Cleaning Validation is a critical component of an effective GMP Compliance program at any regulated drug manufacturing facility. In fact, Cleaning Validation in pharmaceutical industry has been one of the most evolving and debated topic of the year 2018-19 as the industry transitions towards a risk and science based validation from traditional V model and towards Health Based Exposure Limits (HBEL) from traditional methods.
Every major regulator has either revised the Cleaning Validation Guideline in the last 2 years or in the process of revising. In this article, we take a look at the current status of where the Cleaning Validation Guidelines stand for all major regulators and organisations.
1. U.S. Food and Drug Administration (USFDA)
FDA revised its guidance on Equipment Cleaning under Section 211.67 in 21CFR on April 1, 2018. FDA requires that:
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.
Apart from the 211.67, there are many other documents published by the FDA that guide the industry. Some of these links are given at the end of this section. Here are a few noteworthy points:
- Acceptable Residue: FDA has mentioned clearly in the Questions & Answers on Current Good Manufacturing Practices—Equipment that the Contamination that is reasonably avoidable and removable is never considered acceptable. Hence, Cleaning Procedures must not be designed sub-optimally to remove a calculated "acceptable" level of residue but rather based on scientific understanding of the substance and its interaction with other resources within the manufacturing facility. Similarly, analytical methods should not be designed solely on the basis of the acceptable residue that needs to be achieved.
- Total Organic Carbon: FDA has come to terms with using TOC as an acceptable method for monitoring residues routinely and for cleaning validation given that the contaminating material(s) is organic and contains carbon that can be oxidized under TOC test conditions.
- Rinse Sampling: For cleaning validation, rinse samples alone would not be acceptable; firms should also measure the residue or contaminant on the equipment surface using a direct method such as swab (if feasible).
- Continuous Process Verification: Many firms have not implemented this yet. FDA is very clear that a Continuous Verification Program needs to be in place for routing residue monitoring after Cleaning Validation. The frequency of this program will need to be determined based on risk.
FDA doesn't really delve into the methodologies used to establish the residue limits however it refers to some of the traditionally used criteria such as dosage and 10ppm.
- Read the complete FDA Cleaning Validation Guideline from CFR 211.67 here: CFR211.67
- Read the full CFR 211 here: 21 CFR Part 211
- Inspection References: Guide to inspections validation of cleaning processes Validation of cleaning processes
- Questions & Answers on Current Good Manufacturing Practices—Equipment
- Leucine Micro Article on A discourse on calculating residue limits
2. European Medicines Agency (EMA)
EMA has certainly been a frontrunner when it comes to establishing risk-based cleaning validation guidelines for prevention of cross-contamination in shared production facilities. In guidance, effective June 01, 2015, EMA made it mandatory to establish Health-Based Exposure Limits for all the drug products based on Permitted Daily Exposure Values as described in Appendix 3 of ICH Q3C (R4).
The guideline was soon followed up by a Q&A on the implementation of the above guideline. The full Q&A is a must-read however a few key items are listed here.
HBELs should be established for all medicinal products.The toxicological or pharmacological data, on which the HBEL calculation relies, requires periodical reassessment throughout a product’s lifecycle.
How To Use HBELs: Establishing HBELs is just the start. These values work as a basis to determine the additional controls that may need to be put in place via a Quality Risk Management process.
Acceptance vs Alert Limits: While HBELs work as Residue Acceptance Limits, the manufacturers still need to set alert limits based on the historically used Cleaning Limits (such as based on dosage) while ensuring that the Cleaning Processes are capable. This means that if your historical dosage based limit is the worst but that results in CpK < 1.33, the alert limit needs to be set based on the statistical evaluation and not based on the dosage limit.
Analytical Testing at Product Changeover: This is now required unless the risk is quantified low. Risk quantification is done based on the Severity (Toxicity Scale), Probability (Cleaning Process Capability) and Detectability (Visual Threshold).
Using LD50: For drug products, now LD50 can not be used as an adequate point of departure to determine HBELs.
- EMA Cleaning Validation Guideline on setting HBELs EMA HBEL Guideline
- QnA on the implementation of the above guideline EMA HBEL Guideline QnA
3. World Health Organization (WHO)
WHO Cleaning Validation Guideline is very similar to that of FDA. WHO Good Manufacturing practices for active pharmaceutical ingredients (Annex 2) lays out the basic requirements throughout the document but specifically under Sections 5.2 and 12.7. Here are a few things to keep in mind:
Worst Case Approach: WHO clearly accepts the worst product approach to select representative APIs to validate Cleaning Procedures. It further adds that the selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability. It is very unclear though how to incorporate stability into residue limits.
Continuous Process Verification: WHO recommends continuous monitoring using methods such as analytical testing and visual examination. It gives a hint to the risk-based methodology but lack of any further details leaves a lot to be desired.
