Apart from being a core aspect of current Good Manufacturing Practice (cGMP) and Good Validation Cleaning Practice (GVCP) in the pharmaceutical industry, pharmaceutical cleaning validation procedures are a necessary regulatory condition that must be met by pharmaceutical companies in getting safe and effectual drug formulations to patients.
How Is ‘Cleanliness’ Determined in Pharmaceutical Facilities?
The cleanliness of any pharmaceutical equipment/plant is established by using what is known as the Residual Acceptance Limits (RAL). These limits are determined based on several factors such as toxicological/pharmacological effects of ‘residuals’ on equipment surfaces.
The RAL of peculiar residues that are most likely to cross-contaminate following production lines are estimated, validated and used as a reference to determine the effectiveness of any cleaning protocol. Thus the robustness of a particular cleaning procedure lies in its ability to provide quantitative data that can be compared to a different one altogether. While this may sound obvious, in practice it is not easy to use a single criterion to assess different procedures as they are mostly validated using different techniques.
New guidelines recently released by the European Medicines Agency (EMA) not only states that cleaning validation using visual inspection is only acceptable if complemented by an analytical determination to demonstrate cleaning effectiveness. It also mentions that training for personnel involved in pharmaceutical cleaning should be periodically assessed for competence.
This has had a direct impact on the pharmaceutical cleaning validation process particularly about regulatory requirements; the more complicated the manufacturing procedure, the more difficult it is to clean equipment surfaces to meet regulatory standards.
What’s New?
So rather than view cleaning validation as a mere ‘clean-up’ after manufacturing, stakeholders in both academia and the industry have started to consider it as a form of manufacturing on its own. Hence, recent research has suggested a Quality by Design (QbD) approach; wherein expected outcomes would determine how the cleaning protocol is outlined.
More recently, the use of computational modelling and analysis has also been deployed to monitor how critical factors such as mass transfer, temperature changes, solubility, etc., affects the cleaning process and its effectiveness. Process Analytical Technology (PAT) has also been applied to cleaning protocols so as to ensure a continuous cleaning verification regime.
These new regulatory pre-conditions and other issues such as cost and the ecological effects of using large volumes of solvents for cleaning and validation has put immense pressure on Active Pharmaceutical Ingredients (API) and drug product manufacturers.
With tremendous improvements in manufacturing technology/engineering, the pharmaceutical manufacturing process has become and is expected to become more complex and multifaceted.
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