IMPACT OF THE CHANGES TO THE EUROPEAN GMPs ON CLEANING VALIDATION - PART II

Introduction

Part I of this article was published in the April/May issue of the GMP Journal. It covered the important changes in the EU guidance to the cleaning validation and life cycle programme^1,2. This Part II answers Frequently Asked Questions (FAQ) by pharmaceutical manufacturers. These questions were collected from American and European manufacturers over the last 1.5 years. The answers to the FAQs are supported by references for further reading. This article focuses on EU GMP updates related to toxicological and pharmacological assessment.

FAQ by pharmaceutical manufacturers

Recent changes to the EU GMP have triggered the review of manufacturers' cleaning validation programmes and procedures. Several manufacturers are asking clarifying questions to understand how to implement the new changes on their existing system. Here's a sample of those questions:

1. Should Total Organic Carbon (TOC) or conductivity be used for each cleaning cycle in routine monitoring?

Collecting TOC or conductivity data is not required for each cleaning cycle. However, the frequency of such verification or monitoring (e.g., using TOC, conductivity, or other methods) should be linked to a risk based assessment to demonstrate that the cleaning performance meets the acceptance criteria. On the other hand, visual inspection should be done after each cleaning cycle, where possible.

2. What is the difference between ADE, PDE and ADI?

The starting point to establish ADE, PDE and ADI is the No-Observed-Adverse- Effect Level (NOAEL). To determine the ADI, the NOAEL is divided by a default safety margin of 100. Note that exception to a safety margin of 100 might be acceptable in certain conditions⁵. Safety factors for ADE, PDE, ADI have different approaches. ADE and PDE are both expressed in mg/day for a body weight of a 50kg adult and minimum 1 kg animal, while ADI is reported in mg/kg/day.

For a particular compound, the PDE value can vary depending on the route of exposure⁴, while the ADE is applicable for any route of exposure. The ADE can be assumed equivalent to the PDE in certain situations but this needs to be properly justified⁴.

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Definition:
The Acceptable Daily Exposure (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 lifetime³.
The Permitted Daily Exposure (PDE) is defined as 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 lifetime¹.
The Acceptable Daily Intake (ADI) is defined as a measure of the amount of a specific substance (originally applied for a food additive, later also for a residue of a veterinary drug or pesticide) in food or drinking water that can be ingested (orally) on a daily basis over a lifetime without an appreciate health risk.¹¹

3. Is it the responsibility of the contract manufacturer to determine the PDE value of the product manufactured for its client e.g. for the Marketing Authorization Holder (MAH)?

The roles and responsibilities have to be clearly assigned in the quality and supply agreement signed between the two parties⁶. The MAH is usually responsible for determining the PDE of the products and/or the cleaning agents used while the contracted manufacturer is responsible for calculating the new Maximum Acceptable Carry Over (MACO).

4. How should a manufacturer calculate the PDE or ADE value of a product?

The calculation of the PDE, ADE or other scientifically justified method is described in Appendix 3 of International Council for Harmonisation Q3C of Technical Requirements 4 (ICH Q3C (R4)) and Appendix 3 of Veterinary International Cooperation on Harmonisation of Technical Requirements 18 (VICH GL 18). The calculation has to be performed by an experienced toxicologist, who will gather toxicological, pharmacological and clinical or nonclinical data to define a starting point to calculate the NOAEL or Lowest-Observed- Adverse-Effect Level (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 entering in the API formulation and the final medicinal product formulations.
(b) Through a review of different clinical or non-clinical data to assess if the product or cleaning agent residue is non-toxic, toxic, sensitizer, allergenic, etc.

From experience, some manufacturers often choose to use a stricter MACO by adding an additional safety factor to the calculation of the PDE depending on the product use (frequency of use and route of administration). However, to avoid exceeding the acceptance criteria, the cleaning procedure must be capable of achieving residue levels below the stricter MACO⁷.

5. How can the PDE or ADE of a product be calculated if the NOAEL cannot be determined?

If the NOAEL cannot be determined, it is acceptable to use the LOAEL1. If the LOAEL is not available, an estimated (or derived) PDE or ADE value can be calculated1. Several publications provide methods to calculate an estimated PDE for existing or new product in shared facilities^8-10. They provide options to estimate PDE or ADE based on the Thresholds of Toxicological Concern (TTC), Occupational Exposure Level (OEL) or Occupational Exposure Band (OEB). Note that the estimated PDE or ADE can be used as a tool for prioritizing to achieve compliance.

6. If an API can be administered through different administration routes, should the PDE of the API be calculated for each administration route?

It is the toxicologist's responsibility to address this matter and different answers might be acceptable depending on the circumstances:

• Option 1: The PDE can be calculated based on the administration route with 100% bioavailability (worst case scenario). This type of approach can potentially result in the cleaning performance being inadequate to meet the worst case MACO level.
• Option 2: The PDE can be calculated using the administration route with the highest bioavailability. For e.g., if a topical administered product is processed in the same equipment used for an oral administrated product, the PDE of the two products is calculated using the administration route with the highest bioavailability.
• Option 3: The European Medicine Agency (EMA) guidance1 states "Changing the route of administration may change the bioavailability; hence correction factors for routeto- route extrapolation should be applied if there are clear differences (e.g. > 40%) in route-specific bioavailability." Based on this, if there is no clear difference between route-to-route bioavailability, it is possible to group different routes of administration and therefore a correction factor is not applied.

This option might be cost effective for an API administered through different routes. It needs, however, a prior evaluation of the bioavailability of the final product administered through the different routes.

7. Is it acceptable to use 10 ppm as acceptance criteria for cleaning limit if the comparison with the health based limit approach was not performed?