In May 2020, WHO released a working draft for comments Points to consider on the different approaches –including HBEL – to establish carryover limits in cleaning validation for identification of contamination risks when manufacturing in shared facilities. This guidance is certainly inspired by the HBEL revolution that has picked up momentum across all major regulators. It also includes an indicative risk scale to measure hazard based on PDE values which is flawed as it shows risk as a discrete quantity and not as a continuous scale. But I am glad to mention that this has been removed in the Aug 2020 draft.
- WHO good manufacturing practices for active pharmaceutical ingredients Download Here
- Quality assurance of pharmaceuticals: A compendium of guidelines and related materials Download Here
- [May 2020] Points to consider on the different approaches –including HBEL – to establish carryover limits in cleaning validation for identification of contamination risks when manufacturing in shared facilities Download WHO HBEL Draft Here
- [Aug 2020] Points to consider when including6 Health-Based Exposure Limits (HBELs) in cleaning validation Download WHO HBEL Draft Here
4. Pharmaceutical Inspection Co-operation Scheme (PIC/S)
PIC/S followed EMA quickly and released its own version of the new Cleaning Validation Guideline to the prevention of cross-contamination PI 046-1 Guideline on setting HBELs in shared facilities to be effective from July 01, 2018.
This was a monumental step in moving towards a risk-based cleaning validation program since PIC/S has about 50 countries as it’s members. Does this mean that the regulators of over 50 countries will start expecting the cleaning program that is in-line with the EMA regulations? Only time will tell.
Soon after the release of the above-mentioned PIC/S guideline, an AIDE-MEMOIRE was released which is a great resource for every pharma manufacturer as it details the things that the regulators will look for in very specific details. Not only it is an absolute must-read, not following it will lead to a lot of regulatory troubles. It’s referenced in the link below.
During an inspection attention should be paid to the risk management of cross-contamination; however, the amount of time allocated will depend upon the hazard level of the molecules, the type and number of products handled, and the degree to which facilities are proven to be separated and dedicated.
PIC/S came up with another AIDE-MEMOIRE called Cross Contamination in Shared Facilities. One can not recommend this document enough. Anyone looking to understand what all goes into building a holistic risk assessment plan to mitigate cross-contamination in shared facilities must read this document a few times.
For those who may not be aware: PIC/S, which became operational in November 1995, is meant as an instrument to improve co-operation in the field of Good Manufacturing Practices between regulatory authorities and the pharmaceutical industry.
- Aide-Memoire on cross-contamination in shared facilities PI-043-1
- Guideline on Setting HBEL for use in risk identification in the manufacture of different medicinal products in shared facilities PI 046-1
- Guide to GMP for medicinal products Part 1 PE 009-14 (Part I)
- [Jun 2020] Aide-Memoire: Inspection of Health Based Exposure Limit (HBEL) Assessment and use in Quality Risk Management PI 052-1
5. Therapeutic Goods Administration (TGA)
TGA pretty much adopted the PIC/S Cleaning Validation Guideline to Good Manufacturing Practices (PE009-13). This gives us the first sign that the remaining countries may soon come on board to the new ship that is the Risk and science-based Cleaning Validation SOP.
The TGA is adopting version PE009-13 of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products (PIC/S Guide to GMP), excluding Annexes 4, 5 and 14, as the manufacturing principles for: Medicines and active pharmaceutical ingredients and Biologicals that comprise or contain live animal cells, tissues or organs
TGA also published a notice about the transition to new GMP requirements for medicinal products, which is worth having a look.
- TGA interpretation and expectations for demonstrating compliance See Here
- A presentation on Cleaning Validation by TGA
6. Health Canada
Health Canada, in its Cleaning Validation Guidelines (Guide-0028), has listed down quite a few unique requirements that are actually well known in the industry but surprisingly not mentioned in many other guidelines.
We also slightly disagree with Principle 3.5 which specifies the worst-case risk as acceptable along with the actual risk. We feel that the guidelines should not promote the behavior of defaulting to the lazy approach of taking the worst-case risk rather than putting efforts to identify the actual risk.
3.5 Cleaning procedures for products and processes which are very similar do not need to be individually validated. This could be dependent on what is common, equipment and surface area, or an environment involving all product-contact equipment.
Taking all product-contact equipment approach often results in severe inefficiencies in terms of the number of validation batches as well as the cost of compliance. We have described it in more depth in one of the earlier Micro Articles 5 Data-driven strategies to improve GMP cleaning efficiency by 5X.
Another unique guidance is related to doing a cost-benefit analysis of dedicating vs sharing equipment.
4.2 In a multi-product facility, the effort of validating the cleaning of a specific piece of equipment which has been exposed to a product and the cost of permanently dedicating the equipment to a single product should be considered.
