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As the therapeutic landscape grows more complex, so too must the analytical techniques for cleaning validation to ensure the utmost cleanliness is achieved.
Within the bio/pharma industry, there is a certain expectation for companies to maintain required levels of cleanliness within their facilities to ensure products that are manufactured are at minimal risk of contamination. All cleaning processes must also be validated for effectiveness and reproducibility.
As drug products become more complex and sensitive to potential contaminants, there is an increasing demand for cleaning validation throughout industry. According to market research, the cleaning validation market is forecasted to grow by a compound annual growth rate of 5.7% between 2021 and 2027 (1).
Of course, the requirement for manufacturing equipment to be clean is nothing new; as Andrew Kolbert, PhD, senior leader, Technical Solutions, Element, points out, this facet of drug production has been a necessity for 70 years since the introduction of the 21 Code of Federal Regulations (CFR) 210 Part 133.4 (2). “Early efforts [in this field] were focused on avoiding microbiological contamination or just filth, as seen at food manufacturers,” he states.
“In 1978, the GMPs [good manufacturing practices] were amended to 21 CFR Part 210.67, which specifically addressed the issue of cross contamination, as opposed to mere unsanitary conditions, with particular focus on manufacturers that made penicillin and other pharmaceutical products on the same equipment train,” Kolbert continues. The issue of cross contamination was brought to the fore by a case in 1988, he highlights, where a drug product, Cholestyramine Resin, was recalled due to contamination with pesticides as a result of insufficient cleaning of solvent drums (3).
“Cleaning validation is a subject that receives a great deal of attention within biopharmaceuticals, not least due to the risks presented in terms of product adulteration from cross-contamination and, hence, patient harm from improperly cleaned surfaces (and noting additional concerns such as operator protection),” specifies Tim Sandle, head of microbiology at Bio Products Laboratory (BPL) in Elstree, UK.
Sandle also highlights microbial proliferation as an area of importance because of the risk it poses in terms of the numbers of organisms adhering to surfaces and the release of microbial toxins. “Under the least desired conditions, a combination of organic residues and the presence of microorganisms can lead to a biofilm developing,” he says. “Biofilms are difficult to detect, and they are challenging to remove.”
Therefore, it is expected, by the regulatory bodies, such as FDA, that a drug manufacturer has a cleaning process in place for all equipment to ensure that no drug residue exceeds the maximum allowable carryover (MACO) level—a level that is determined based on toxicological risk—and that there are no cleaning agent residues and so forth, Kolbert asserts. “The cleaning process must also be validated to ensure it is consistently reproducible and effective. The exact form of this validation depends on the nature of the equipment as well as the cleaning process,” he says. “If cleaning is to be done manually, the reproducibility across workers will be need to be explored. If solvents or detergents are used, reduction to an acceptable level must be demonstrated.”
“Approaching cleaning validation should always begin with a risk assessment,” emphasizes Sandle. “To be effective, the risk assessment needs to be built upon a thorough understanding of the equipment to be cleaned and the cleaning reagents and mechanisms.”
Additionally, any residue(s) that needs to be removed must be identified and the optimal method to remove the residue(s) must be considered, Sandle continues. “For example, some residues are best cleaned by either an alkaline or acidic cleaner (or both types of cleaning agent may be required). To ensure the designed process has a greater chance of being effective, it is also important to understand how the residue is actually being removed (which requires detail of the residue chemistry),” he states.
“The next step is whether to use product residues or an alternative soil to challenge the designed cleaning process,” Sandle adds. “Users need to assess whether product residues are suitable for the cleaning validation because some process soils pose little challenge to the cleaning system, and it may be more appropriate to use a surrogate with greater viscosity and binding characteristics.”
Furthermore, Sandle points out that consideration should be made to how much residue may be permitted to be left, which will impact the level of cleaning that is required. “This [consideration] means selecting appropriate sampling methods, typically based on rinsing and swabbing, and the appropriate test methods for microbial and chemical analysis,” he says. “With methods, there needs to be an understanding about the metrology of the test instruments and the likelihood they can quantify the minimum acceptable residue. In addition to typical analytical method validation parameters (specificity, accuracy, linearity, limit of detection, precision), the actual sampling procedure must be qualified.”
For Kolbert, swabbing all of the drug product contact surfaces along the manufacturing train using the simplest analytical finish that will achieve an appropriate limit of detection is the most common approach. “If the drug product has a chromaphore, HPLC [high-performance liquid chromatography] or even UV [ultraviolet]/vis [visible] may be sufficient,” he says. “It is important to detect not only the drug product but any degradants or by-products that may be created.”