The European guideline on cleaning validation assigns the responsibility to the manufacturer for calculating the MACO using the health based approach^1,2. 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 (ISPE risk MaPP) or the EMA guidance^1,3,12. Therefore, the use of the 10 ppm criterion without adequate justification from a healthbased approach is unacceptable¹³. Moreover, the worst case residue determined based on the health based approached may be different compared to that using the 10 ppm criterion¹². 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 calculation¹⁴.

8. Is it possible to increase the cleaning limit to the new MACO calculated using health based approach, if the new MACO is higher than the MACO currently used on site?

If the "visually clean" criterion is achieved, the answer is likely "yes" because it increases the "margin of safety" between the cleaning process capability and the new MACO limit. The risk to increase the MACO limit without a sound justification might lead to an observation from an auditor, such as: "why have you increased the MACO limit if the cleaning process was working?" It is a fair observation.
The answer might be different depending on the situation:
(a) if the current cleaning procedure is capable of achieving residue levels below the MACO currently used on site, the cleaning limit is not increased to the new MACO.
(b) If the current cleaning process capability and analytical detection are above or equal to the MACO currently used (very low to no safety of margin), in this case, an increase of the MACO can be justified. In fact, the health based limit is considered as scientific and demonstrated to be safe for the patient.

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9. Is it true that biotechnology manufacturers should not worry about the PDE concept?

Annex 15 states: "10.6.1. Therapeutic macromolecules and peptides are known to degrade and denature when exposed to pH extremes and/or heat, and may become pharmacologically inactive. A toxicological evaluation may therefore not be applicable in these circumstances." This sentence is applicable only if the manufacturer demonstrates that the residue is toxicologically or pharmacologically inactive by the cleaning and sanitization process in place^1,2,7.

Several biotechnology manufacturers have demonstrated - using different detection methods (as product specific immunoassays such as ELISA or EIA) - that biopharmaceutical APIs are denatured and degraded after cleaning to be toxicologically or pharmacologically inactive^15,16. On the other hand, several other biopharmaceutical manufacturers are determining the PDE of their final product, especially if it is an antibody-drug-conjugate or if the process contains heavy metal or small molecules¹⁶.

Note: if a detergent is used for cleaning, then the PDE must be assessed for the detergent.

Conclusion

Cleaning validation and setting cleaning limits is complex, and different approaches (answers) can be acceptable depending on the circumstances. Therefore, factors influencing cleaning performance and setting limits must be understood to avoid inadequate cleaning procedure or exceeding specification resulting in risk to the patient.

 

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.

References:
¹ European Medicine Agency (EMA), Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities, (2014).
² European Commission, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - Annex 15, Qualification and Validation, (2015).
³ International Society for Pharmaceutical Engineering (ISPE), Risk-Based Manufacture of Pharmaceutical Products, vol.7, 1srt ed., 35-46, (2010).
⁴ El Azab W., Impact of the changes to the European Good Manufacturing Practice on Cleaning Validation: Part I, GMP Journal, edition April/ May, (2016).
⁵ Reference Dose (RfD): Description and Use in Health Risk Assessments - Background Document 1A March 15, 1993 https://www.epa.gov/ iris/reference-dose-rfd-description-and-use-health-risk-assessments
⁶ European Commission, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, chapter 7: Outsourced activities, (2013).
⁷ Walsh A., Cleaning Validation for Biologics Can alternative approaches to the Permitted/Acceptable Daily Exposure (PDE/ADE) Be Justified?, BioPharm International Supplements, (2015). http://www.biopharminternational.com/cleaning-validation-biologicscan-alternative- approaches-permittedacceptable-daily-exposure-pdeade-be
⁸ Teasdale A., D. Naumann B., Allison G., Luo W., M. Callis C., K. Shipp B., Rutter L., Seaman C., EMA Guideline on Setting Health-Based Exposure Limits, Pharmaceutical Technology, Vol. 40 (1), (2015).
⁹ Dolan D.G., Naumann B.D., Sargent E.V., Maier A., Dourson M., Application of the threshold of toxicological concern concept to pharmaceutical manufacturing operations. Regul Toxicol Pharmacol, 43, 1-9, (2005).
¹⁰ Kroes R., Renwick A.G., Cheeseman M., Kleiner J., Mangelsdorf I., Piersma A., Schilter B., Schlatter J., van Schothorst F., Vos J.G., Wurtzen G., Structure-based thresholds of toxicological concern (TTC): guidancefor application to substances present at low levels in the diet, Food and Chemical Toxicology, 42, 65-83, (2004).
¹¹ World Health Organization, "Principles for the safety assessment of food additives and contaminants in food," Environmental Health Criteria, vol. 70, (1987).
¹² Crevoisier M., Lovsin Barle E., Flueckiger A., G. Dolan D., Ader A., Walsh A., Cleaning Limits-Why the 10-ppm Criterion should be Abandoned,,Pharmaceutical Technology, vol. 40 (1) (2016).
¹³ Le Blanc D., Should 10 PPM be Used for Limits? (July 2016) http://cleaningvalidation.com/files/116314751.pdf
¹⁴ Fourman G., Mullen M., Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations, Pharmaceutical Technology, (1993).
¹⁵ Sharnez R., Methodology for Assessing Product Inactivation During Cleaning Part I: Setting Acceptance Limits of Biopharmaceutical Product Carryover for Equipment Cleaning, Journal of Validation Technology, Vol. 18, Issue 4, (2012).
¹⁶ Mott A., Henry B., Wyman E., Randall G., Bellorado K., Blümel M., Clark M.E., Parks M., Hayes R., Runkle S., Luo W., Methodology for Assessing Product Inactivation During Cleaning Part II: Setting Acceptance Limits of Biopharmaceutical Product Carryover for Equipment Cleaning, Journal of Validation Technology, Vol. 19, Issue 4, (2013).