Learn about the basics of cleaning validation, FDA guidelines and protocol development guide questions, and how a cleaning validation software can proactively help ensure regulatory compliance and product quality.
Published January 21st, 2021
Cleaning validation is a procedure of establishing evidence that cleaning processes for manufacturing equipment prevents product contamination. Cleaning validation should be properly documented to demonstrate Current Good Manufacturing Practice (CGMP) for finished pharmaceuticals.
Cleaning Validation: Inspection and Verification of Processes
Cleaning validation is required because Active Pharmaceutical Ingredients (APIs) cross-contaminated with chemical residues and microbes can compromise patient safety. Ineffective cleaning processes not only lead to more downtime and batch failures, but it also result in FDA rejection and costly fines due to drug adulteration.
While the U.S. Food and Drug Administration (FDA) has yet to release cleaning validation guidelines for pharmaceutical firms, they provide a reference material for the inspections regularly carried out by investigators and other FDA personnel. In the document, FDA generally expects:
Currently, neither the FDA nor the federal regulation for equipment cleaning and maintenance (Section 211.67) mention certain types of cleaning validation. However, it is generally accepted in the pharmaceutical industry that there are two types of sampling methods for cleaning validation: direct and indirect.
While the total number of cleaning methods used in pharmaceutical cleaning validation has yet to be completely determined, this industry article has listed the most types so far and it generally includes the following:
Accurately setting the acceptance criteria for the limit in cleaning validation is crucial to determine the results of the study. To better evaluate whether or not cleaning methods are effective, cleaning validation acceptance criteria can be generally categorized into three various testing parameters:
Cleaning Validation: Acceptance Criteria
Cleaning validation in the pharmaceutical industry mostly entails certain jargons that manufacturing personnel should be familiar about. Here are twelve of the most common abbreviations related to pharmaceutical cleaning validation and what they mean:
The world of cleaning validation can seem confusing at first glance, and there are a lot of questions surrounding the specifics of cleaning method procedures and cleaning validation protocols. Below are answers to some of the most frequently asked questions regarding cleaning validation:
Yes, as long as any piece of equipment or manufacturing system is used in the production, processing, packing, or holding of drug products, cleaning validation is required. Moreover, the FDA inspects the cleaning process especially for dedicated equipment (e.g. fluid bed dryer bags) because they can be more difficult to clean and the likelihood of contamination can be higher.
Even when federal regulations do not specify exactly how often cleaning validation should be done, the FDA enforces Section 211.67a of Current Good Manufacturing Practice for Finished Pharmaceuticals to address the matter:
“Equipment and utensils shall be cleaned, maintained, and, as appropriate for the nature of the drug, sanitized and/or sterilized 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.” [emphasis added]
In other words, the FDA expects equipment cleaning at the necessary frequency to prevent drug adulteration. Regularly performing cleaning validation is useful for determining how often equipment should be cleaned as required by law. More importantly, it is essential in verifying if cleaning processes are actually effective in preventing contamination.
As a general guide or starting point, cleaning validation should be conducted for the initial qualification of a manufacturing process or equipment. Additionally, this review published in the International Journal of Pharmaceutical Erudition enumerates five more instances when cleaning validation should be done:
This article published in the Brazilian Journal of Pharmaceutical Sciences reported that their calculation of a worst case index (WCI) was based on drug solubility, difficulty of equipment cleaning, and occupancy of products in the production line. Refer to the solubility factor table below for more information:
S > 1,000,000
100,000 < S < 1,000,000
33,000 < S < 100,000
10,000 < S < 33,000
1,000 < S < 10,000
Very slightly soluble
100 < S < 1,000
Practically insoluble or insoluble
S < 100
Developing a cleaning validation protocol for each cleaning process per piece of equipment is an integral part of government requirements, as specified in Section 211.67b: “Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product.”
Effective cleaning validation can reduce quality costs, maintain product integrity, and improve patient safety. Listed below are three simple guide questions to help quality assurance and production departments design cleaning validation protocols effectively:
Effective cleaning validation clearly defines:
Operational, validation, and laboratory personnel should understand all decontamination steps, process residue details, hold times, and worst cases related to the equipment and product. Quality managers should regularly evaluate acceptable limits, soiling conditions, and incoming raw material inspections.
Related: Key Determinants in Validating Manufacturing Processes
The FDA inspects pharmaceutical manufacturers to verify compliance with relevant regulations, such as Section 211.67 (Equipment Cleaning and Maintenance). Some of its provisions include:
Establishing and implementing practical steps to make sure that baseline requirements are met can also enable pharmaceuticals to adequately prepare for FDA inspections. Use preparedness checklists and conduct internal audits to address the different types of FDA inspections.
If a pharmaceutical facility manufactures various products, multifactorial inputs in the manufacturing process makes cleaning validation more difficult. The monitoring strategy for cleaning validation should be well-documented, especially for manual cleaning procedures and visual inspections. Paper-based cleaning validation, reporting, and record-keeping can be challenging and time-consuming.
Cleaning Validation Protocol: 3 Helpful Guide Questions
Optimize your process, improve regulatory compliance, save time, and increase productivity with iAuditor by SafetyCulture. Easily perform scheduled inspections, internal audits, and site walkthroughs using mobile devices. Prove the effectiveness of cleaning validation through proper documentation with iAuditor:
This template is used to complete the process validation protocol by reporting the verification of the equipment/system final design against the user, functional, and/or design specifications. Easily identify key equipment parts, utilities supply, and environmental requirements.
Perform systematic audits of a pharmaceutical manufacturing facility and measure compliance with GMP guidelines, including equipment control and cleaning validation. This template has been converted to iAuditor from the ISPE GMP Audit Checklist for Drug Manufacturers.
Use this checklist as an aid to prepare the personnel, site, and documentation needed before an FDA compliance inspection. Determine red flags to help prioritize what still needs to be done and measure the readiness of the facility using scoring.
Help your business improve productivity through workplace cleanliness and efficiency. Eliminate unnecessary items stored in the manufacturing site and ensure machines, equipment, and tools are kept clean and in working order.
Assess the overall cleaning and disinfecting practices, sterile preparation compounding, and infection control in pharmacies. Easily inspect the attire, hygiene, and aseptic technique of pharmacy staff members, storage and waste management, and primary engineering controls.
This digitized MDSAP template is based on the US FDA’s MDSAP QMS Internal Assessment Checklist. Evaluate how aligned is the company’s QMS to MDSAP, including release of products and services, control of non-conforming outputs, and performance improvement.
SafetyCulture Staff Writer
Shine has been professionally writing about virtually anything since her internship for a digital publisher of niche blogazines. She is passionate about building a culture of continuous improvement in the environmental, health, safety, and quality space through well-researched, engaging, and impactful content.
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