Also, if a detergent mix or solvent is required for the cleaning process then merely analyzing the rinsate does not suffice, Kolbert admonishes. “The product path components must also be tested for residue by direct swabbing,” he states. “A commonly used metaphor is if you are cooking in a pot, it is not enough to analyze the water rinse, you also need to look at the pot for old product residue that may break off over time.”
Increasingly, companies are utilizing highly potent drugs in biopharmaceuticals, which is creating challenges in terms of cleaning validation, asserts Kolbert. These drugs have extremely low MACO, which has driven analytical limits of detection to barely achievable levels, he adds. As a result, it is becoming necessary to use liquid chromatography coupled with tandem mass spectrometry to hit the toxicologically driven thresholds, Kolbert states.
In Sandle’s opinion, the main challenges in cleaning validation are in relation to residue removal, which is partially dependent upon the required level of cleanliness and the level of cleanliness that can actually be achieved—which relates to the design of the equipment. “Ideally, equipment selection will have embraced quality-by-design and there will be no inaccessible parts,” he continues. “However, in reality, some areas of large items of equipment are easier to clean than others and the main challenges that arise are often cantered on developing cycles that can reach challenging locations [such as] narrow pipes, u-bends, valves, and so on.”
Another area that is sometimes neglected is consideration of the age of equipment, Sandle specifies. “Manufacturing activities have the potential to induce abrasion and corrosion,” he says. “Hence, consideration must be given to ageing equipment with any aspect of cleaning.”
Regulators expect companies to conduct a risk assessment, Sandle points out. “With the risk process, it is good practice to use a multi-disciplinary team. The team should assess indirect product contact pars in relation to: the ability to build-up residues and the ability to transfer residues to product contact sites,” he explains.
Additionally, there is an expectation from regulators that all sample locations selected are represented and that potential ‘worst cases’ are indicated, Sandle notes. “I have seen several regulatory findings for cleaning validation that has been undertaken using locations that are not sufficiently challenging,” he says.
“A common regulatory issue also relates to manual cleaning,” Sandle continues, “especially around verification [as to whether] the operators can continue to undertake manual cleaning to a reliably high standard.”
Essentially, the cleaning process needs to be documented and demonstrated to be valid as per the regulatory bodies’ guidance, such as FDA outlined in Validation of Cleaning Processes (7/93) (3), confirms Kolbert. “There are a number of pitfalls that must be avoided, such as an overreliance on rinse analyses instead of direct observation of the equipment product contact paths; lack of sufficient evidence of reproducibility of any manual steps in the cleaning process; and verification of the absence of cleaning agents at the conclusion of cleaning,” he emphasizes.
“Perhaps the most important lesson from regulatory findings is the importance of running a risk assessment to manage the process, focusing on the proactive identification of hazards, selecting the optimal process to reduce the risk presented by these hazards, and with that ensuring there is a suitable measure of detection in place to verify the outcome,” Sandle says.
Sandle hopes that there will be increased use of rapid methods in cleaning validation that can provide real-time assessments in the near future.
“Adenosine triphosphate (ATP), protein residue, and glucose residue swabs are among the more useful rapid methods, although further development is required to improve accuracy and repeatability,” he highlights. “Of the different ‘PAT [Process Analytical Technologies] methods’, ATP bioluminescence technology offers a higher sensitivity compared with colorimetric methods.”
In terms of management of cleaning validation processes, software developments are piquing Sandle’s interest, including some that are employing artificial intelligence. “Such packages can help to sort equipment into types where a matrix approach is preferred, as well as enabling scheduling and for setting re-validation targets,” he states.
At its very essence, cleaning validation will require greater consideration, simply as a result of the evolving therapeutic landscape, Kolbert asserts. “The increased use of biological therapeutic agents in pharmaceutical manufacturing will require increased complexity of analytical techniques as activity of the residue is as important as chemical presence,” he summarizes.
1. MMR. Pharmaceutical Cleaning Validation Market: Industry Analysis and Forecast (2021–2027) by Product Type, Validation Test, and Region. Report, October 2021.
2. CFR Title 21, 210 Part 133.4 (Government Printing Office, Washington, DC).
3. FDA. Validation of Cleaning Processes (7/93), Inspection Guide. Aug. 26, 2014.
Felicity Thomas is the European/senior editor for BioPharm International.