Creative BioMolecules operates a cGMP plant with 1000L mammalian cell and 1000 L bacterial fermentation capacity. The plant is used for contract manufacturing as well as for CBM’s proprietary products. These case studies will review five campaigns of five products over the last three years. In each case, the goal was to demonstrate that the equipment was properly cleaned and ready for the next campaign.
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A swab-sampling method was developed for cleaning validation of a residual active pharmaceutical ingredient in samples collected after cleaning the sampling suite. A summary of the strategies and results of the method development is presented. The developed extraction method produced an acceptable level of recovery and precision.Cross contamination with active ingredients is a real concern. The Code of Federal Regulations (CFR) states that “Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official, or other established requirements” (1). Cleaning validation is required in the pharmaceutical field to avoid potential clinically significant synergistic interactions between pharmacologically active chemicals (2).
Destin A. LeBlanc Cleaning Validation Technologies, Technical Consulting Services In discussing monitoring for cleaning validation, it is important to carefully define what one means by “monitoring”. As used here, the term “monitoring” refers to the routine measurements taken on the cleaning process that serve as indicators of whether the process is in a state of control (or considered from the opposite point of view, serve as indicators that the process either is not or may not be in a state of control). The purpose of monitoring is not to have clear evidence that the surfaces are acceptably clean. To do that, one would have to sample the surfaces (much as one would do in a cleaning validation protocol).
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Pharmaceutical plants must have visually clean equipment to operate according to good manufacturing practices. Formulators must visually inspect manufacturing equipment for cleanliness before formulation work begins (1). Manufacturers establish and perform visible cleanliness and analytical methods to ensure regulatory compliance. An analyst conducts a visual inspection and confirms visible cleanliness before taking swab samples for chemical analysis (2). The formulator of the subsequent batch conducts a visual inspection before manufacturing work begins. A correlation between available analytical data and visible cleanliness of manufacturing equipment over an extended period of time can expand the practice of performing visual inspections in lieu of swab sampling.
Currently, liquid chromatograph–ultraviolet spectrometry (LC–UV) is typically applied to cleaning validations because of its familiarity, robustness, ease of use, and regulatory acceptability. For low-dose compounds, equipment requiring low residue limits, and compounds lacking strong chromophores, the enhanced sensitivity and selectivity of liquid chromatography–mass spectrometry–mass spectrometry (LC–MS–MS) facilitates rapid method development for the detection of low levels of residues of active pharmaceutical ingredients (APIs). LC–MS–MS is an acceptable technique for the analysis of API residues for cleaning validation. More importantly, in applications where sensitivity and selectivity are inadequate using traditional modes of detection, LC–MS–MS offers substantial advantages. LC–MS–MS will afford faster development and analysis time, potentially making it the predominant tool of choice.
Although we commonly talk about "disinfectant validation," the US Food and Drug Administration validates only processes (1). Disinfectants themselves are qualified—that is, found to be effective in the context of a given process, just as we qualify the clean steam supply for an autoclave and then validate the steam sterilization process. The approach to disinfection should be similar, so that a working definition for disinfection process validation would be "establishing documented evidence that a disinfection process will consistently remove or inactivate known or possible pathogens from inanimate objects."
Cleaning validation (CV) is driven by regulatory expectations to ensure that residues from one product will not carry over and cross contaminate the next product.1,2 Regulatory scrutiny is more rigorous in a multiproduct facility compared to a single product establishment. Companies are usually cited either for not having a sound cleaning validation or not meeting the protocol acceptance criteria. Because failing a protocol acceptance criteria is considered a substantial regulatory risk, companies are forced to spend money and resources even though there is minimal or no product risk.
Cleaning validation is a critical consideration in the pharmaceutical industry. Inadequate cleaning can result in contamination of drug products with bacteria, endotoxins, active pharmaceuticals from previous batch runs, and cleaning solution residues. Such contaminants must be reduced to safe levels, both for regulatory approval and to ensure patient safety.
Currently, there are multiple publications, as well as guidelines from regulatory agencies that make the critical process of equipment cleaning validation easier. These sources provide in-depth information for the validation specialist, making the development and implementation of a robust cleaning validation program possible within any particular facility developing or manufacturing parenteral, biological, or sterile ophthalmic products.
Extremely important, specific, and above all, mandatory, are the requirements established by regulatory agencies such as the US Food and Drug Administration (FDA), the European Medicinal Evaluation Agency (EMEA), Australia's Therapeutic Goods Administration (TGA), etc. For example, the 2004 Code of Federal Regulations (CFR) Title 21, Volume 4, Section 211.67, states:
Before formal cleaning validation programs were instituted, visual inspection was the primary means of determining equipment cleanliness. The use of visual inspection is still typically a component of a cleaning validation program and for routine inspections of cleaning effectiveness, but the use of visual inspection as a sole criterion for equipment cleanliness has not been successfully implemented as a valid approach for cleaning validation.
A validated cleaning program based on quantitative visual inspections in conjunction with swab testing is possible. Acceptable visible-residue limits (VRLs) can be established in conjunction with and compared with swab results. Assuming the swab results demonstrated a validated cleaning procedure, if the results are in agreement, then the VRLs may be used going forward. A similar argument has been successfully used to defend the use of rinse sampling established in conjunction with swab results.
The use of visual inspection as a criterion for equipment cleanliness has always been a component of cleaning validation programs. Mendenhall proposed the use of only visual examination to determine equipment cleanliness as long ago as 1989 (1). He concluded that visible cleanliness criteria were more rigid than quantitative calculations and clearly adequate. The US Food and Drug Administration limited the use of visually clean criterion between lots of the same product (2). LeBlanc raised the question of whether a visible limit as the sole acceptance criterion could be justified (3).
