Implications of calculating the PDE as the exposure limit for the analysis of risks in shared installations PDF

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techNo / Process Implications of calculating the PDE as the exposure limit for the analysis of risks in shared installations By Beatriz CARRERO - AZIERTA & Matthieu CHAREYRE - SOCOSUR CHEM [email protected] A ppraisal after implementation of the EMA Directive (EMA/CHMP/CVMP/ SWP/169430/2012)...

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Implications of calculating the PDE as the exposure limit for the analysis of risks in shared installations Matthieu Chareyre-Socosur, Matthieu Chareyre

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techNo / Process

Implications of calculating the PDE as the exposure limit for the analysis of risks in shared installations By Beatriz CARRERO - AZIERTA & Matthieu CHAREYRE - SOCOSUR CHEM [email protected]

A

ppraisal after implementation of the EMA Directive (EMA/CHMP/CVMP/ SWP/169430/2012) on the establishment of exposure limits on health-based criteria during the manufacture of different drugs in shared installations.

1. Introduction In November 2014, the European Medicines Agency (EMA) published the Directive EMA/ CHMP/ CVMP/SWP/169430/2012(1) on the establishment of exposure limits based on health criteria during the manufacture of different drugs in shared installations. In January 2015, the European Commission also revised Chapters 3 and 5 of the EU GMP Guidelines, updating the sections on the prevention of cross-contamination. These updates entered into force in March of the same year. Further, Annex 15 of the EU GMP Guidelines (item 10.6) stipulates that "The residual contamination limits of the product must be based on a toxicological assessment". The dates for implementation of the new EMA Guidelines were June 2015 for new products and December 2015 for existing products 24 I La Vague N° Special I 2018 - 2019

(with deferral of these deadlines for a year for veterinary products). Up until then, the limit values of 10 ppm or 1/1000 of the lowest clinical dose were used for cleaning validations. The use of conventional limits translated, on the one hand into excessively restrictive limits for low toxicity products, far exceeding the limits necessary to guarantee patient safety. And on the other hand, the conventional limits did not offer enough protection for products considered to be highly toxic Up until then, the categories with the highest risks concerned “certain hormones", "certain cytotoxic agents", etc., with no specific criteria. Release of the EMA Directive implies determining exposure limits in accordance with toxicological criteria, and on the basis of characteristics inherent to each substance. The

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techNo / Process PDE (Permitted Daily Exposure) is calculated from pharmacological, toxicological and pharmacokinetic data and is similar to the ADE value (Acceptable Daily Exposure) described in the IPSE (International Society for Pharmaceutical Engineering) RiskMaPP.(2) The two values represent the maximum daily dose of a substance that is not likely to cause adverse effects in an individual who is exposed to this dose or to a lower dose, every day throughout their life. In order to facilitate the implementation of these new GMP regulations in the pharmaceutical industry, the Azierta team of toxicology experts launched a project to calculate PDE values for Active Pharmaceutical Ingredients ("API"), as external service provider in January 2015. With an experience that is unique in Europe as a result of having performed the toxicological assessment and preparation of 1200 PDE monographs, we conducted an in-depth meta-analysis of the data obtained. A classification of PDE values was established, identifying 5 groups and allocating a danger level to each of them. The results were analyzed against the ATC classification (anatomical, therapeutic, chemical) therapeutic groups.

therapeutic, pharmacological and chemical properties. In the first level, the APIs are distributed between the 14 main groups which are then subdivided into five levels. For this study, only classifications up to the third level were taken into account. A B C D G H J L M N P R S V

ALIMENTARY TRACT AND METABOLISM BLOOD AND BLOOD-FORMING ORGANS CARDIOVASCULAR SYSTEM DERMATOLOGICALS GENITO-URINARY SYSTEM AND SEX HORMONES SYSTEMIC HORMONAL PREPARATIONS, EXCLUDING SEX HORMONES AND INSULIN ANTI-INFECTIVES FOR SYSTEMIC USE ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS MUSCULO-SKELETAL SYSTEM NERVOUS SYSTEM ANTIPARASITIC PRODUCTS, INSECTICIDES AND REPELLENTS RESPIRATORY SYSTEM SENSORY ORGANS VARIOUS

