Toxicology for pharmaceutical production as seen by a non-toxicologist Quality Director, R-Pharm GC T.M. Vyazmina

Normative documents Order of the Ministry of Industry and Trade of the RF as of 14 June,2013 No.916 “On the Approval of Good Manufacturing Practice Rules” EudraLex, volume 4 “EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use”, Part I: “Chapter 3: Premises and Equipment”, Annex 15 “Qualification and Validation”; Active Pharmaceutical Ingredients Committee (APIC) “Guidance On Aspects Of Cleaning Validation In Active Pharmaceutical Ingredient Plants” May 2014; ICH Q3C(R5) “Impurities: Guideline For Residual Solvents” February 2011; PDA Technical Report No. 29 “Points to Consider for Cleaning Validation”, 2010; European Medicines Agency (EMA) “Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities”, 2012; FDA “Guide to inspections validation of cleaning processes”; WHO Technical Report Series 937; State Pharmacopoeia of the Russian Federation, Article “Validation of Analytical Methods”; ICH Harmonized Tripartite Guideline Q2 “Validation of analytical procedures: Text and methodology”; USP <1225> “Validation of compendial procedures”; EDQM PA/PH/OMCL (13) 82 2R “Validation of analytical procedures”; European Medicines Agency (EMA) “Guideline on setting health based exposure limits”; EMA “Guideline On The Limits Of Genotoxic Impurities”; “Control Banding In The Pharmaceutical Industry”, Merck & Co., Inc; NIOSH “Occupational Exposure Banding Decision Logic” Lauralynn Taylor McKernan, Sc.D., CIH National Institute for Occupational Safety and Health Centers for Disease Control and Prevention; “Guidelines for the Production of Medicinal Products Containing Hazardous Substances”. Project General partner: Strategic partners: Official partners: Regional partners:

Toxicology Group for GMP Processes of R-Pharm JSC Quality Directorate Toxicology Group for GMP processes within R-Pharm JSC Quality Directorate was organized in 2016. Toxicology Group has a unified database for MSDS files (material safety data sheets) of third-party manufacturers Aims and tasks of Toxicology Group: Development and refinement of approaches to the determination of toxicological properties of medicinal products Processing, actualization and reporting about toxicological and pharmacological properties of medicinal products: PDE, OEL/OEB Toxicological and pharmacological assessment of a medicinal product in regard to possible sharing of facilities for the production of medicinal products at the project stage The following documents were developed: In-house standard: “Management of Information on Toxicological and Pharmacological Properties of Medicinal Products” Standard operating procedure: “Order of cooperation in the sphere of toxicological and pharmacological assessment of medicinal products” Standard operating procedure: “Toxicological and pharmacological assessment of medicinal products in regard to possible sharing of facilities for the production of medicinal products at the project stage” Standard operating procedure: “Calculation of maximum acceptable carry-over of the medicinal product under study into the next medicinal product and of maximum permissible content of residual substance in a sample”

Approaches to determination of hazard class for active substances, determination of toxicity Overview diagram of toxic substance management Determination of hazard class of a substance OEB/MAC Organization of production and cleaning according to the established hazard class Risk analysis for prospective shared production Cleaning to safety limits and documentary proof of the cleaning done to the required level MACO (PDE/TDD/10ppm)

Approaches to determination of hazard class for active substances, determination of toxicity Several classifications of substance toxicity exist: European approach – OEB system (with exact OEL values) based on EMA “Guideline on Setting Health Based Exposure Limits”; OEB – Occupational Exposure Band OEL – Occupational Exposure Limit Russian approach – current GOST 12.1.007-76; When MAC is determined, the SRLI is applied, MAC – maximum allowable concentration; SRLI - safe reference level of impact Parameter name Limits for hazard class 1 2 3 4 Maximum allowable concentration (MAC) of hazardous substances in workplace air, mg/m³ Less than 0.1 0.1-1.0 1.1-10.0 More than 10.0 Median lethal dose, in stomach, mg/kg Less than 15 15-150 151-5 000 More than 5 000 Median lethal dose, on skin, mg/kg Less than 100 100-500 501-2 500 More than 2 500 Median lethal dose, in air, mg/m³ Less than 500 500-5 000 5 001-50 000 More than 50 000 Potential inhalation toxicity index (PITI) More than 300 300-30 29-3 Less than 3 Zone of acute action Less than 6.0 6.0-18.0 18.1-54.0 More than 54.0 Zone of chronic effect 10.0-5.0 4.9-2.5 Less than 2.5 1 class – extremely hazardous substances 2 class – highly hazardous substances 3 class – moderately hazardous substances 4 class – low-hazardous substances

