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This article describes Cleanability Testing and how statistical techniques can be used with Cleanability data for determining "Hardest-to-Clean" pharmaceutical products for use in cleaning validation studies. The article also demonstrates how Cleanability testing is valid for selecting "Hardest-to-Clean" products, while currently used approaches su...
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... After that, the coupons are taken out and scrutinized to find out how much stuff was taken out or is still on the surface. [27] Cleaning Agents [28,29,30] Cleaning products are divided into numerous major groups. 1) Solvents; 2) Water; 3) Commodity chemicals Alkaline Chemical -NaOH Acidic Chemical -Phosphoric acid Oxidizer chemical -NaOCl > pH 7 4) Developed cleaning products 5) Water-based detergent formulation Cleaning Method [10,31,32,22] 1) Manual cleaning 2) Semi-automatic procedures 3) Automatic procedures 4) CIP (Clean-in-place) 5) COP (Clean-out-of-place) 6) Time-related factors 7) Amount of cleaning cycles Manual cleaning [33] Hard to confirm. ...
... We have already seen that the cleanability of products plays a very significant role. 6 While it may seem difficult to determine the answer to this question for each of these factors, there are statistical tools available that can help. Before discussing how to identify critical cleaning process parameters in a cleaning process it is first important to understand what a process is. ...
... 1. Determine the cleanability of all products to identify the hardest to clean. 6 2. Perform an Ishikawa analysis of parameters potentially affecting the cleaning process. 3. Perform a definitive screening design of the hardest-to-clean product to identify critical factors from the Ishikawa analysis. ...
The publication of the ASTM (American Society for Testing and Materials) E3106 "Standard Guide for Science-Based and Risk-Based Cleaning Process Development and Validation" in 2018 brought an increased emphasis on performing cleaning process development studies prior to any validation efforts. ASTM E3106 emphasized that cleaning agents and cleaning processes should not be adopted randomly, or chosen simply based on what has been used in the past, or was used at other facilities. Cleaning processes must be developed with the intent of reducing the risk of cross contamination and identifying appropriate cleaning parameters for both the type of compound/product and the equipment or medical device to be cleaned. This includes the type of, and the need for, cleaning agents. Cleaning processes should have their critical cleaning parameters identified and optimized as this will reduce cleaning process residues to the lowest levels and provide the highest level of safety to patients. While these important goals may sound daunting and require excessive efforts, they can actually be achieved in a short amount of time and with a minimal amount of energy and resources, if the science, risk and statistics-based approaches of ASTM E3106 are used.
... 16 If the Cpu Score is acceptable, the product can move to step 3. 3. The "cleanability" of the new product is measured and compared to the existing "hardest-to-clean" product. 17 If the cleanability of the new product is acceptable, the product can move to step 4. 4. The visual detection limit (visual threshold) should be determined for the new product and the VDI calculated. 14 If the VDI is acceptable, visual inspection alone could be justified. ...
In April of 2018, the European Medicines Agency (EMA) posted a Q&A on
their guideline for setting health-based exposure limits. In it, two new questions and
answers appeared (Q#7 and Q#8) that are directly applicable to the use of visual inspection in cleaning. In these two Q&As, the regulatory requirements for implementing visual inspection as one of the tools available for cleaning validation were now rather well defined and all that was needed now was a detailed guidance on how to implement cleaning programs that satisfy these criteria. In March of 2019, members of the ASTM E55 Committee on Manufacture of Pharmaceutical and Biopharmaceutical Products and members of the ASTM F04 Committee on Medical and Surgical Materials and Devices collaborated on writing a new Standard Guide on Visual Inspection that resulted in the publication of ASTM E3263-20 in December 2020. The ASTM E3263-20 had been written, in part, to provide the necessary guidance for establishing qualified visual inspection programs to comply with these newly clarified regulatory expectations. A detailed article introducing the standard was announced in social media discussion groups involved with pharmaceutical and medical device cleaning. Shortly after announcing these articles, the article authorship team was contacted by a former inspector with the Medicines and Healthcare Products Regulatory Agency (MHRA) to obtain a copy of this standard, which was provided by ASTM. After review, the former MHRA inspector asked if it was possible to make some revisions to make the standard more acceptable to the Pharmaceutical Inspection Co-Operation Scheme (PIC/S), which had recently adopted the European Medicines Agency’s (EMA) Q&A on Health Based Exposure Limits. The E55/F04 Joint Cleaning Team initiated a new Work Item on the ASTM website to revise the ASTM E3263 with the participation of the former MHRA inspector, and with the addition of a WHO inspector and three representatives of the FDA. This article is focused on the updates as compared to the 2020 Standard
... ☆ This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. prerequisites for cleaning validation to prevent cross-contamination and assure product purity (ASTM, 2020;Song et al., 2019;Song and Walsh, 2020a). CAs may contain a single ingredient or be a complex mixture of many chemicals formulated to optimise the cleaning performance for a specific use. ...