Health Canada has done the best job of describing the revalidation requirements. It requires a real-time mechanism to assess the impact of relevant changes on the cleaned status of the facility. These changes may be:
- Changes in the cleaning procedure;
- Changes in the raw material sources;
- Changes in the formulation and/or process of products;
- New products;
- Changes in the formulation of detergents;
- New detergents;
- Modifications of equipment.
11.1 A change control system is in place to ensure that all changes that might impact the cleaning process are assessed and documented. Significant changes should follow a satisfactory review and authorization of the documented change proposal through the change control procedure. Minor changes or changes having no direct impact on final or in-process product quality should be handled through the documentation system. The review should include consideration of the re-validation of the cleaning procedure.
- Health Canada Cleaning Validation Guideline Guide-0028
7. Parenteral Drug Association (PDA)
PDA has published two separate documents related to Cleaning Validation. PDA Technical Report 29 for Actives and PDA Technical Report 49 for Biotechnology products.
PDA Cleaning Validation Technical Reports are the most comprehensive guides when it comes to going into the depths of the Cleaning Validations and establishing a Cleaning Validation SOP for your firm.
We highly recommend every reader to get a copy and dive deep into the details.
- PDA Technical Report 29: Points to Consider for Cleaning Validation PDA TR 29
- PDA Technical Report 49: Points to Consider for Biotechnology Cleaning Validation PDA TR 49
8. International Society For Pharmaceutical Engineering (ISPE)
ISPE also revised its Baseline Guide on Risk-MaPP (Risk-Based Manufacture of Pharmaceutical Products) and published in 2nd edition in 2017. The revisions are mostly in line with the 2015 EMA guideline on setting HBELs. This guideline has done a wonderful job in describing the high-level principles as well as practical implementation details for establishing a Cleaning Validation SOP that is based on science and risk.
ISPE also released another guidance document in Sep 2020 named Cleaning Validation Lifecycle - Applications, Methods, & Controls. [I am currently reading through this guide and will be posting some thoughts here soon]
- Baseline Guide Vol 7: Risk-Based Manufacture of Pharma Products 2nd Edition ISPE Risk-MaPP
- [Sep 2020] Cleaning Validation Lifecycle - Applications, Methods, and Controls ISPE Cleaning Validation Guideline
9. Active Pharmaceutical Ingredients Committee (APIC)
APIC Cleaning Validation Guideline is used by many organizations especially the ones that produce only raw API materials. APIC also revised its 2014 Guideline on aspects of Cleaning Validation in Active Pharmaceutical Ingredient plants in the year 2016 to incorporate the EMA guidance on using HBELs. The main changes were introduced in Chapter 4, Acceptance Criteria.
Even though a popular and widely adopted guideline, and appreciated by many for the details that it provides related the uniqueness in managing small molecules, APIC is criticised frequently for its confusing terminology and inconsistencies throughout the document. Here is an example of a blatant mistake that was present in APIC 2014 and carried over to APIC 2016. Apparently, the Maximum Allowable Carryover of mistakes is pretty relaxed when it comes to APIC!
In 2016, The APIC guidance was upaded to bring it in line with the EMA Guidance on setting the HBEL (health-based exposure limits). The key changes were introuced in the Chapter 4, Acceptance Criteria. In 2021, a further updated guidance has been published which address several comments received from the industry as well as align it better with the EMA Q&A on use of Health Based Exposure Limits (HBELs)
We would recommend reading it if you looking to deep dive into the specifics of handling cleaning validation at an API manufacturing plant.
- Guidance on aspects of Cleaning Validation in Active Pharmaceutical Ingredient Plants APIC Cleaning Validation 2016
- Guidance on aspects of Cleaning Validation in Active Pharmaceutical Ingredient Plants APIC Cleaning Validation 2021
10. American Society For Testing and Materials (ASTM)
ASTM E3106 - 18e1 (Standard Guide for Science-Based and Risk-Based Cleaning Process Development and Validation) is the latest document that has come out related to the Cleaning Validation Standards. A unique thing about these standards is that it incorporates many of the science-based, risk-based, and statistical concepts and principles introduced in the FDA’s Guidance for Industry Process Validation. This guide supports and is consistent with, elements from ICH Q8, ICH Q9, ICH Q10, and ICH Q11.
This standard is gradually becoming popular and, in our opinion, is really what the industry needs: science-based, risk-based and statistics-based approach to establishing a Cleaning Validation SOP.
We also did receive an indication during a webinar conducted by Dr. Andrew Walsh that the following standard guides are underway:
- Standard Practice guide for the Qualification of Visual Inspection of Pharmaceutical Manufacturing Equipment and Medical Devices for Residues
- Standard Practice guide for the Calculation of Cleaning Validation Limits
Our belief (and hope) is that the above upcoming guides will become a must-have practical reference for any Cleaning Validation teams across the globe.
-  ASTM Standard is available here: ASTM E3106
-  Standard Guide for Derivation of Health-Based Exposure Limits (HBELs) ASTM E3219