IMPACT OF THE CHANGES TO THE EUROPEAN GMPs ON CLEANING VALIDATION - Part I

Over the past few years, several changes were made to the Eudralex European Good Manufacturing Practice (EU GMP) guidelines and directives on medicinal products. The reason for these revisions to the EU GMPs is the so called 'directive on falsified medicinal products' ( D i r e c t i v e 2011/62/EC). The objective was to adapt the EU GMP directives and guidelines to account for new manufacturing technologies, and to align the EU GMP with other European (EMA) and international guidelines (FDA, ICH). Prevention of cross-contamination was one of the topics at the center of the recent EU GMP updates.

Prevention of cross-contamination is amongst the top 10 "deficiencies observed" from 2011 to 2013 by the Medicines Health Regulation Agency^[1;2]. Robust cleaning validation and setting health based exposure limits have been identified as effective ways to prevent cross-contamination. As a result of that, new sets of requirements around these topics were added to the EU GMP updates.

This article covers key changes to cleaning validation guidance, including setting limits and identifying worstcase active residue that should be part of the cleaning life cycle program.

New changes to cleaning validation requirements The following documents explain the new requirements on cleaning validation:

• The EMA revised its guideline "on setting health based exposure limits…", applicable as of June 2015[3]. Active or detergent residue limits (Maximum Acceptable Carry Over - MACO) have to be assessed through health-based limits using the Permitted Daily Exposure (PDE). The PDE represents a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime. The PDE is calculated using the NOAEL (No Observed Adverse Effect Level), the body weight and five uncertainty factors, e.g., toxicological and pharmacological clinical or non-clinical data. The PDE has to be assessed by an experienced toxicologist. The Lowest Observable Effect Level (LOEL) would be acceptable to use if the NOAEL data could not be determined[?]. Finally, the toxicological data has to be part of the worst-case product identification assessment, except if the active residue is known to be degraded and may become pharmacologically or toxicologically inactive.
• The EU GMP Annex 15 "Qualification and Validation", applicable as of the 1 October 2015[5], requires cleaning validation to be based on a scientific and risk based approach. As a result, a "visually clean only" criterion is no longer acceptable. The number of validation runs required may be determined through a risk assessment justification. To demonstrate robust cleaning, sufficient data is to be captured through continuous monitoring or on-going verification. The ongoing verification frequency will be driven by the quality and business risk assessment results. The Guideline also requires that the active residue limit is calculated using toxicological data (health based limit). As such, the worst case residue should be determined based on solubility, cleanability, and potency, including toxicological data review. Finally, dedicated equipment should be considered when a cleaning process is ineffective in order to remain below the calculated limit.
• The EU GMP chapter 3 "Premise and Equipment" and Chapter 5 "Production" were also revised and applicable as of 01 March 2015. The documents place emphasis on prevention of cross-contamination and on toxicological assessment[6;7]. The transitional arrangement for toxicological assessment implementation is different and is tighter than the one proposed in the EMA guideline. As a consequence, an implementation strategy should be developed to justify potential deficiency to the Eudralex implementation timeline.

Recommendation

Berlin, Germany4/5 December 2024

Root Cause Analysis

Impact of the changes on active setting residue limits for actives

The 1/1000th of the minimum therapeutic dose that gives a pharmacologi- cal effect (dose-based) was used to calculate MACO^[8;9]. This is known as the traditional approach. However, for toxic active residue or compound without dose-based data, the MACO is calculated using an oral minimum Lethal Dose 50 in rats (LD50), i.e., cleaning detergent. Other toxicity studies, such as acute systemic, aquatic, cytotoxicity, etc. could also be used based on the route of administration of the product and/or impact to the quality of the next product produced. A safety factor based on industry best practices for the type of product and patient is also applied. Finally, the empiric limit of 10 ppm and visually clean was used as a default when the 1/1000th or the LD50 could not be determined or resulted in a value that was impractical.

