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Welcome to e-CV, the cutting-edge solution for managing cleaning validation with precision and ease. Designed for Pharmaceuticals, Active Pharmaceutical Ingredient (API), R&D, Vaccines and Biosimilar companies, our software automates critical calculations and adapts effortlessly to changes in your facility and product line.
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Cleaning validation is a pivotal element of any effective GMP compliance program in regulated drug manufacturing facilities. In recent years, particularly from 2017 to 2020, this area has undergone significant transformation and debate as the industry shifts from traditional validation models to a more risk and science-based approach. This transition also includes moving from traditional methods to Health-Based Exposure Limits (HBEL).
In response, nearly all major regulatory bodies have either updated their cleaning validation guidelines within the past four years or are in the process of doing so. We’ll explore the current landscape of cleaning validation guidance across major regulators and organizations.
USFDA (U.S. Food and Drug Administration):
On April 1, 2018, the FDA revised its guidance on equipment cleaning under Section 211.67 of 21 CFR. The FDA now mandates that:
"Equipment and utensils must be cleaned, maintained, and, where appropriate for the nature of the drug, sanitized and/or sterilized at suitable intervals to prevent malfunctions or contamination that could compromise the safety, identity, strength, quality, or purity of the drug product beyond official or established requirements."
This directive is a cornerstone of GMP cleaning and pharmaceutical cleaning practices.
In addition to Section 211.67, the FDA has issued numerous other documents to guide the industry. Links to some of these resources are provided end of this session:
While the FDA does not specify the methodologies for establishing residue limits, it does refer to traditional criteria such as dosage and the 10 ppm standard.
Useful Links USFDA:
EMA (European Medicines Agency)
The European Medicines Agency (EMA) has been a pioneer in setting risk-based cleaning validation guidelines aimed at preventing cross-contamination in shared production facilities. In its guidance, effective from June 1, 2015, the EMA made it mandatory to establish Health-Based Exposure Limits (HBELs) for all drug products, based on Permitted Daily Exposure (PDE) values as outlined in Appendix 3 of ICH Q3C (R4).
Following this, the EMA released a Q&A document to clarify the implementation of the guidelines. While the full Q&A is essential reading, a few key highlights are as follows:
How to Use HBELs:
Establishing Health-Based Exposure Limits (HBELs) is only the first step. These values serve as a foundation for determining any additional controls needed through a Quality Risk Management (QRM) process, which is essential for effective cleaning validation.
By integrating HBELs into the QRM process, companies can ensure that appropriate measures are in place to maintain product safety and quality throughout the manufacturing lifecycle.
Acceptance vs. Alert Limits:
While HBELs serve as Residue Acceptance Limits, manufacturers must also establish alert limits based on historically used cleaning limits, such as dosage-based criteria. However, it's crucial to ensure that the cleaning processes are capable. For example, if your historical dosage-based limit is overly stringent but results in a CpK of less than 1.33, the alert limit should be determined through statistical evaluation rather than relying solely on the dosage limit.
Analytical Testing at Product Changeover:
Analytical testing during product changeover is now mandatory unless the risk is quantified as low. Risk quantification is based on three key factors: Severity (Toxicity Scale), Probability (Cleaning Process Capability), and Detectability (Visual Threshold). These elements are essential in assessing risk within cleaning validation.
Using LD50:For drug products, LD50 is no longer considered an appropriate point of departure for determining HBELs
Useful Links EMA:
WHO (World Health Organization)
The World Health Organization (WHO) Cleaning Validation Guidelines closely mirror those of the FDA. WHO's Good Manufacturing Practices for Active Pharmaceutical Ingredients (Annex 2) outlines fundamental requirements throughout the document, with specific emphasis on Sections 5.2 and 12.7. Key points to consider include:
Worst-Case Approach: WHO explicitly endorses the worst-case product approach for selecting representative APIs to validate cleaning procedures? It suggests that the selection should be based on factors such as solubility, cleaning difficulty, and the calculation of residue limits considering potency, toxicity, and stability. However, the guidance remains unclear on how to incorporate stability into residue limit calculations—a critical aspect in worst-case scenarios for cleaning validation.
Continuous Process Verification: WHO recommends ongoing monitoring through methods like analytical testing and visual inspection. Although it alludes to a risk-based methodology, the guidance lacks detailed instructions, leaving room for improvement in continuous process verification for cleaning validation.
Useful Links WHO:
PIC/s (Pharmaceutical Inspection Co-operation Scheme)
The Pharmaceutical Inspection Co-operation Scheme (PIC/S) quickly followed the EMA's lead and introduced its own version of the new cleaning validation guideline to prevent cross-contamination, known as PI 046-1 Guideline on Setting HBELs in Shared Facilities, which took effect on July 1, 2018. This marked a significant step toward a risk-based cleaning validation program, especially given that PIC/S has around 50 member countries.
Does this mean that regulators in over 50 countries will begin aligning their expectations with EMA regulations regarding cleaning programs? Only time will tell.
Shortly after the release of the PIC/S guideline, an Aide-Mémoire was published—a valuable resource for pharmaceutical manufacturers as it outlines exactly what regulators will scrutinize. Not only is it a must-read, but failure to comply with its recommendations could result in regulatory challenges. The document is referenced in the link below.
During inspections, special attention should be paid to the risk management of cross-contamination. However, the time spent on this will depend on factors such as the hazard level of the molecules, the variety and number of products handled, and the degree to which facilities are proven to be adequately separated or dedicated.
PIC/S also released another Aide-Mémoire titled Cross-Contamination in Shared Facilities. This document is essential reading for anyone looking to develop a comprehensive risk assessment plan to prevent cross-contamination in shared facilities. It is particularly relevant for cleaning validation and quality risk management, and should be reviewed thoroughly.
