PharmaLex

The steps involved in manufacturing pharmaceutical products require rigorous processes to ensure the safety of patients. One important step is cleaning validation – a critical element in current good manufacturing practice (cGMP).

The U.S. Food and Drug Administration defines the purpose of cleaning validation as demonstrating that a ‘particular cleaning process will consistently clean the equipment to a predetermined standard.’

According to the PIC/S guide to GMP for medicinal products, Annex 15 Qualification & Validation, ‘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.’

Given that most facilities manufacture many different drugs, they must have strategies that eliminate the risk of cross-contamination. Where adequate cleaning validation is not in place, companies risk product recalls and other quality issues, damaging the reputation of the company and its products. 

Regulations and Guidelines on Cleaning Validation

Regulatory authorities require that manufacturers validate that their cleaning procedures are adequate and that they have a process that guarantees that equipment and systems are not contaminated with harmful chemicals, microbial burdens, or other substances.

In the U.S., cleaning validation compliance for pharmaceutical products is governed by the Title 21 Code of Federal Regulations (CFR), Part 211, current good manufacturing practice for finished pharmaceuticals, specifically 21 CFR 211.67, equipment cleaning and maintenance. 

"Cleaning validation is integral to the safe manufacturing of pharmaceutical products."

The European Medicines Agency (EMA) requires establishing health-based exposure limits (HBELs) for all drug products based on allowable daily exposure values as described in Appendix 3 of ICH Q3C.

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

• Remove any residue or debris that would detrimentally impact the effectiveness of the disinfecting agent used.

•  Minimize chemical, microbial and particulate contamination of the product during the process and prior to disinfection.

In the medical device industry, cleaning validation primarily refers to validating the cleaning of the finished medical device itself rather than the equipment used to manufacture it. In the U.S., cleaning validation compliance for medical device products is governed by the Title 21 CFR, Part 820, Quality System Regulation or 21 CFR 820, QSR, specifically 21 CFR 820.70 (e) Contamination Control and (h) Manufacturing Material.

The ICH guideline Q9 introduced risk-based concepts and principles associated with cleaning methods and their validation. Risk management has become mandatory in almost all GMP areas, including cleaning validation.

To assist in such risk management, nonprofit organizations and standards groups such as the American Society for Testing and Material (ASTM) have published comprehensive guidelines. The ASTM’s publication, Standard Guide for Science-Based and Risk-Based Cleaning Process Development and Validation, labeled E3106-18, applies a life-cycle approach to cleaning process validation, which includes the development, qualification, and verification of cleaning processes and details on risk assessment.

In addition, the Active Pharmaceutical Ingredients Committee (APIC) issued revised guidance in 2021 on cleaning validation of active pharmaceutical ingredient plants. 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 in such a way that risks to patients related to cleaning validation are understood, assessed for impact and mitigated as necessary.

How Has Cleaning Validation Changed Over Time?

Cleaning validation has changed significantly from a relatively simple process of verifying that cleaning equipment functioned properly to reduce traces of the product being manufactured to a complex system that includes data analysis and review to show that the validation process ‘consistently meets predetermined specifications.’

Today, it is not enough to simply verify that the equipment is clean – manufacturers must also ensure that the cleaning process does not adversely affect the quality of the product. This requires a comprehensive understanding of the manufacturing process and how different cleaning agents may interact with different materials. It also necessitates sophisticated analytical methods 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 a non-specific method such as total organic carbon (TOC), pH and conductivity.

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. This type of software can be invaluable in identifying trends and potential problems within the cleaning process. With the help of these tools, manufacturers can continue to improve the safety and quality of their products while reducing costs associated with rework or recall.

Challenges with Cleaning Validation

One of the challenges with cleaning validation, as experience has shown, is that it can be difficult to establish a clear and consistent process. This is because cleaning validation is often seen as an afterthought rather than an integral part of the manufacturing process. As such, it can be difficult to get buy-in from all stakeholders for a cleaning validation project.

Furthermore, there can be a lack of understanding about what needs to be done to validate the cleanliness of equipment. This can lead to frustration and confusion among those involved in the process. It is also worth noting that cleaning validation can be a time-consuming and resource-intensive exercise. This is particularly true if multiple pieces of equipment need to be cleaned and validated.

Integral to addressing these challenges is to ensure cleaning validation is properly documented as evidence that cGMP has been followed. Deficiencies with cleaning validation commonly result in FDA warning letters, with as many as 42 such warning letters being issued to manufacturers in fiscal year 2022.

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 robotics. Robots are used extensively in many industries and are now being tested for use in cleaning validation. This will offer advantages such as the ability to work in difficult or dangerous environments and the potential for increased accuracy and consistency. The revised Annex 1 encourages the adoption of robotic solutions, noting, '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.’

Another area that may bring innovation is the use of data analytics. Data analytics can help identify trends and areas for improvement in cleaning validation programs, which can then be used to change procedures or training programs to improve overall performance.

Conclusion

Cleaning validation is integral to the safe manufacturing of pharmaceutical products. It is essential in any good manufacturing process to ensure that all components have been thoroughly cleaned and disinfected before use. With stricter regulations being enforced worldwide, companies need to stay up to date on cleaning validation processes and ensure they are meeting the necessary standards. By doing so, they can protect their customers from potential health risks while maintaining safe and efficient production lines.

About the author

MirianJanett Alvarez, QMC Puerto Rico Director at PharmaLex, is a cleaning validation subject matter expert. She has worked in the pharmaceutical, biotechnology, medical device and food industries for more than 25 years in commissioning and qualification, validation, and quality systems.