Why Cleaning Validation Still Tops FDA 483 Observations

Introduction to The Future of Cleaning Validation Series

Cleaning validation has been a focus of discussion among industry experts and regulators since the FDA introduced 21 CFR Parts 210 and 211 in 1978, emphasizing the avoidance of cross contamination in pharma and the protection of patient safety. In recent years, agencies like the FDA have issued an increasing number of cleaning- and cross-contamination-related observations, signaling stricter regulatory expectations for cleaning strategies.

This three-part blog series unpacks the past, present, and future of cleaning validation in GMP environments. Part 1 explores why cleaning validation continues to top FDA inspection findings, despite decades of regulatory focus. Part 2 examines how regulators and industry leaders are shifting toward risk-based, lifecycle-driven approaches that balance compliance with efficiency. Finally, Part 3 looks ahead to the digital future of cleaning validation, where automation, real-time monitoring, and Pharma 4.0 innovations are transforming traditional cleaning validation practices into a proactive, data-driven process.

Ready to dive in? Let’s start with Part 1, where we explore the fundamentals of cleaning validation and why it continues to raise regulatory red flags.

A Brief History of Cleaning Validation

The concept of cleaning validation in pharma has evolved significantly over the decades, driven by increasing regulatory oversight and the need for stronger product safety measures. Initially, cleaning processes were largely unregulated, relying on general best practices rather than formalized validation methods. However, as pharmaceutical manufacturing expanded and product complexity grew, regulators introduced stringent requirements to prevent cross-contamination and ensure product integrity.

Understanding this history helps manufacturers appreciate the rationale behind today’s regulatory expectations and why cleaning validation continues to be a critical focus for operational facilities.

Why Is Cleaning Validation Important?

At its core, cleaning validation is the process of confirming that equipment, utilities, and facilities that may come into contact with the drug manufacturing process are effectively cleaned to control cross-contamination and ensure patient safety, product efficacy, and quality. The goal is to establish practical, reliable methods that comply with current good manufacturing practices (cGMPs).

As the FDA states:
“Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements” (21 CFR 211.67[a], 2014).

Cleaning validation is widely applied in industries such as pharmaceuticals, biotechnology, food, and medical devices. It involves documenting evidence that cleaning procedures consistently remove residues of previously manufactured products, cleaning agents, and microbial contaminants to predefined acceptable levels.

When cleaning validation fails, the risks are real. Failure to control cross-contamination in pharma can lead to product recalls, reputational damage, and in severe cases, patient injury or death (Becker, 2022; Chapman, 2021).

Why Discuss Cleaning Validation in an Operational Facility?

Managing cleaning validation effectively is essential for the successful operation of pharmaceutical manufacturing facilities. Key reasons to prioritize a robust cleaning validation system include:

• Patient safety: Residual contamination can pose health risks, particularly for parenteral and inhalable medicines.
  
  
• Product quality: Preventing contamination maintains high product safety and efficacy standards.
  
  
• Regulatory compliance: A well-documented, science-based process is fundamental to passing inspections under FDA cleaning validation guidelines. Noncompliance can lead to warning letters, import alerts, or other serious penalties.
  
  
• Reputation and trust: Strong cleaning validation practices protect a company’s standing with regulators, customers, and partners.
  
  
• Operational efficiency: Effective programs minimize downtime, reduce batch rejections, and improve productivity and batch throughput.
  
  
• Product integrity: Rigorous cleaning validation ensures products consistently meet their target quality profiles.

FDA 483 Data: Cleaning Validation Still Tops Observations

Between 2010 and 2020, 25% to 30% of FDA warning letters referenced validation-related issues, including some related to cleaning validation, making validation the most frequently cited category (Rathore et al., 2022; see Figure 1).

Figure 1. Validation-related violations consistently ranked at the top of FDA warning letters between 2010 and 2020. Adapted from Rathore et al., 2022, Journal of Pharmaceutical Innovation

In the most recent fiscal year, FDA Form 483s for Drug cGMP still focus on fundamental issues such as procedures, investigations, written instructions, laboratory controls, equipment design, and equipment cleaning and maintenance. Each CFR item listed in Table 1 represents a top 10 citation in the current Inspections Data Dashboard.

Table 1. Selected top citations from the FDA Inspections Data Dashboard (Drug cGMP) FY 2024 dataset, highlighting how cleaning-related observations (§211.67(a)) remain among the leading citations.