Useful Links PIC/s:
TGA (Therapeutic Goods Administration)
The Therapeutic Goods Administration (TGA) has essentially adopted the PIC/S Cleaning Validation Guideline into its Good Manufacturing Practices (PE009-13). This marks the first indication that other countries may soon follow suit, embracing the risk- and science-based approach to Cleaning Validation Standard Operating Procedures (SOPs).
The TGA has adopted version PE009-13 of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products (PIC/S Guide to GMP), with the exception of Annexes 4, 5, and 14. These serve as the manufacturing principles for medicines, active pharmaceutical ingredients, and biologicals containing or composed of live animal cells, tissues, or organs.
The TGA has also issued a notice regarding the transition to the new GMP requirements for medicinal products, which is worth reviewing.
Useful Links TGA:
HC (Health Canada)
Health Canada, in its Cleaning Validation Guidelines (Guide-0028), outlines several unique requirements that are well-known within the industry, yet surprisingly absent from many other guidelines.
We also have a slight disagreement with Principle 3.5, which allows for the worst-case risk to be considered acceptable alongside the actual risk. We believe the guidelines should discourage the tendency to default to the worst-case scenario as a shortcut, rather than putting in the necessary effort to accurately assess the actual risk—particularly in the context of cleaning validation risk assessment.
Principle 3.5: Cleaning procedures for products and processes that are very similar do not need to be validated individually. This may depend on factors such as common equipment, surface area, or an environment involving all product-contact equipment, as part of an effective cleaning validation procedure.
Another unique aspect of the guidelines is the recommendation to perform a cost-benefit analysis of using dedicated versus shared equipment. Dedicated equipment refers to equipment exclusively used for a single product.
Principle 4.2: In a multi-product facility, the effort required to validate the cleaning of a specific piece of equipment exposed to a product, and the cost of permanently dedicating the equipment to a single product, should be carefully considered.
Health Canada provides one of the most comprehensive descriptions of revalidation requirements. It emphasizes the need for a real-time mechanism to assess the impact of any relevant changes on the cleaned status of the facility. These changes may trigger the need for cleaning validation revalidation.
Key changes that may require revalidation include:
A change control system must be in place to ensure that all changes potentially impacting the cleaning process are properly assessed and documented. Significant changes should undergo a thorough review and be authorized through the formal change control procedure. Minor changes, or those with no direct impact on final or in-process product quality, should be managed through the standard documentation system. The review should also consider whether revalidation of the cleaning procedure is necessary as part of the cleaning validation revalidation process.
Useful Links HC:
PDA (Parenteral Drug Association)
The Parenteral Drug Association (PDA) has published two essential documents on cleaning validation: PDA Technical Report 29 for active pharmaceutical ingredients and PDA Technical Report 49 for biotechnology products. These reports provide detailed guidance on cleaning validation specific to these areas.
PDA’s Cleaning Validation Technical Reports are among the most comprehensive resources available, offering in-depth insights into the cleaning validation process. They provide valuable tools for establishing a Cleaning Validation SOP, including a protocol template and a detailed cleaning validation protocol.
We highly recommend that readers obtain a copy and explore these reports thoroughly for a deeper understanding.
Useful Links PDA:
ISPE (International Society for Pharmaceutical Engineering)
The International Society for Pharmaceutical Engineering (ISPE) revised its Baseline Guide on Risk-MaPP (Risk-Based Manufacture of Pharmaceutical Products) and published the 2nd edition in 2017. These revisions closely align with the 2015 EMA guidelines on setting Health-Based Exposure Limits (HBELs). The guide provides an excellent balance of high-level principles and practical implementation details, offering a science- and risk-based approach to establishing a Cleaning Validation SOP. It significantly enhances cleaning validation quality risk management.
In September 2020, ISPE also released a new guidance document titled Cleaning Validation Lifecycle – Applications, Methods, & Controls.
Useful Links ISPE:
APIC (Active Pharmaceutical Ingredients Committee)
The APIC Cleaning Validation Guideline is widely used by organizations, particularly those focused on producing raw API materials. In 2016, APIC revised its 2014 guideline on cleaning validation in Active Pharmaceutical Ingredient (API) plants to incorporate the EMA guidance on Health-Based Exposure Limits (HBELs). The primary updates were made in Chapter 4, Acceptance Criteria, with a focus on cleaning validation for APIs.
While this guideline is popular and appreciated for its detailed approach to managing small molecules, it has faced criticism for confusing terminology and inconsistencies throughout the document. For instance, a notable error from the 2014 version was carried over into the 2016 update—suggesting a somewhat "relaxed" approach to the maximum allowable carryover of mistakes in APIC!
In 2021, the guidance was updated again to address industry feedback and better align with the EMA's Q&A on the use of HBELs. The key changes continued to focus on refining Acceptance Criteria in Chapter 4.
For those seeking an in-depth understanding of cleaning validation in API manufacturing plants, especially with a focus on active pharmaceutical ingredients, this guideline is a highly recommended read.
Useful Links APIC:
ASTM (American Society for Testing and Materials)
ASTM E3106 - 18e1 (Standard Guide for Science-Based and Risk-Based Cleaning Process Development and Validation) is one of the latest documents related to cleaning validation standards. What sets this guide apart is its incorporation of science-based, risk-based, and statistical concepts introduced in the FDA’s Guidance for Industry Process Validation.
The guide aligns with key elements from ICH Q8, ICH Q9, ICH Q10, and ICH Q11, ensuring consistency with ICH guidelines for cleaning validation.
This standard is steadily gaining popularity and, in our view, is exactly what the industry needs: a science-based, risk-based, and statistics-based approach to establishing a Cleaning Validation SOP.
Useful Links ASTM: