In the pharmaceutical industry, proper critical cleaning, sanitation, and sterilization are essential to avoid biological, chemical, and environmental contamination and to ensure the safety and efficacy of drug products. Aqueous cleaning solutions[1] offer several benefits over solvent-based technologies. Seeking support from a highly knowledgeable cleaning detergent supplier with a deep understanding of the pharma/biopharma industry and its cleaning needs, combined with extensive experience in developing cleaning solutions and a broad portfolio of cleaning reagents, is an effective strategy for ensuring successful cleaning protocol development and validation. Critical cleaning denotes situations where the level of cleaning directly impacts the value of the end product or manufacturing efficiency.
[1]Editor’s note: This article is derived from and serves as a companion piece for the newly updated (March 2023) e-book The Aqueous Cleaning Handbook: A Guide to Critical Cleaning Procedures, Techniques, and Validation by Moussourakis et al. from Alconox Inc. and published by AI Technical Communications.
The Importance of Critical Cleaning in the Pharma/Biopharma Sectors
Cleanliness and well-organized procedures typically lead to greater efficiency and productivity in any workplace. In the pharmaceutical industry, proper cleaning, sanitation, and sterilization ensuring the safety and efficacy of drug products is paramount. This requires a variety of means to avoid biological, chemical, and environmental contamination. Cleaning must necessarily precede any disinfection or sterilization process to ensure effectiveness. The process of removing residues to a critically clean level ensures that the disinfection or sterilization process is not deterred by a lingering residue barrier or film.
At a minimum, a contaminated batch of drug substance or drug product must be reworked to ensure proper specifications, extending the time before it can reach the market; in many cases, contaminated product must be discarded. When working with limited or especially high-value drug substances and raw materials, contamination can be especially costly for manufacturers. If the drug maker is one of only a few suppliers, it can also mean shortages of necessary medications for patients. In the worst-case scenario, contamination is not discovered before drug products reach patients, resulting in illness and/or death. Failure to comply with regulatory requirements regarding cleaning and cleaning validation also carries a high risk of reputation damage and the potential for significant future economic losses for the manufacturer.
The level of cleaning and sanitation required in a pharmaceutical or biopharmaceutical manufacturing facility depends on the activities performed in specific areas within the plant. Areas other than production suites or ballrooms must be regularly cleaned to remove dust, dirt, and other debris.
Manufacturing areas require more extensive cleaning, including disinfection, sterilization, and decontamination of process equipment, floors, walls, and other surfaces, depending on the type of production involved. Cleanrooms require the highest level of cleaning at the greatest frequency.
Monitoring of surfaces is also an essential part of the cleaning process, as it confirms cleaning performance and provides advanced warning of the potential for a developing contamination issue.
Similarly, a high level of cleanliness must be maintained in quality control, analytical, and process-development laboratories to ensure that no contamination of samples or process materials occurs, which could lead to incorrect data generation and decision-making based on invalid information.
Equipment and Other Substrates Requiring Cleaning
Cleaning is not limited to obvious surfaces, such as walls and floors. The exterior and interior surfaces of permanent (usually stainless-steel) reaction vessels, bioreactors, transfer vessels, tubing, pumps, purification equipment, lyophilizers, particle-sizing equipment, spray driers, and filling and packaging equipment must be maintained in a contaminant-free state. The surfaces of tables, trays, and implements (e.g., beakers, flasks, test tubes) must also be clean, whether on the manufacturing floor or in the laboratory.
Essentially, any surface exposed to materials involved in the production of a drug substance or drug product, including those for managing (storage, mixing, transferring) raw materials, buffer solutions, excipients, and other ingredients used to produce or formulate drug products must come presterilized (single-use components) or be cleaned regularly following established and validated cleaning protocols.
