Cleaning Validation Increasingly Under the Regulatory Spotlight

The steps involved in manufacturing pharmaceutical products require rigorous processes to ensure the safety of patients. One important such process is cleaning validation — a critical element in current good manufacturing practice (CGMP). The US Food and Drug Administration (FDA) defines the purpose of cleaning validation as demonstrating that a “particular cleaning process will consistently clean the equipment to a predetermined standard” (1). And according to the Pharmaceutical Inspection Co-Operation Scheme (PIC/S), “cleaning validation is documented evidence that an approved cleaning procedure will reproducibly remove the previous product or cleaning agents used in the equipment below the scientifically set maximum allowable carryover level” (2).

Given that many manufacturing facilities often use the same equipment to make more than one drug substance/product, companies must have strategies that eliminate risks of cross-contamination. Without adequate cleaning validation in place, drug companies risk product recalls and other quality issues that can damage both the reputation of a company and its products — with potential risk to patients as well.

Regulations and Guidelines

Regulatory authorities require manufacturers to validate that their cleaning procedures are adequate and that they can guarantee that equipment and systems will not be contaminated with harmful chemicals, microbial burdens, or other substances. In the United States, cleaning validation compliance for pharmaceutical products is governed by Title 21, Part 211 of the Code of Federal Regulations (CFR) (3). The European Medicines Agency (EMA) requires companies to establish health-based exposure limits (HBELs) for all drug products based on allowable daily exposure values as described in Appendix 3 of the Q3C document from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) (4, 5).

In August 2022, a full revision of the EU GMP Annex 1 was released, providing guidance on the minimum controls that are required to protect sterile medicinal products during manufacturing (6). The annex, which came into operation on 25 August 2023, requires that each cleaning process be validated to

• remove all residue or debris that would harm the effectiveness of the disinfecting agent used

• minimize chemical, microbial, and particulate contamination of products both during processing and before disinfection (7).

In the medical-device industry, cleaning validation primarily refers to validating the cleaning of finished medical devices themselves rather than the equipment used to manufacture them. In the United States, such compliance for medical-device products is governed by 21 CFR 820.70 (e) “Contamination Control” and (h) “Manufacturing Material” (8).

ICH guideline Q9 introduced risk-based concepts and principles associated with cleaning methods and their validation (9). Risk management has become mandatory in almost all GMP areas, including cleaning validation. To assist in such efforts, nonprofit organizations and standards groups such as the ASTM International have published comprehensive guidelines. For example, ASTM publication E3106-22 applies a life-cycle approach to cleaning process validation, which includes the development, qualification, and verification of cleaning processes, with details on risk assessment (10).

In addition, the Active Pharmaceutical Ingredients Committee (APIC) issued revised guidance in 2021 on cleaning validation for plants making active pharmaceutical ingredients (APIs) (11). APIC notes that integrating cleaning validation within an effective quality system, underscored by quality management processes, should give assurance that API manufacturing operations are performed such that risks to patients related to cleaning validation are understood, assessed for impact, and mitigated as necessary.

Change Over Time

Cleaning validation has evolved significantly from a relatively simple process of verifying that cleaning equipment functioned properly to reduce traces of a product being manufactured into a complex system that includes data analysis and review to demonstrate that the process “consistently meets predetermined specifications” (12).

It is not enough simply to verify that equipment is clean; manufacturers also must ensure that associated cleaning processes do not compromise the quality of products made using such equipment. That requires a comprehensive understanding of manufacturing processes and how different cleaning agents can interact with different materials. Sophisticated analytical methods are needed to detect impurities at very low levels. Sample testing can include specific methods such as high-performance liquid chromatography (HPLC), gas chromatography (GC), and mass spectrometry (MS), or nonspecific methods such as total organic carbon (TOC), pH, and conductivity measurements.

