toxicology the quality aspects - משרד הבריאות€¦ · - ich m7 - assessment and control...

Toxicology – The quality aspects

Ayelet Cohen-Yeshurun, B.Pharm, Ph.D Pharmaceutical Regulation – Quality Assessor

The Institute for Standardization and Control of Pharmaceuticals

של חומרי רפואהולתקנים לביקורת המכון

13.2.2018

• Background

• Genotoxicity and carcinogenicity

• Overall toxicology

• Submissions

• Examples

Content

של חומרי רפואהולתקנים לביקורת המכון

של חומרי רפואהולתקנים לביקורת המכון

Background

Tox studies

Variations in DS:

- Synthesis

- Specifications of impurities

Variation In DP:

- Formulation

- Composition

-manufacturing process

-spec of degradation products/ impurities

Out of spec

“Clinical variations”:

- New indications

- Change in dosing regimen

New submissions

של חומרי רפואהולתקנים לביקורת המכון

Background

When do we need tox studies in DS?

- The DS has a specific monograph (USP, EP, JP, BP) and the levels of impurities exceed the specific monograph limits (release and shelf life).

- Levels of impurities exceed the ICH Q3A qualification thresholds.

- The impurity is not a major metabolite of the DS in human. - In case of genotoxic impurities: the levels of impurities exceed the ICH

Q3A Identification threshold.

של חומרי רפואהולתקנים לביקורת המכון

Background

₋ Level of impurity/ degradation product exceed the ICH Q3B qualification thresholds or the EMA Guideline on setting specifications for related impurities in antibiotics .

- For genotoxic impurities: The level of the impurity exceeds the ICH Q3B Identification threshold.

של חומרי רפואהולתקנים לביקורת המכון

Background -

When do we need tox studies in DP?

- The impurity/ degradation product is not a major metabolite of the DS.

- The levels of the impurity/ degradation product exceed those of the innovator DP.

Qualification threshold

Identification threshold

Reporting threshold

0.2% 0.1% Semi-synthesis

0.2% 0.15% Fermentation (single)

0.5%/ 0.2% 0.2% 0.15% Fermentation (family)

- The DP has a specific monograph (USP, JP, BP) and the levels of impurity/ degradation product exceed the specific monograph limits (release and SL).

Genotoxicity

של חומרי רפואהולתקנים לביקורת המכון

Literature review

In silico –

DEREK, Leadscope, MCASE…

Muller et al. Regulatory Toxicology and Pharmacology, 2006

N-Nitroso-

Aflatoxin

Azoxy-

של חומרי רפואהולתקנים לביקורת המכון

Genotoxicity

What should be included?

Impurities included in the ICH

M7 appendix

R – NH – N O

ICH S2(R1)

- Bacterial reverse mutation assay - Ames test - Appropriate

- Chromosomal aberration – 30% false positive

- Mouse lymphoma assay (MLA)

- S9 Mix / Rat liver cells

In vitro/ In vivo:

של חומרי רפואהולתקנים לביקורת המכון

Genotoxicity

TTC – Threshold of Toxicological Concern

How do we set a limit?

Genotoxic compound with

sufficient evidence for a

threshold-related mechanism

- Interaction with mitotic spindle

- Topoisomerase inhibition

- Inhibition of DNA synthesis

- Metabolic overload

- Physiological disturbances

PDE – Permitted Daily Exposure

Genotoxic compound without

sufficient evidence for a

threshold-related mechanism

Especially DNA-reactive

chemicals

Concentration limit

של חומרי רפואהולתקנים לביקורת המכון

Genotoxicity

PDE – Permitted Daily Exposure

PDE = 𝑁𝑂𝐸𝐿 𝑥 𝐵𝑜𝑑𝑦 𝑤𝑒𝑖𝑔ℎ𝑡

𝐹1 𝑥 𝐹2 𝑥 𝐹3 𝑥 𝐹4 𝑥 𝐹5

F1 – a factor to account for extrapolation between species

F2 – A factor to account for variability between individuals = 10

F3 – A variable factor to account for toxicity studies of short-term exposure

F4 – May be applied in cases of severe toxicity (non-genotoxic

carcinogenicity, neurotoxicity, teratogenicity…)

F5 – A factor that may be applied in cases where no NOEL was not

established. When LOAEL is available a factor of up to 10 could be used

depending on the severity of the toxicity.

NOEL – No Observed Effect Level

של חומרי רפואהולתקנים לביקורת המכון

Genotoxicity

ICH Q3C -IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS

TTC – Threshold of Toxicological Concern

How do we set a limit?