Different Residues in Pharma and Biopharma Manufacturing
Pharmaceutical drugs formulated using small molecule active pharmaceutical ingredients (APIs) are produced using synthetic chemistry processes that are very different from the cell culture and microbial fermentation processes employed to produce biologic drug substances. Consequently, while many of the surfaces that must be cleaned are similar, the relevant residues can differ significantly.
Different residues require different cleaning protocols. The structure, functional groups, molecular polarity, solubility, and molecular weight of a given residue will dictate which cleaning method and cleaning chemistry are most appropriate. Some residues are not readily classified, and, in these cases, it is recommended that bench-scale cleaning verification studies are performed before conducting larger-scale cleaning trials.
Residues commonly observed in pharmaceutical manufacturing include titanium dioxide, petrolatum, oils, emulsions, ointments, carbopols and various synthetic polymers, lacquers, zinc oxides, steroids, alcohols, sugars, various starches and other natural polymers, salts, metallics, pigments, amines, ethers, and alkaloids, among many others.
While many of the same excipients and buffers are used in the production of biologic drugs (e.g., sugars, alcohols, ethers, amines, salts and various polymers), there are some residues unique to biopharma manufacturing. Most common are protein, organic, cellular, and fermentation residues. It also merits noting that downstream processing of biologics often involves different equipment from that used for the purification of small molecule drug substance. Examples include reverse osmosis and ultrafiltration/diafiltration membranes, which have their own specific cleaning regimens.
Scheduling and Validation Considerations
Validation that cleaning protocols are effective is critical, primarily for product contact surfaces and surfaces where indirect transfer of contaminants or other products may occur. While establishing standard protocols is required for cleaning surfaces such as floors and walls, validation of cleaning performance is may not be required, depending on location classification. For products that are manufactured infrequently (e.g., one batch every two years), cleaning verification is required rather than validation, as it is unlikely that the identical cleaning procedure will be used each production run owing to changes in the use of the production equipment between batches.
Appropriate time should be allotted for cleaning validation, as it is a lengthy and time-consuming process. Validation involves demonstration that the cleaning process consistently removes expected residues or contaminants to acceptable levels. It is essential that relevant residues are identified, methods for detection and quantitation established, sampling protocols developed, residue acceptance criteria determined, method validation studies performed, and procedures documented and operators trained. If any part of the cleaning process is changed, revalidation is often necessary.
Working with a cleaning product supplier that has extensive experience supporting pharma and biopharma manufacturing operations can help accelerate the cleaning validation process.
A Look at the Regulatory Landscape
Requirements for cleaning and cleaning validation are covered in general regulations regarding current Good Manufacturing Practices and guidances on cGMP expectations for different types of drug substances and drug products. Examples include the following:
- The FDA’s Process Validation: General Principles and Practices: Guidance for Industry, January 2011
- The FDA’s Guide to Inspections, Validation of Cleaning Processes, which covers equipment leaning for chemical residues.
- 21 CFR Part 210 Current Good Manufacturing Practice in Manufacturing Processing, Packing, or Holding of Drugs
- 21 CFR Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals
- EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use: Annex 15: Qualification and Validation
- PIC/S GMP Guide PE 009-16, Guide to Good Manufacturing Practice for Medicinal Products Annexes
- ICH Q7 Good manufacturing practice for active pharmaceutical ingredients: Scientific guideline
Regulatory inspectors consider all aspects of cleaning validation performance and look for sound rationale backed by appropriate and comprehensive policies, processes, analytical methods, and so on. The proliferation of multiproduct facilities used to produce smaller volumes of numerous different types of drug substances and drug products has heightened interest in cleaning validation, as microbial and other types of contamination from the environment and raw materials are not the only concerns. In these facilities, cross-contamination is a significant risk that must be avoided, with cleaning protocols playing a major role.
The development of cleaning protocols is expected by regulatory authorities to be based on a thorough risk assessment that takes into account the specific equipment and materials used in a given process, and thus the potential residues and contaminants that may be present. It should include both direct contact surfaces and opportunities where indirect transfer may occur.
