories, or insights that don’t fit into any of the previous sections. What else would you like to add?

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Angela Beard, CSP, PMP

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In order to have a robust program a matrix should be created starting with equipment trains and which product ‘touch’ each piece of equipment. Looking at the shared equipment trains, you can determine the worst case for each piece of equipment, as the worst case product for the facility may not share many pieces of equipment. A worst case per equipment should be developed. Additionally, campaign length should be considered. A worst case product based on solubility, or potency may only run 1 time every few months, whereas another product may run multiple batches, multiple times a month therefore creating a higher potential for failure

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oksana williams

Lead Validation Engineer @ Pfizer | Cleaning Validation, Process Improvement
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It is important to review cleaning test methods that will be used to evaluate collected samples on a subject of limit of detection (LOD) and limit of quantification (LOQ). The calculated acceptance criteria must be above the LOQ of a selected test method to accurately quantify results.

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Sumit Pipaliya

Validation Engineer | CQV | QA | CSV | GxP | QMS | Regulatory Compliance
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P&ID should be highlighted with the CIP flow path to show dead legs and dead spots in the cleaning path. Sampling points shall be considered at the longest distance at the end of the loop. Clean equipment Hold time and Dirty equipment Hold time study is also considered as a part of cleaning validation.

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What are the best practices for documenting the rationale and justification for the worst-case configuration?

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1 Define the worst-case criteria

2 Identify the worst-case equipment train

3 Identify the worst-case product

4 Identify the worst-case cleaning method

5 Justify the worst-case configuration

6 Avoid common pitfalls and errors

7 Here’s what else to consider

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