The increasing complexity of cleaning validation has led to the development of specialized software that can help manufacturers manage and analyze data related to their processes. Such programs can be invaluable for identifying trends and potential problems with cleaning processes. These software solutions enable evaluation of different variables, such as the calculation of cleaning-validation limits from maximum allowable carryover (MACO) of residue from previous products. Such applications also can assist with sampling plans, risk assessments, and/or matrix approaches.

Modern software solutions can speed up cleaning-validation processes and help manufacturers to manage and analyze data related to them. These tools enable manufacturers to collect, analyze, and interpret vast amounts of data and thus make informed decisions regarding the effectiveness and efficiency of their cleaning processes. In turn, drug makers can improve the safety and quality of their products while reducing costs associated with rework and recalls.

HTTPS://WWW.ISTOCKPHOTO.COM

Challenges

One difficulty with cleaning validation, as experience has shown, is in establishing clear and consistent processes. Cleaning validation often is considered as an afterthought rather than an integral part of a manufacturing process. In many cases, a lack of clear standard operating procedures (SOPs) causes operators to interpret cleaning instructions differently, which can lead to variations in outcomes. Even with proper SOPs, inadequate training can limit understanding of correct procedures and further hinder the establishment of consistent processes.

Another perennial challenge is variability in the adventitious agents that can be brought into a manufacturing site. Microorganisms can survive on surfaces and equipment, forming biofilms that resist conventional cleaning methods and often require specific cleaning agents or methods to remove them effectively. In addition, complex equipment and even facilities themselves — with intricate designs and hard-to-reach areas, for example — can affect the thoroughness and effectiveness of a cleaning process.

Deficiencies with cleaning validation commonly bring FDA warning letters. Some 42 such letters were issued to manufacturers in 2022, for example (13). Drug manufacturers should invest in establishing comprehensive and well-documented SOPs that clearly outline specified cleaning procedures, required equipment, and acceptable limits for residue levels. Those documents should be reviewed and updated regularly to reflect changes that arise in regulations and best practices. Training and education programs should be implemented to ensure that personnel involved in cleaning validation are adequately trained in the associated procedures and protocols. Organizations should invest in effective cleaning agents and methodologies that can remove many types of contaminants and microbial biofilms. Regular monitoring and testing of cleaning processes are also crucial to verifying the effectiveness and consistency of a cleaning-validation process and to demonstrating CGMP compliance.

The Future of Cleaning Validation

Cleaning-validation processes will continue to evolve as new technologies are developed and adopted. One such area is the use of automation. Robots are used extensively in many industries and now are being tested for use in cleaning validation. Advantages include the ability to work in difficult or dangerous environments and the potential for increased accuracy and consistency. The revised Annex 1 encourages adoption of robotic solutions: “The use of appropriate technologies (e.g., restricted access barriers systems (RABS), isolators, robotic systems, rapid microbial testing and monitoring systems) should be considered to increase the protection of the product from potential extraneous sources of particulate and microbial contamination such as personnel, materials and the surrounding environment, and assist in the rapid detection of potential contaminants in the environment and product” (6).

Data analytics are another means of innovation. They can help companies identify trends and areas for improvement in cleaning-validation programs, then use those insights to change procedures or training programs and improve overall performance. For example, data analytics can help manufacturers to identify the types of microorganisms brought into their production areas. Such information can help companies implement targeted cleaning measures, such as using specific disinfectants or modifying cleaning procedures to target identified microorganisms.

Data analytics also can reveal trends related to the detection of product degradants in equipment. During cleaning validation, equipment is inspected thoroughly for the presence of residues and degradants that can compromise product quality. By analyzing the data collected during such inspections, organizations can identify common product degradants, their sources, and potential causes. Other potential uses of data analytics include identification of trends in the efficacy of cleaning agents and procedures as well as the frequency and severity of cleaning-validation failures. By identifying those issues and subsequently addressing them, companies can enhance their cleaning-validation programs and minimize the risk of noncompliant cleaning operations.

