Prevention of cross-contamination is one of the topics in the centre of the recent European Guidelines to Good Manufacturing Practice (GMP) updates. Various EU Guidelines to GMP chapters and annexes were updated to set new requirements regarding cross-contamination control. Robust cleaning validation and setting health-based exposure limits have been identified as effective ways to prevent cross-contamination.
Validation is still among the top 10 of the 2015 and 2016 GMP inspection deficiencies published by the UK Medicines and Healthcare Products Regulatory Agency (MHRA)1,2. With regards to cleaning validation and cross-contamination control observations, the MHRA expects the manufacturer to consider the toxicity and potency risk of a new product in order to determine the need for any degree of dedicated facility or equipment1. The quality assessment and cleaning risk assessment must integrate the toxicity or the potency, the sensitisation and the cleanability of existing and new products (i.e. including investigational medicinal product (IMP) and active pharmaceutical ingredient (API)) prior to receiving and using them on site1.
The qualified person (QP) must have visibility of critical documents referring to, for example, the product quality, the cross-contamination and the cleaning risk assessments. Therefore, the QP must be aware of the cleaning validation strategy in place to implement the new set of requirements. The QP must further confirm that the product quality impact assessment demonstrates that the product is still safe for the patient, based on the gap analysis performed by the manufacturer. Finally, it is recognised that the QP will need to rely on the pharmaceutical quality system (PQS) and that the QP should have on-going assurance that this reliance is well founded3. Note that the quality system is in the first rank of top 10 inspection deficiencies observed by the MHRA during 2015 and 2016 while, in 2013 it was in the second rank1,2,4.
The first part of this article covers key changes to cleaning validation guidance, including setting limits and identifying worst-case active residue that should be part of the cleaning life cycle program. The second part will discuss the various QP responsibilities regarding the new set of requirements for cleaning validation.
Regulatory requirements for cleaning validation
The following documents explain the new requirements on cleaning validation5.
- The European Medicines Agency (EMA) revised its Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities, applicable since June 20156. Active or detergent residue limits (maximum acceptable carry over – MACO) must 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. The lowest observable adverse effect level (LOAEL) would be acceptable to use if the NOAEL data could not be determined7. The PDE must be assessed by an experienced toxicologist. The toxicologist will gather toxicological, pharmacological and clinical or non-clinical data to define a starting point to calculate the NOAEL or LOAEL. This can be done in two different ways:
(a) a review of the Safety Data Sheet (SDS) and data in the literature of the starting materials used in the API formulation and the final medicinal product formulations, or
(b) through a review of different clinical or non-clinical data to assess if the product or cleaning agent residue is non-toxic, toxic, sensitiser, allergenic, etc. Finally, the toxicological data must 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 Guidelines to GMP Annex 15 Qualification and Validation (applicable since 1 October 20158) 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 unless a scientific justification supports otherwise. 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 to render results below the calculated limit.
- The EU Guidelines to GMP Chapter 3 Premise and Equipment and Chapter 5 Production were also revised and applicable since 1 March 2015. The documents place emphasis on prevention of cross-contamination and on toxicological assessment9,10.
Impact of the changes on cleaning limit to be used
The new regulations require the MACO calculation to include the use of the health-based exposure limits based on the method for establishing the PDE or other scientifically justified methods, as described in Appendix 3 of International Council for Harmonisation (ICH) Q3C (R4) and Appendix 3 of the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) GL 186. It is known that, for a compound, the PDE value could vary amongst toxicologist and route of exposure5.
The worst-case active residue is considered the one with the lowest MACO value including the results of the solubility and cleanability assessment (see Figure 1). Consequently, if for non-dedicated equipment the MACO based on health-based limits is lower than the established limit, 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 MACO currently used is the safest to prevent cross-contamination. In some cases, an increase of the cleaning limit can be justified11.