For cleaning specifically, §211.67(a) — equipment cleaning, sanitizing, and maintenance remains a leading observation, often linked to weak procedures, poor limit justification, and documentation gaps. This reinforces the need for a lifecycle, quality risk management (QRM)-based program with health-based exposure limit (HBEL) or permitted daily exposure (PDE)-derived limits and Part 11/Annex 11 controls.

These notices document objectionable conditions that may violate the Food, Drug, and Cosmetic Act and can damage a company’s reputation. They often trigger deeper inspections or follow-up action. For manufacturers, recurring findings highlight systemic weaknesses in both cleaning practices and documentation.

For companies seeking to strengthen compliance, understanding the root causes of these observations is essential. Common issues include weak protocols, insufficient studies, poorly justified residue limits, and gaps in monitoring or documentation. In a recent ValGenesis blog post, we outlined practical strategies for avoiding common FDA 483 observations in cleaning validation, offering actionable steps manufacturers can take to close these gaps before they lead to costly failures.

Global Regulatory Perspectives on Cleaning Validation

Beyond the FDA, regulators worldwide also place strong emphasis on cleaning validation. Listed below are some of the most relevant agency directives that outline expectations for an effective cleaning validation system. (Read “What are the Regulatory Expectations for Cleaning Validation?” for a closer look at the stringent regulations governing cleaning validation in GMP environments.)

• EMA (European Union): The EMA requires cleaning validation for all product-contact equipment and has introduced health-based exposure limits (HBELs) to strengthen patient protection. Manufacturers are expected to calculate, apply, and periodically reassess these limits as part of quality risk management.
  
  
• ANVISA (Brazil): ANVISA defines cleaning validation as documented evidence that an approved cleaning procedure reproducibly removes residues and reduces microbial load to a scientifically established safe level. This perspective reinforces global alignment around rigorous, documented practices to minimize cross-contamination.
  
  
• Health Canada: Health Canada’s cleaning validation guide (GUI-0028) provides detailed guidance on cleaning assessment requirements, selection of agents and methods, acceptance criteria development, evaluation of cleaning effectiveness through analytical methods, comprehensive documentation requirements, and change control expectations. The guidance reflects Health Canada’s expectation that manufacturers demonstrate control of cleaning processes as part of maintaining GMP compliance.
  
  
• Industry organizations (PDA, ISPE, ASTM, WHO, PIC/S, APIC): These organizations provide additional frameworks and harmonized expectations, from PDA’s technical reports to ASTM’s standardized, science- and risk-based frameworks. Together, they reinforce that cleaning validation must be approached as a continuous, lifecycle-driven process and an essential cornerstone of GMP compliance worldwide. 

Looking Ahead to Part Two

The evidence is clear: traditional, manual cleaning validation approaches are no longer enough to ensure safety, efficiency, and regulatory success.

In Part 2 of this series, we’ll examine how regulators worldwide are pushing the industry toward risk-based, lifecycle-driven cleaning validation models. You’ll see how this shift not only aligns with global expectations but also helps companies improve efficiency, strengthen compliance, and future-proof their operations.

This three-part blog series from our Industry Insight, The Future of Cleaning Validation. Download the full version to explore the complete story behind cleaning validation’s past, present, and future.

References

Agência Nacional de Vigilância Sanitária (ANVISA). (2022). Instrução Normativa IN No 138, de 30 de Março de 2022. 

Allison, G., Carlson, J., Osborne, J., Randall, G., Riss, P.-M., Verghese, G., Walsh, J., & Yankah, B.-M. (2012). Technical Report No. 29 (Revised 2012): Points to consider for cleaning validation. Parenteral Drug Association (access required).  

ASTM International. (2022). ASTM E3106: Standard guide for science-based and risk-based cleaning process development and validation (access required).

Chapman, K. (2021, June 29). Sartan contaminant recall hits generics manufacturers. Royal Society of Chemistry.

Committee for Medicinal Products for Human Use (CHMP). (2014). Setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities — Scientific guideline. European Medicines Agency. 

European Medicines Agency. (2018). Questions and answers on implementation of risk-based prevention of cross-contamination in production.

Health Canada. (2021). Cleaning validation guide (GUI-0028).

Rathore, A. S., Li, Y., Chhabra, H., & Lohiya, A. (2022). FDA warning letters: A retrospective analysis of letters issued to pharmaceutical companies from 2010–2020. Journal of Pharmaceutical Innovation.

Rivera, E. (2021). Cleaning validation program maintenance in a process life-cycle model. ISPE Pharmaceutical Engineering Journal.

U.S. Food and Drug Administration. (2024). Inspections Data Dashboard (Drug CGMP).