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May 2019
TOXICITY EVALUATION OF DEGRADATION PRODUCTSAn Industry Persperctive
Mariah Ultramari, [email protected]
Founded by Mariah Ultramari with the objective of
collaborating actively with the world's knowledge of
impurities in medicines in Brazil and Latin America.
PhD in toxicology, Mariah dedicated her last 10 years
studying degradation products in pharmaceuticals,
contributing actively to the evolution of knowledge in the
analytical and toxicological area ensuring quality and
safety of the products to the patients.
Spektra
AGENDA
❖ Background
❖ Product Development Workflow
❖ Zeneth ©
❖ Derek and Sarah Nexus©
❖ Qualification studies workflow
❖ Impurity qualification report
❖ Cases
2017RDC n.171
BACKGROUND
2008IT n.1 Degradation Product
2012CP n.11
2013RDC n.58
2015RDC n.53Guideline n.4
2015ICH M7
4
2016ANVISA
member of ICH2019Q&A
1999ANVISA’s creation
2017RDC 200 Compatibility Studies
2006ICH Q3B (R2)
(1996)
2018GESEF
2014RDC 60 Compatibility Studies
2005RE n.1 Stability Guideline
Legislation Timeline
BACKGROUND
5
Degradation Product Brazilian Legislation
❖ RDC nº 53, december 2015
❖ Guideline nº 04, december 2015
❖ ICH M7 (R1), march 2017
❖ Q&A, march 2019
BACKGROUND
6
World X Brazil
2006ICH Q3B (R1)
1996ICH Q3B
1995ICH Q3A
2002ICH Q3A (R1)
2003ICH Q3B (R1)
2006ICH Q3A (R2)
2014ICH M7
2019ICH M7 (R1) - revision
2017ICH M7(R1)
2015RDC 53
2015Guideline n.4
✓ ICH M7(R1)
✓ ICHQ3B (R2)
✓ ICHQ3A (R2)
PRODUCT DEVELOPMENT WORKFLOW
7
1 2 3 4 5 6
Kick-off
Pre-Formulation Studies
Compatibility
Formulation & Method
Development
Stability IndicatingMethod
Stability Study
IdentificationQualification
Adapted from Antonio Anax Presentation sep 2018
ZENETH
8
API
Drug Product
➢ Degradation Assessment
➢ Degradation Product Identification
➢ ICH M7 support
➢ Compatibility Studies
➢ Degradation Assessment
➢ Degradation Product Identification
➢ ICH M7 support
RDC 53/2015
DEREK and SARAH NEXUS
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API
Drug Product
➢ ICH M7
➢ General toxicity evaluation
➢ ICH M7
➢ General toxicity evaluation
✓ RDC 53/2015✓ ICH M7✓ ICH Q3A and B
IMPURITY QUALIFICATION WORKFLOW
1RDC 53/2015 – Art. 10°
I. Degradation products that are significant metabolites present in animal and/or
human studies are generally considered qualified;
II. An observed amount and the limit of acceptance of a degradation product are
properly justified in the scientific literature or official compendia; or
III. An observed amount and the limit of acceptance of a degradation product do not
exceed the limit observed in toxicological studies.
IMPURITY QUALIFICATION WORKFLOW
Adapted from Antonio Anax Presentation at Sindusfarma, 2018
2 SCREENING MUTAGENICITY
GENERAL TOXICITY
ICH M7
Expert rule-basedStatistical-based
QSAR Models
Acute toxicity 14 days
Chronic toxicity 28-90 days
Scientific Literature
In silico prediction
GENOTOX POTENCIAL
Ames Test
IN SILICO PREDICTION
❖ Mutagenicity – ICH M7
EXPERT SYSTEM STATISTICAL MODEL
Human written rulesMachine learning
techniques
Qualitative Prediction Quantitative Prediction
Expert comments Calculated probability
Manual Data Analysis Automated Data Analysis
(Barber et al., 2017)
ICH M7
Adapted from Antonio Anax Presentation at Sindusfarma, 2018
GENOTOX EVALUATION
❖ Mutagenicity – ICH M7: Ames Test
Adapted from Antonio Anax Presentation at Sindusfarma, 2018
GENERAL TOXICITY
EXPERT SYSTEM
PARAMETERS
Species
Bacteria
Dog
Primate
Rabit
Rodents
Endpoints
Carcinogenicity
Genotoxicity
Irritation
Neurotoxicity
Organ toxicity
Reproductive toxicity
Respiratory Sensitization
Skin Sensitization
DRUG PD
HERG channel inhibition in vitro
Adapted from Antonio Anax Presentation at Sindusfarma, 2018
GENERAL TOXICITY
Scientific Literature
➢ Books➢ Papers➢ Structure similarity➢ ADME
GENERAL TOXICITY
GENERAL TOXICITY
GENERAL TOXICITY
Acute toxicity 14 days
Chronic toxicity 28-90 days Control Group
Graduated Doses
14 days
28 days
90 days
Toxicity Assessment
OECD 407, 408
Adapted from Antonio Anax Presentation at Sindusfarma, 2018
IMPURITY QUALIFICATION REPORT
✓ Release and Stability specifications – same as GRMED orGEPRE;
✓ Impurities/degradation products description and limits;✓ Qualification studies sumarized description and justifications;✓ Qualification studies reports✓ Papers✓ Raw data and software validation certificate✓ Technical opinion of other health authorities with detailed
description of impurities, qualification limits and approval
GESEF
CASES
COMPATIBILITY STUDY
Experiment Design 1
Formulation:✓ API
✓Diluent
✓Pigments
✓Antioxidant
✓ Lubricant
API15 days
COMPATIBILITY STUDY
✓Hydrolysis H+/OH-
✓Oxidation
✓Heat
✓Light
COMPATIBILITY STUDY
Reference sample
✓NaOH 1M/60°C/10days 12%
✓HCl 1M/RT/10days 10%
✓Oxidation 3%H2O2/24h 10%
✓Heat 60°C/10days 7%
✓ Light 1 cycle 7%
COMPATIBILITY STUDY
Experiment Design 1
Formulation:✓ API
✓Diluent
✓Pigments
✓Antioxidant
✓ Lubricant
15 days
100% API
EUREKA!
ICH M7 + EXPERT REVIEW
ICH M7 + EXPERT REVIEW
✓ Reference
✓ Literature
Ames Test
QUESTIONS
25
Obrigada!
►
Mariah Ultramari, PhD
Soluções Científico-Regulatórias
+55 11 9952-30937
Rua Rido Roque 186 - São Paulo - SP, CEP 02474-000 - Brasil
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