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Because conventional cleaning methods can risk product loss, biopharmaceutical manufacturers are often reluctant to use PDE/ADE limits to validate cleaning processes.
Cleaning validation for biologics, particularly those that are manufactured in commercial stainless-steel equipment, has always been tricky. One worrisome issue has been the potential loss of product as the result of the cleaning process. Cleaning processes can degrade protein molecules, and biologic products-such as therapeutic antibodies-have been known to degrade and denature under extreme conditions, such as high heat and high or low pH. This can often result in loss of pharmacological activity. Yet, the cleaning of biomanfacturing equipment often requires that equipment surfaces be exposed to extreme pH and temperatures to ensure sterilization.
FDA expects manufacturers to have written procedures on how their cleaning processes will be validated (1), and expects the validation procedure to specify the personnel responsible for performing and approving the validation study. Companies must also indicate staff members who will be responsible for establishing the acceptance criteria for the validation and the timing for when revalidation will be required.
The agency further expects companies to prepare specific, written cleaning validation protocols before carrying out studies that they expect to perform on each piece of manufacturing equipment. The written protocols should address important issues, such as the company’s sampling procedures, the analytical methods that will be used, and the sensitivity of those methods.
Fortunately, advances in analytical technology have made it possible to detect even very low levels of residue left behind from manufacturing and cleaning processes, according to FDA. However, when residue or contamination is not detected, that may be due to a limitation in the sensitivity of the analytical method used.
Absence of detectable levels of residue or contamination is not itself a guarantee that a piece of equipment or the entire manufacturing system is clean. Because of this, the agency recommends that companies challenge the analytical method used for detection by combining it with sampling methods. This allows manufacturers to show that contaminants can still be recovered from equipment surfaces after cleaning. After all, a negative test (i.e., where no contaminants are detected) could be due to poor sampling technique.
Sampling techniques are important for determining contamination levels, and FDA accepts two general types: direct surface sampling and rinse solutions (1). Direct surface sampling allows accessible but hard-to-clean areas to be evaluated, so that data can be used to establish an acceptable residue or contamination level per given surface area.
Dried residue, or residue that is insoluble, can easily be sampled by physically removing it. However, FDA has cautioned manufacturers that, in order to do direct sampling, they must first determine early on in their cleaning validation program what type of sampling material they will use and how the material will affect test data because there is potential for the sampling material to interfere with testing.
For the rinse sample method, advantages include use of a larger surface area for sampling and ability to test inaccessible systems (e.g., ones that cannot be routinely disassembled). However, the residue or contaminant may not be soluble, or may be obstructed by the physical structure of the equipment. As a result, evaluation of any system’s cleanliness should not rely solely on evaluation of the rinse solution, but rather evaluation of the equipment itself. The rinse solution should not simply be tested for water quality, but rather for the presence of specific contaminants.
Data must be recorded and documented during the sample testing procedures. Testing uncleaned equipment will establish what an unacceptable result would look like when indirect testing methods are used.
Alternative cleaning validation methods involve using a gauge other than permitted daily exposure (PDE) or acceptable daily exposure (ADE), or changing the limits set by regulators for these standards. It has been argued that protein molecules are degraded by the cleaning processes used to meet PDE or ADE limits (2), which has led to a search for alternative cleaning validation methods.
In the European Medicines Agency’s (EMA’s) guideline on setting health-based exposure limits (3), the agency states that it would be acceptable to use approaches other than PDE/ADE limits to determine health-based exposure limits, provided that the alternative approaches are “adequately and scientifically” justified. EMA also understands that, because the cleaning methods for “therapeutic macromolecules and peptides” can result in the degradation or denaturation of those molecules due to their exposure to extreme heat and/or pH, “the determination of health based exposure limits using PDE limits of the active and intact product may not be required” (3).
Loss of biological product during cleaning processes can be costly, and especially challenging when a company is testing its cleaning validation method on a potentially new biologic product. To help mitigate expensive losses, companies may look for alternatives to their molecule that they can use as a “worst-case product” scenario for their cleaning validation methods.
In one study, a worst-case product scenario was tested for the cleaning validation of brolucizumab (4), Novartis’ Beovu, prior to its approval by FDA in October 2019 for treating wet age-related macular degeneration (5). In the study, five molecule candidates for worst-case product were subjected to cleanability and solubility tests, with the caveat that a worst-case product must be more difficult to clean than the actual biologic product. This would ensure that acceptable cleaning settings would be established for the bioreactor when manufacturing the actual biologic product (4).
Going through this exercise helped the researcher demonstrate the multidisciplinary nature of cleaning validation, which is one aspect of good manufacturing practices (GMP) regulations that is still not well understood or gets little attention (4). FDA’s requirements largely focus on the need to record and document all steps used in cleaning processes. To that end, a company must be meticulous in its cleaning validation documents, including defining the equipment that is cleaned as well as the equipment used in cleaning processes; demonstrating understanding of the given drug’s properties; and describing analytical methods used to determine the level of cleanliness (or presence of contaminants). Sample residue collection from surfaces must also be recorded. The overall approach to cleaning validation, therefore, requires expertise in various disciplines and cooperation among those disciplines.
Air-liquid residues can be detrimental for biologics manufacturing and can come from a variety of sources, including hydrocarbons, polymers, mineral silicates, lubricants, and siloxanes (found in valves, gaskets, and tubing) (6). Hydrocarbons such as steramide, erucamide, and oleamide, are mold-release agents used to prevent caking of powders. They are often used in manufacturing the bags (e.g., those used for storage and transport) and biologics equipment.
Polymers such as nylon, polytetrafluoroethylene, and silicone are necessary components of equipment used in raw material manufacturing and are also used in bags or containers meant for raw material storage. These substances can be a source of raw material impurities. Likewise, mineral silicates, lubricants, and siloxanes can also be sources of raw material impurities, all of which can appear in bioprocess preparation tanks (6).
Common cleaning approaches that pharmaceutical manufacturers use to combat these residues include increasing spray (e.g., employing a rotating spray device), raising cleaning temperature to around 75 °C–85 °C, and using a formulated cleaning agent. In addition, the industry may increase the concentration of the cleaning agent and/or use an oxidizing cleaning agent or a detergent additive combined with an alkaline cleaning solution (so long as temperature is kept between 50 °C and 65 °C) (6).
1. FDA, “Validation of Cleaning Processes (7/93), Guide to Inspections Validation of Cleaning Processes,” fda.gov, accessed March 16, 2020.
2. A. Walsh, Biopharm International’s The Future of Bioprocessing eBook 28 (14) 14–22 (2015).
3. EMA, Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities (CHMP, CVMP, November 2014).
4. D. Steyaert, “Cleaning Validation of Biologicals: Determination of a Worst-Case Product for RTH 258,” Master’s Thesis Paper (2016–2017).
5. Novartis, “Novartis Receives FDA Approval for Beovu, Offering Wet AMD Patients Vision Gains and Greater Fluid Reductions vs Aflibercept,” Press Release, Oct. 8, 2019.
6. B. Kroeger, “Current Trends in Cleaning Validation,” presentation for Parenteral Drug Association, PDA.org/docs, accessed Feb. 11, 2020.
Vol. 44, No. 4
When referring to this article, please cite it as F. Mirasol, “Alternative Cleaning Validation Methods for Biologics,” Pharmaceutical Technology 44 (4 ) 2020.