The new regulations require the MACO calculation include use of the health based exposure limits based on the method for establishing the Permitted Daily Exposure (PDE) or other scientifically justified method, as described in Appendix 3 of ICH Q3C (R4) and Appendix 3 of VICH GL 18^[3]. It is known that for a particular compound, the PDE value could vary amongst toxicologist and route of exposure. Another way to calculate the MACO is using the Acceptable Daily Exposure (ADE). The ADE is defined as an exposure or dose that is unlikely to cause an adverse health effect if an individual was to be exposed by any route (e.g., oral, dermal, tissue contact) at or below this dose on a daily basis for a lifetime^[10]. Similar to the ADE, determination of a PDE involves hazard identification by reviewing all relevant toxicological and pharmacological data, determination of the NOAEL, and use of several adjustment factors to account for various uncertainties. As a consequence, the ADE could be considered as equivalent to the PDE, given any route of exposure, if the body weight of 50 Kg for an adult and minimum 1 Kg for an animal is used (see Table 1).

Depending on the veterinary active residue, the MACO limit could be very low for lightweight animal products. So, in some cases, the MACO value would be lower than the Limit of Detection or Quantification (LOD or LOQ). Dedicated equipment seems to be the easy answer. Setting limits for any active residue should be based on understanding the process capability of the equipment, sampling method, LOD of analytical method and visual residue limit. As a result, a justified risk based approach differentiating veterinary product used for animals entering in the human food chain could potentially justify a higher MACO value because the veterinary PDE should be lower than the human PDE. Otherwise the equipment should be dedicated.

The worst case active residue is considered the active with the lowest MACO value (see Figure 1). As a consequence, for non-dedicated equipment, if the MACO based on health based limits is lower than the established limit, then a cleaning revalidation should be performed. The number of runs requires a risk-based justification. On the other hand, if the currently established limits are lower than the health based limits, a simple justification should be written to demonstrate that the currently used MACO is the safest to prevent cross-contamination.

 

Fig. 1: Cleaning programme strategy for acceptance criteria setting Reference used: EMA, 2014; ISPE, 2010; APIC, 2014

 

Finally, the health-based limits should generally be higher than the traditional approach or the empiric limit. This could be used by manufacturers to justify a rollout PDE identification after the guideline deadline.

Recommendation

22/23 January 2025

HPLC Data Integrity - Live Online Training

Conclusion

The recent changes in the EU GMP have triggered the review of manufacturer's cleaning validation programs and cleaning procedures. As a consequence, to adequately assess the gap with the current cleaning requirements, the new regulatory requirements must be understood and integrated into cleaning life cycle programs. In addition, regulators are expecting that the cleaning limit used by the manufacturer should be justified using a risk-based approach to demonstrate safety to the product and patient. Finally, limits should be set based on understanding the process capability of the equipment, sampling method, analytical method, visual residue limit and the pharmacological/toxicological residue limit.

 

Author:
Walid El Azab
... is a Technical Services Manager for STERIS Life Science. He currently provides technical support related to cleaning chemistries, disinfectants and sterility assurance products and their application and validation. Walid is an Industrial Pharmacist and is Secretary of the Belgium Qualified Person association.

Source:
¹ Medicines & Healthcare products Regulatory Agency (MHRA) top defi ciency. Accessed on 05. April 2015 at: http://www.gmp-compliance.org/enews_03189_MHRA-publishes-GMP-Deficiency-Data-Review-April-2011---March-2012.html 
² Medicines & Healthcare products Regulatory Agency (MHRA) top defi ciency. Accessed on 05. April 2015 at: http://webarchive.nationalarchives.gov.uk/20141205150130/http://www.mhra.gov.uk/home/groups/pl-a/documents/websiteresources/con464241.pdf. 
³ European Medicines Agency (EMA), Guideline on setting health based exposure limits for use in risk identifi cation in the manufacture of different medicinal products in shared facilities, November 2014.
⁴ Lai Yeo Lian, M. Ovais. (2008) Setting Cleaning Validation Acceptance Limits for Topical Formulations Pharmaceutical Technology, Band 32, Issue 1. 
⁵ European Commission, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - Annex 15, Qualifi cation and Validation, 2015. 
⁶  European Commission, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - chapter 3, Premises and Equipment, 2015.
⁷  European Commission, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - chapter 5, Production, 2015.
⁸ Fourman, G., and Mullen, M., "Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations," Pharmaceutical Technology, April 1993.
⁹  Active Pharmaceutical Ingredients committee (APIC), Guidance on Aspect of Cleaning Validation in Active Pharmaceutical Ingredient Plants, May 2014.
¹⁰ International Society for Pharmaceutical Engineering (ISPE), Risk-Based Manufacture of Pharmaceutical Products, September 2010.