Genotoxic compound with

sufficient evidence for a

threshold-related mechanism

- Interaction with mitotic spindle

- Topoisomerase inhibition

- Inhibition of DNA synthesis

- Metabolic overload

- Physiological disturbances

PDE – Permitted Daily Exposure

Genotoxic compound without

sufficient evidence for a

threshold-related mechanism

Especially DNA-reactive

chemicals

Concentration limit

של חומרי רפואהולתקנים לביקורת המכון

Genotoxicity

TTC – Threshold of Toxicological Concern

TTC = 1.5μg/day

Concentration limit (ppm) = 𝑇𝑇𝐶 𝜇𝑔/𝑑𝑎𝑦

𝑑𝑜𝑠𝑒 𝑔/𝑑𝑎𝑦

N - Nitroso

Aflatoxin

Azoxy

של חומרי רפואהולתקנים לביקורת המכון

Genotoxicity

TTC = 0.15μg/day

EMA – GUIDELINE ON THE LIMITS OF GENOTOXIC IMPURITIES

R – NH – N O

When can we exceed the TTC?

- Shorter duration of exposure

- Genotoxicity of the DS

- Reduced life expectancy (<5yrs)

- Treatment of life-threatening condition

- The impurity is a substance to which humans are exposed to at higher levels

- Genotoxic metabolites

Single genotoxic impurity

>3 genotoxic impurities

של חומרי רפואהולתקנים לביקורת המכון

Genotoxicity

Genotoxicity

When would these impurities be omitted from DS specifications?

1. In case of a potential impurity, not found in practice in the

synthesis/manufacture of DS.

2. The impurity is formed in a step before the final synthesis step and:

i. It is controlled in the intermediate

ii. It was demonstrated in spiking experiments that the presence of

the impurity does not exceed 30% of concentration limit.

3. The impurity is formed in the final synthesis step but does not exceed

30% of concentration limit – skip test may be permitted (supported by

data from 3 commercial batches).

של חומרי רפואהולתקנים לביקורת המכון

EMA - Q and A on Guideline on the limit of genotoxic impurities

EMA - GUIDELINE ON THE LIMITS OF GENOTOXIC IMPURITIES

של חומרי רפואהולתקנים לביקורת המכון

Genotoxicity

- Discussion regarding the potential genotoxic impurities - Indicate all the genotoxic / carcinogenic chemical substances

including: - Reagents - Intermediates - Side-products

Toxicology

של חומרי רפואהולתקנים לביקורת המכון

Literature review:

- Toxicokinetics and Pharmacokinetics

- Toxicity - acute and chronic toxicity

- Reproductive toxicology – fertility, teratogenicity and

development of neonates

- Safety Pharmacology

- Immunotoxicology (if relevant)

- Pediatric safety (if relevant)

של חומרי רפואהולתקנים לביקורת המכון

Toxicology

what do we expect?

If not – pre-clinical studies

Available databases

literature

FDA

EFSA

ATSDR

DrugBank

HMDB

EPA

IARC

WHO

CDC

NIOSH

OSHA

TGA

OECD

ToxNet

של חומרי רפואהולתקנים לביקורת המכון

Toxicology

- Literature: - genotoxicity (PDE/TTC calculation) - overall toxicology - In silico - in vitro / in vivo - Pre-clinical studies - Clinical studies - Justifications:

- Special indications - Metabolite (supported by appropriate experiments) - Other ways of exposure - Etc…

של חומרי רפואהולתקנים לביקורת המכון

Toxicology - Summary

Toxicology

Innovative: Generic:

- Development

- Literature review

- Pre-clinical studies

- Clinical studies

- Development

- Literature review

- Only genotoxicity studies submitted without full toxicology review

- New impurity due to a development of a new analytical method: qualified by use

- TTC = 1.5μg/dose - Insufficient literature review – well known

databases not included - Papers not supporting the impurity as a metabolite

e.g developing a new method for identification and quantification of the impurity

- The impurity is not more toxic than the DS

של חומרי רפואהולתקנים לביקורת המכון

Examples

של חומרי רפואהולתקנים לביקורת המכון

References

- ICH M7 - ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC)

IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIAL CARCINOGENIC RISK

- ICH S2(R1) – Guidance on Genotoxicity Testing and Data Interpretation

for Pharmaceuticals Intended for Human Use.

- EMA – Guideline on the Limits of Genotoxic Impurities

- EMA - Questions and Answers on the 'Guideline on the Limits of

Genotoxic Impurities'

- FDA - Guidance for Industry: Genotoxic and Carcinogenic Impurities in

Drug Substances and Products: Recommended Approaches

- ICH - Safety Guidelines

- ICH Q3A – Impurities in New Drug Substances

- ICH Q3B – Impurities in New Drug Products

- ICH Q3C - IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS

Ayelet Cohen-Yeshurun B. Pharm, Ph.D Pharmaceutical Regulation – Quality Assessor The Institute for Standardization and Control of Pharmaceuticals Ministry of Health Jerusalem, Israel. Tel: 972-2-6551773 Fax: 972-2-6551767 email: ayelet.yeshurun@moh.gov.il

של חומרי רפואהולתקנים לביקורת המכון

של חומרי רפואהולתקנים לביקורת המכון