Cleaning agents (CAs) are used in multipurpose facilities to control carryover contamination of active pharmaceutical ingredients (APIs) to scientifically justified limits. While this is often done with the PDE methodology used for API impurities, it is unclear if it is justifiable and necessary for cleaning agents, which generally represent a comparatively lower health risk.
Comparing calculated oral PDE values for CA ingredients (CAIs) from four companies with PDEs of a selected number of small-molecule APIs showed that the toxicity of CAIs is several orders of magnitude lower. Furthermore, a critical review of the toxicity and everyday exposure to the general population of the main CAIs functional groups showed that the expected health risks are generally negligible. This is particularly true if the associated mode of actions cause local toxicity that is usually irrelevant at the concentration of potential residue carryover.
This work points towards alternative approaches to the PDE concept to control CAIs’ contamination and provides some guidance on grouping and identifying compounds with lower health risks based on exposure and mode of action reasoning. In addition, this work supports the concept that limit values should only be set for CAIs of toxicological concern.
Visual Inspection has been widely used for many years by the pharmaceutical, biologics and medical device industries after cleaning to release manufacturing equipment and devices. However, visual inspection has never been demonstrated to be an effective, reliable or safe method to use for these inspections. Recently the European Medicines Agency (EMA) issued a Q&A to their Guideline on determining health based exposure limits (HBELs) where they described what criteria had to be met for visual inspection to be acceptable to the EMA for release of manufacturing equipment. Some form of guidance or a standard has been needed to guide these industries on how to meet these criteria and demonstrate that operators/QA inspectors are capable and qualified to accurately assess the absence or presence of residues on manufacturing equipment or medical devices. This article discusses the development and publication of a new ASTM International (American Society for Testing and Materials) Standard Practice for the qualification of visual inspection.
The rationale for selecting a cleaning agent is of great importance in the cleaning of pharmaceuticals and medical devices. Cleaning agents cannot be chosen randomly and must be shown to be appropriately chosen and effective. This article discusses how bench-scale studies can be used for selecting the best cleaning agent for certain products and provide answers to the two most common questions:
1 - Which cleaning agent provides the best cleaning?
2 - Can we demonstrate that two cleaning agents are equivalent?
This article discusses two long existing ASTM Standards, the G121 Standard Practice on preparing coupons for cleanability testing and the G122 Standard Method for evaluating the effectiveness of Cleaning Agents and cleaning processes for use in oxygen service that have been updated and had their scopes expanded to include cleanability testing for pharmaceutical and medical device manufacturing.
This article will provide a detailed discussion of the science-, risk-, and statistics-based approaches in the American Society for Testing and Material (ASTM) E3106 "Standard Guide for Science Based and Risk Based Cleaning Process Development and Validation".
The International Congress on Harmonization Quality Risk Management Guidance (ICH Q9) lists both cleaning (in Annex II.4) and validation (in Annex II.6) as potential areas for the application of quality risk management. This clearly implies that the ICH Q9 principle for adjusting the level of "effort, formality, and documentation" based on the level of risk could be applied to cleaning and its validation. Previous articles discussed how science-based and data-derived scales could be created from HBELs (health-based exposure limits), from the process capability (Cpu) of cleaning processes, from the detection limits for total organic carbon (TOC) analyses of these compounds, or from visual inspection. Another article discussed how these scales could be used to measure the level of risk in cleaning validation. This article builds on these discussions and shows how these HBEL-based and process capability-based scales can be combined into a matrix that provides a clear visual guide for adjusting the level of effort, formality, and documentation for cleaning validation based on the level of risk.
