toxicology the quality aspects - משרד הבריאות€¦ · - ich m7 - assessment and control...
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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
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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
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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.
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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.
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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
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Literature review
In silico –
DEREK, Leadscope, MCASE…
Muller et al. Regulatory Toxicology and Pharmacology, 2006
N-Nitroso-
Aflatoxin
Azoxy-
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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:
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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
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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
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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).
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EMA - Q and A on Guideline on the limit of genotoxic impurities
EMA - GUIDELINE ON THE LIMITS OF GENOTOXIC IMPURITIES
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Genotoxicity
- Discussion regarding the potential genotoxic impurities - Indicate all the genotoxic / carcinogenic chemical substances
including: - Reagents - Intermediates - Side-products
Toxicology
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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)
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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…
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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
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Examples
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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: [email protected]
של חומרי רפואהולתקנים לביקורת המכון
של חומרי רפואהולתקנים לביקורת המכון