Approaches to determination of hazard class for active substances, determination of toxicity (European approach) Class of hazard OEB Maximum allowable concentration in the air Maximum allowable concentration on surface Hazard Group Substance management practices OEB 1 ≥ 1000 µg/m³ ≥ 10 mg/100 cm² A General GMP/GLP requirements OEB 2 100 ÷ 1000 µg/m³ 1 ÷ 10 mg/100 cm² B GMP/GLP requirements, Local exhaust ventilation, exhaust hood OEB 3 10 ÷ 100 µg/m³ 0,1 ÷ 1 mg/100 cm² C Practically self-contained treatment, restrictive air flow, substance containers, safety type containers for HEPA filters OEB 4 1 ÷ 10 µg/m³ 10 ÷ 100 µg/100 cm² D Self-contained systems OEB 5 < 1 µg/m³ < 10 µg/100 cm² E Automated and robotized production, absence of manual operations and human interference OEL (Occupational Exposure Limit) is an exact value of maximum permissible content of a substance within the OEB (Occupational Exposure Band).

OEL calculation and its toxicology-related nuances Determination of basis (POD) for calculations (error may come up to two-three orders). Expert’s main task: from the big amount of studies, to determine the basic value to be used for calculations. (There is no explicit algorithm for the selection of basis, usually the lowest value is used with regard to the population used for the studies and duration of the studies) Main possible mistakes: Baseline study was selected from unreliable source Baseline study was selected relying only on one source (no quality analysis of literature data) Baseline study was determined without population/duration of study taken in account Baseline study was determined ignoring toxicity of studied effects UFL is a floating factor applied in case of unknown/known no-effect dose (1-10) Expert’s main task: to establish the un-/availability of no-effect dose using reliable sources of information. Use of unreliable sources of information Erroneous interpretation of no-effect dose based on the results of studies

OEL calculation and its toxicology-related nuances UFD – possible/impossible to determine the lowest PoD (1-10) Expert’s main task: based on the results of reliable (according to the specialist’s opinion) studies, to determine whether the lowest PoD has been identified in the course of studies. Main possible mistakes: Use of unreliable information sources Erroneous conclusion on the PoD identification/ non-identification MF – modifying factor (1-10) Expert’s main task: based on the knowledge about toxic effects and their influence on human body, to determine the factor to be used for calculation Toxic effects not taken in account Toxic effects applied repeatedly (if the effect has been used in one of the factors) Toxic effects have not been identified in the source Risk level of a certain toxic effect is misjudged. Conclusion: If calculation is performed by an insufficiently competent specialist, error may reach several orders (instead of second OEB class we may receive class four, and vice versa).

MACO calculation and its toxicology-related nuances Main ways of MACO calculation: From PDE From therapeutic dose From ppm Calculation of MACO from therapeutic dose: For some groups of drugs depending on their specificity, the therapeutic dose does not reflect the potential severity of consequences, for example: For oncology drugs, therapeutic doses are often set at high levels (400-2 000 mg) whereas their negative impact on the human body begins from several micrograms. For neuroleptics, therapeutic doses are often set at low levels (1 mg) whereas the severity of effects is significantly lower than for many other groups of medicinal products. Conclusion: Calculation objectivity directly depends on the group of medicinal products