Cleaning validation is integral to the safe manufacturing of high-quality pharmaceutical products. It is essential for every CGMP-compliant process that uses multiuse equipment or facilities to ensure that all components are cleaned and disinfected thoroughly before use. With stricter regulations being implemented and enforced around the world, companies need to stay up to date on cleaning validation technologies and best practices to ensure that all necessary standards are met. By doing so, drug makers can protect their customers from potential health risks while maintaining safe and efficient production lines.

References
1 Recommendation 12. Questions and Answers on Current Good Manufacturing Practice Requirements — Equipment. US Food and Drug Administration: Silver Spring, MD, 16 November 2022; https://www.fda.gov/drugs/guidances-drugs/questions-and-answers-current-good-manufacturing-practice-requirements-equipment#12.

2 Annex 15. Guide to Good Manufacturing Practice for Medical Products. Pharmaceutical Inspection Co-Operation Scheme: Geneva, Switzerland, 1 October 2015; https://picscheme.org/users_uploads/news_news_documents/ps_inf_11_2015_pics_gmp_revised_annex_15.pdf.

3 21 CFR 211.67. Equipment Cleaning and Maintenance. US Code Fed. Reg. Title 21, Subchapter C; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211.

4 EMA/CHMP/CVMP/SWP/169430/2012. Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities. European Medicines Agency: London, UK, 2014; https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-setting-health-based-exposure-limits-use-risk-identification-manufacture-different_en.pdf.

5 ICH Q3C(R8) Guideline for Residual Solvents. US Fed. Reg. 86, 2021: 70850–70852; https://database.ich.org/sites/default/files/ICH_Q3C-R8_Guideline_Step4_2021_0422.pdf.

6 Annex 1: Manufacture of Sterile Products. European Commission: Brussels, Belgium, 22 August 2022; https://health.ec.europa.eu/system/files/2020-02/2020_annex1ps_sterile_medicinal_products_en_0.pdf.

7 Section 5.4. Annex 1: Manufacture of Sterile Products. European Commission: Brussels, Belgium, 22 August 2022;

https://health.ec.europa.eu/system/files/2020-02/2020_annex1ps_sterile_medicinal_products_en_0.pdf.

8 Part 820: Quality System Regulation. US Code Fed. Reg. Title 21, Subchapter H. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=820.

9 ICH Q9(R1). Quality Risk Management. US Fed. Reg. 88, 2023: 28565–28566; https://database.ich.org/sites/default/files/ICH_Q9%28R1%29_Guideline_Step4_2023_0126_0.pdf.

10 ASTM E3106-22. Standard Guide for Science-Based and Risk-Based Cleaning Process Development and Validation. ASTM International: West Conshohocken, PA, 11 August 2023; https://www.astm.org/e3106-22.html.

11 Guidance on Aspects of Cleaning Validation in Active Pharmaceutical Ingredient Plants. Active Pharmaceutical Ingredients Committee: Brussels, Belgium, February 2021; https://www.gmp-compliance.org/files/guidemgr/APIC_Cleaning-validation-guide_2021.pdf.

12 Guide to Inspections Validation of Cleaning Processes. US Food and Drug Administration: Silver Spring, MD, 26 August 2014; https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-guides/validation-cleaning-processes-793.

13 Cleaning in 6th Place in the FDA Warning Letter Statistics. ECA Academy News 7 December 2022; https://www.gmp-compliance.org/gmp-news/cleaning-in-6th-place-in-the-fda-warning-letter-statistics.

Mirian J. Alvarez Berrios is a cleaning validation subject-matter expert and serves as QMC director at PharmaLex US, 21 Diana Street, Amelia Industrial Park, Guaynabo, Puerto Rico 00968;

1-787-918-1662; [email protected]. She has worked in commissioning and qualification, validation, and quality systems in the pharmaceutical, biotechnology, medical device, and food industries for over 25 years. The contents of this article are solely the opinion of the author and do not represent PharmaLex GmbH or its parent company, Cencora Inc. We strongly encourage readers to review the references provided herein and all other available information related to the topics mentioned and to rely on their own experience and expertise in making related decisions.