Figure 1. In Place, In Use, In Control
The 10 ppm criterion does not comply with the scientific approach proposed by the International Society for Pharmaceutical Engineering Risk-Based Manufacture of Pharmaceutical Products or the EMA guidance6,12,13. Therefore, the use of the 10 ppm criterion without adequate justification from a health-based approach is unacceptable13. Moreover, the worst-case residue determined based on the health-based approach may be different compared to that using the 10 ppm criterion14. Note that the 10 ppm criterion was initially used in a publication by Fourman and Mullen to provide a default value and not as a substitute for a dose-based calculation15.
This article will be continued in next week’s LOGFILE. Don’t miss the various QP responsibilities regarding the new set of requirements for cleaning validation.
- Medicines and Healthcare Products Regulatory Agency. MHRA GMP Inspection Deficiency Data Trend 2015. London, UK: MHRA. Available at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/582841/MHRA_GMP_Inspection_Deficiency_Data_Trending_2015.pdf (Accessed 8 February 2017).
- Medicines and Healthcare Products Regulatory Agency. MHRA GMP Inspection Deficiency Data Trend 2016. London, UK: MHRA. Avaialble at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/609030/MHRA_GMP_Inspection_Deficiency_Data_Trend_2016.pdf (Accessed 22 April 2017).
- European Commission. EudraLex Volume 4 Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. Annex 16 Certification by a Qualified Person and Batch Release. Brussels, Belgium, European Commission; October 2015.
- European Medicine Agency. ICH Guideline Q10 on Pharmaceutical Quality System. London, UK: EMA; January 2011.
- El Azab W. Impact of the changes to the European Good Manufacturing Practice on Cleaning Validation: Part I. GMP Journal 2016; April/May.
- European Medicine Agency. Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities. London, UK: EMA; November 2014.
- Lai Yeo Lian, Ovais M. Setting cleaning validation acceptance limits for topical formulations. Pharmaceutical Technology 2008;32(1). Avaialable at: http://www.pharmtech.com/setting-cleaning-validation-acceptance-limits-topical-formulations
- European Commission. EudraLex Volume 4 Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. Annex 15 Qualification and Validation. Brussels, Belgium: European Commission; 2015.
- European Commission. EudraLex Volume 4 Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. Chapter 3 Premises and Equipment. Brussels, Belgium: European Commission; 2015.
- European Commission. EudraLex Volume 4 Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. Chapter 5 Production. Brussels, Belgium: European Commission; 2015.
- El Azab W. Impact of the changes to the European Good Manufacturing Practice on Cleaning Validation: Part II – Frequently Asked Questions. GMP Journal 2016;Oct/Nov.
- International Society for Pharmaceutical Engineering. Risk-Based Manufacture of Pharmaceutical Products, First Edition, Volume 7. Bethesda, MD, USA: ISPE; 2010, pp. 35–46.
- Le Blanc D. Cleaning Memo for July 2016. Should 10 PPM be Used for Limits? Winter Haven, FL, USA: Cleaning Validation Technologies; July 2016. Available at: http://cleaningvalidation.com/files/116314751.pdf
- Crevoisier M, Lovsin Barle E, Flueckiger AG, Dolan D, Ader A, Walsh A. Cleaning limits – why the 10-ppm criterion should be abandoned. Pharmaceutical Technology 2016;40(1). Available at: http://www.pharmtech.com/cleaning-limits-why-10-ppm-criterion-should-be-abandoned
- Fourman G, Mullen M. Determining cleaning validation acceptance limits for pharmaceutical manufacturing operations. Pharmaceutical Technology 1993; April.
Walid El Azab is a Technical Services Manager for STERIS Life Science and a former QP. He currently provides technical support related to cleaning chemistries, disinfectants and sterility assurance products and their application and validation. His areas of expertise include both upstream and downstream biopharmaceutical operation and validation. Walid earned a Master’s degree in Industrial Pharmaceutical Sciences from the University of Liège, Belgium and is a certified Lean Six Sigma green belt. Walid also gives Industrial Pharmaceutical Sciences Master’s courses at the University of Liège. Finally, Walid is an active member of the PDA, ISPE, ECA, A3P and is Secretary of the Belgium QP Association (UPIP-VAPI).
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