Mariah Ultramari, PhD mariah@spektraconsultoria.com Evaluation … · Mariah Ultramari, PhD...

May 2019

TOXICITY EVALUATION OF DEGRADATION PRODUCTSAn Industry Persperctive

Mariah Ultramari, PhDmariah@spektraconsultoria.com.br

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

9

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

mariah@spektraconsultoria.com.br

Rua Rido Roque 186 - São Paulo - SP, CEP 02474-000 - Brasil

26