The cleaning method, its mechanism, and the cleaning reagents involved should also be considered in the risk assessment. Many cleaning processes have the potential to leave their own residues, including the cleaning reagents themselves, as well as degradation products generated by the breakdown of contaminants or residual product from the previous run. Finally, this evaluation should also consider different detection methods to identify those most suitable for the specific application.
Focus on Aqueous Critical Cleaning for Pharma/Biopharma
Critical cleaning can be performed via many different methods, including physical and chemical treatments. Chemical cleaners may be solvent- or water-based. Aqueous cleaners are generally preferred over solvent-based cleaners, as the former are typically biodegradable and nontoxic, while the latter often have acute and chronic toxicological profiles, flammability, or combustibility. Water-based detergent cleaners for pharmaceutical and biopharmaceutical cleaning applications are generally complex mixtures specifically formulated to create greater chemical and mechanical cleaning action.
In these mixtures, surface active agents (surfactants), or excellent wetting agents, allow the cleaning solutions to penetrate into crevices while getting under soils to facilitate their removal. Dilute solutions often effectively remove even worst-case substances from a variety of hard surfaces, including stainless steel, glass, or plastic.
Pharmaceutical manufacturing of drug substances based on small molecules includes intermediate and active ingredient production using synthetic chemistry (often mediated by complex metal or enzymatic catalysts) followed by purification using distillation, chromatography, crystallization, and other processes. The active ingredients are then used to produce tablets and capsules, liquid suspensions and emulsions, topical creams and ointments, and parenteral products administered via injection.
Residues that must be removed range from easy-to-clean water-soluble excipients to difficult-to-clean petrolatum/metal oxide mixtures. Residual drug products in multiproduct manufacturing facilities can also be challenging to remove sufficiently. Despite the wide diversity of potential contaminants, to simplify regulatory compliance and reduce the probability of using the wrong detergent, it is desirable to use as few cleaners as possible that function effectively under many conditions (manual, soak, ultrasonic, and clean-in-place (CIP) systems) to remove the entire range of residues encountered.
Aqueous cleaners are typically basic or acidic and of varying strengths. Alkaline cleaners are generally used on oily residues, while acidic cleaners are used on inorganic residues. Additional ingredients are added to achieve specific performance attributes, such as minimization of foam generation or maximization of emulsification. Robust fully formulated cleaners that contain wetting agents, emulsifiers, dispersants, chelating agents, and anti-redeposition agents will give the broadest and most robust residue removal.
Such aqueous cleaners have been widely used in R&D labs and pharmaceutical manufacturing areas to clean metal, glass, and polymer components, as well as difficult-to-clean processing equipment. Both liquid and powder forms are available; liquids are seen as easier to handle and more accurately dispense, while powders are more economical, particularly for manual cleaning.
For parenteral products, in addition to the typical residues, pyrogens (endotoxins or cellular debris that can cause fevers after internal exposure) are a key concern. While pyrogens can be controlled by heat, mild alkaline powdered and liquid detergent cleaners can be used to remove pyrogenic residues and be part of a depyrogenation program on a variety of surfaces whether they are sensitive to heat or not.
A detergent selection guide for pharmaceutical cleaning is presented in Table 1.1
Cleaning requirements for biopharmaceutical manufacturing are similar to those for the production of small-molecule drugs. The different residues that must be removed, however, reflect the fact that biologics are produced using living cells or organisms and are often complex mixtures produced during fermentation, cell culture, cell lysis, and cell harvesting.
Cleaning protocols must leave surfaces free of any substances that can interfere with culture and fermentation growth or cause unacceptable batch-to-batch contamination. Biotechnology residues that are organic in nature are traditionally well-handled by aqueous detergents consisting of high-emulsifying surfactants and/or alkaline hydrolysis cleaning mechanisms. For removal of proteinaceous residues, enzymatic, alkaline hydrolysis, and/or oxidative cleaning mechanisms are highly effective.