MACO calculation and its toxicology-related nuances MACO calculation from ppm criterion: “Guidance On Aspects Of Cleaning Validation In Active Pharmaceutical Ingredient Plants” from Active Pharmaceutical Ingredients Committee (APIC) gives the following recommendations: ppm band to be applied is 5-500. For non-toxic products, 100 ppm is the recommended value. The selected ppm value should be supported by scientific evidence. The majority of companies still use the approach based on 10 ppm. MACO calculation from ppm raises concerns. Frequent contradictions appear between documents and even inside one document. For non-toxic or highly toxic products, accuracy is low since such an approach is averaged. Conclusion: Lack of uniformity, subjective approach, low accuracy.

MACO calculation and its toxicology-related nuances MACO calculation from PDE: Determination of basis (POD) for calculations (error may come up to two-three orders). Expert’s main task: from the big amount of studies, to determine the basic value to be used for calculations. (There is no explicit algorithm for the selection of basis, usually the lowest value is used with regard to the population used for the studies and duration of the studies). To determine, which specific dose (NOAEL, LOAEL, NOEL, LOEL) the selected basis may be attributed to. Main possible mistakes: Baseline study was selected from unreliable source Baseline study was selected relying only on one source (no quality analysis of literature data) Baseline study was determined without population/duration of study taken in account Baseline study was determined ignoring toxicity of studied effects Misinterpretation of the dose attribution for the basis (NOAEL, LOAEL, NOEL, LOEL)

MACO calculation and its toxicology-related nuances F4 is a factor to be used at toxicologist’s discretion (1-10) Expert’s main task: to set the factor value based on the knowledge of toxic effects and the level of their influence on human body. Main possible mistakes: Toxic effects not taken in account Toxic effects are unidentified in the source Risk level of a certain toxic effect is misjudged. F5 is a floating factor applied in case of unknown/known no-effect dose (1-10) Expert’s main task: to establish the un-/availability of no-effect dose using reliable sources of information. Use of unreliable sources of information Erroneous interpretation of no-effect dose based on the results of studies Conclusion: If calculation is performed by an insufficiently competent specialist, error may reach several orders. It will have direct impact on MACO, detection limit of the standard technique for residual amounts and routine cleaning control.

Main shortcomings of the existing training programs for toxicologists We have looked at currently running courses for toxicologists in Europe and Russia, some of them are listed below: http://www.eurotox.com/education/education-training-program/, http://www.key2compliance.com/cs5220.php), Medical University of Innovations and Development, Qualification Upgrade Program in Toxicology, Program of certification of qualified person for the topic of toxicology (toxicological chemistry). Conclusions: The majority of courses are not related to pharmaceutical industry. Total absence or superficial study of procedures of science-based assessment of medicinal products in the view of potential sharing of facilities for the production of several medicinal products. Total absence or minimum amount of study cases for their evaluation in the view of PDE and OEL calculation. Summary: Science-based assessment is performed by insufficiently competent specialist. Science-based assessment is performed by a highly-qualified toxicologist, but with no explicit procedures available for facilitating decision-making in some controversial situations. Decisions are taken based on the expert’s experience and opinion on the toxicity evaluation approaches.

‘TO SHARE OR NOT TO SHARE: THAT IS THE QUESTION!’ In the Russian Federation, as well as in the European Union, currently no requirements exist towards training, qualification, certification of toxicologists for pharmaceutical production, who then would be able to perform expert evaluation of challenging, borderline situations and make a competent decision about shared/dedicated facilities to be used for the production of medicinal products. In Europe, a work group is organized, the toxicologist’s CV, work experience and scientific publications are reviewed – based on that their competency is deemed sufficient or insufficient for the expert work to be performed. Subjectivity of expert evaluation and lack of information on pharmacological and toxicological characteristics, absence of clear uniform standards in the use of calculation method frequently prevent the manufacturer from taking the correct, flexible decision. The only correct decision is to exclude the possibility of combining the incompatible or hardly compatible medicinal products from the regulations: GMP and other normative documents governing production management and quality control. Regulatory norms should become explicit.

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