2. Methodology The study did not include products limited to veterinary use.

2.1 Calculation of the Permitted Daily Exposure (PDE) One hundred and fifty international pharmaceutical laboratories ordered a PDE report for their API (Active Pharmaceutical Ingredient) according to their needs. 1,200 active substances in total were assessed by a team of AETOX/EUROTOX experts. The PDE Value was determined by following the procedures described in the following reference guidelines: • ICH Topic Q3C (R4): Impurities – Guideline for residual solvents (CPMP/ICH/283/95)(3) • VICH GL18(R): Impurities- Residual solvents in new veterinary products, active substances and excipients (EMA/CVMP/ VICH/502/99-Rev.l)(4) • ICH Q3D: Elemental impurities (Sept. 2015)(5) The toxicological evaluation was performed by a review of the literature, identifying both the dangers and critical effects associated with the substance. From these reviews, a point of departure ("POD") was selected to calculate the PDEs. Using the information available the starting value most appropriate to each case was determined on an individual basis. The POD values used were the following: • No-observed-adverse-effect level "NOAEL", • No-observed-effect level "NOEL", • Lowest-observed-adverse-effect level "LOAEL", • Lowest-observed-effect-level "LOEL", • Threshold of toxicological concern "TTC", Depending on the POD selected, and taking account of both the preliminary study and the toxicological data found for the substance concerned, the safety factors (F1, F2, F3, F4, F5) of the equation, described in the literature(3), were determined for calculation of the PDE. The PDE values obtained were expressed in mg/day.

2.2 ATC Classification To conduct the study of PDE values in accordance with therapeutic groups, each API was allocated its ATC code (Anatomical, Therapeutic, Chemical code).(6) In this classification system, active substances are divided into different groups depending on the target organs on which they act and their

2.3 PDE Categories On the basis of the different categories described in the Occupational Health for OEL values (Occupational Exposure Limits) by Safebridge(7) and Naumann,(8) we established different categories of PDE to analyze the results obtained. Different levels of dangerous substances were defined depending on their PDE value, 5 groups (1 to 5) differentiated by increasing toxicity (Table 1). Group 1 comprises PDE values > 1 mg/day and is associated with a very low danger level. Group 2 comprises a PDE range between 1 and 0.1 mg/day associated with a low danger level. Group 3 has a PDE range between 0.1 and 0.01 mg/day with a moderate API danger level. Level 4 has a PDE range between 0.01 mg/day and 1 μg/day and is associated with a high danger level. The final level, Group 5, comprises all PDE values below 0.001 mg/day (1 μg/day) associated with a very high danger level (Table 1). Group

PDE Categories

Danger level

1

> 1 mg/day

Very low

2

≤ 1 mg/day ; >0,1 mg/day (100-1000 µg/day)

Low

3

≤ 0,1 mg/day ; >0,01 mg/day (10-100 µg/day)

Moderate

4

≤ 0,01 mg/jour ; >0,001 mg/jour 1-10 µg/jour)

High

5

≤ 0,001 mg/day (1 µg/day)

Very high

Tableau 1. PDE Categories

3. Results and interpretation 3.1 Point of departure values (POD) Figure 1 represents the different types of values that were used as points of departure to determine the PDE. In most cases, NOAEL – NOEL values taken from toxicological studies (41% and 15% respectively) were used to calculate the values. Owing to an absence of studies giving these values or a lack of reliability of the latter, the therapeutic dose, such as LOEL, was used in 40% of cases. When no NOAEL value was available, the TTC value (Threshold of toxicological concern) was

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used as a point of departure for genotoxic substances (1%).

Figure 4 presents the distribution of the different therapeutic classes according to the PDE categories for groups 1, 2, 3 and 4.

Figure 1. Point of departure (POD) used to calculate the PDE (n=1200)

3.2 Types of substances (API) In Figure 2, we can see the distribution of substances according to the different ATC therapeutic classes. Most of these fall within class N (nervous system) and class A (alimentary tract and metabolism) with 16.3% and 15.6% of the products total respectively. Approximately 5% of all substances are intended exclusively for veterinary use and were excluded from these investigations.

Figure 4. Distribution of APIs according to ATC classification for groups 1, 2, 3 and 4 (PDE category levels) A more in-depth examination of the group of substances presenting a very high danger level (level 5, PDE 1 mg/day, associated with a very low danger level. • 29% of the APIs assessed can be included in group 2, with a PDE range between 1 and 0.1 mg/day. These substances are considered to have a low danger level. • 17% of substances have PDE values between 0.1 and 0 .01 mg/ day and are considered as having a moderate danger level. • Group 4 comprises 12% of APIs in the study with a PDE range between 0.01 mg/day and 1 μg/day associated with a high danger level. • The last level, group 5, comprises all PDE values below 0.001 mg/ day (...