A brief detergent selection guide for biotechnology cleaning applications is presented in Table 2.1
Ongoing Challenges
Even with the advanced cleaning solutions available to pharma and biopharma manufacturers today, challenges still exist to consistently achieve effective critical cleaning of production areas. Proper planning based on deep process, analytical and cleaning technology knowledge, careful selection of process equipment, consideration of cleaning requirements as processes scale from lab to commercial production, adequate scheduling that allows sufficient time for development of effective cleaning protocols and validation of their performance, and implementation of monitoring and maintenance solutions can all help avoid common problems. Performance of a thorough risk assessment and continuous training of operators regarding different cleaning chemistries and methods are also both essential.
The challenges increase for highly potent compounds, which are becoming more commonplace in both the pharma and biopharma sectors. For these drugs, very low levels can have harmful effects to healthy people, animals, and/or the environment. For highly potent drug substances and drug products manufactured in multiproduct facilities, detecting extremely low levels of these compounds following cleaning protocols is necessary to prevent cross-contamination. However, that can be difficult with conventional analytical technologies used in cleaning validation; the use of liquid chromatography–tandem mass spectrometry is frequently required to assure effective detection. Other specific residue detection techniques are employed as well.
The increasing prevalence of multiproduct facilities is a trend that itself creates challenges to the development of effective cleaning protocols. In many cases, these facilities produce a diversity of drug substances with widely ranging properties using a wide array of raw materials and process equipment. Development of simplified cleaning protocols that can address all potential contaminants and residues becomes difficult. More complex cleaning solutions, in turn, require higher levels of operator training and qualification to ensure that cleaning protocols are implemented appropriately.
Best Practices for Successful Aqueous Cleaning in the Pharma and Biopharma Sectors
While cleaning in the pharma and biopharma sectors is largely a costly and time-consuming activity, there are steps that can be taken to increase the efficiency of cleaning process development, validation, and implementation. Seeking support from a highly knowledgeable cleaning reagent supplier with a deep understanding of the pharma/biopharma industry and its cleaning needs, combined with extensive experience in developing cleaning solutions and a broad portfolio of cleaning detergents, is among the most effective strategies.
The use of cleaning products and associated processes designed to reduce downtime and maximize efficiency also helps to reduce the time and cost of critical cleaning while ensuring reliable validation. Fit-for-purpose cleaning solutions designed with the assistance of supplier cleaning professionals for specific pharma/biopharma applications also minimize downtime and thereby maximize production capacity. Furthermore, simpler but effective aqueous detergent cleaning solutions based on optimized cleaning agents that achieve cleaning faster and at potentially lower water temperatures reduce operator exposure and thus improve their safety.
Getting cleaning protocols and procedures right the first time using carefully engineered detergents and cleaning processes established with the help of experienced cleaning experts also eliminates the need for re-cleaning, which is inefficient, time-consuming, and costly. Finally, and most importantly, the use of optimal cleaning processes reduces the risk of contamination.
Future Directions in Pharma/Biopharma Cleaning
The pharmaceutical industry is founded on innovation, and that includes continued investment in the development of more advanced cleaning technologies. For biomanufacturing, the advent of more rapid analytical methods with high sensitivities is a promising development. More work needs to be done to improve their performance, but if suitable accuracy and repeatability can be achieved, such methods will help accelerate cleaning validation.
Separately, advances in digital technologies, such as artificial intelligence and machine learning, could benefit the selection of cleaning chemistries, establishment of validation targets, classification of equipment to reduce the number of different cleaning solutions needed, scheduling of cleaning, and more.
References
- Moussourakis, Michael J. Jeff I. Phillips, Stacy R. Silverstein, and Malcolm C. McLaughlin. The Aqueous Cleaning Handbook: A Guide to Critical Cleaning Procedures, Techniques, and Validation. Alconox Inc. 2023.