Description
The Food and Drug Administration (FDA or Agency) is announcing the availability of a final guidance for industry entitled “M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk” (M7(R2) Guidance) and two supplemental documents entitled “M7(R2) Addendum: Application of the Principles of the ICH M7 Guidance to Calculation of Compound-Specific Acceptable Intakes” (M7(R2) Addendum) and “M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk Questions and Answers” (M7(R2) Questions and Answers). The M7(R2) Guidance, M7(R2) Addendum, and M7(R2) Questions and Answers were prepared under the auspices of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The guidance and supplemental documents are intended to harmonize the considerations for assessment and control of DNA reactive (mutagenic) impurities.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
4Scope of the mutagenic impurities assessment; AI calculated for potential pharmaceutical impurities; General context of ICH guidelines for industry; benzyl chloride as an impurity in drugs; Hydrazine is used in the synthesis of these products; Derivation of an AI for inhaled pharmaceuticals; Application of limits in pharmaceutical products; Application of ICH M7 principles to pharmaceutical impurities.
formaldehyde as a drug product impurity
limit in active pharmaceutical ingredient (API) or drug product
Low, nontoxic concentrations of substances in drugs
Stakeholders
2elevated risk of head and neck cancers associated with acetaldehyde exposure in heavy drinkers
Entity responsible for submitting NDINs
Regulatory Context
Regulatory Activities
3ICH guidelines standardized safety reporting and marketing application submissions
regulatory process of deriving safety limits from carcinogenicity data
Applied to derive AIs instead of TTC-based values
Document Types
4Selected to calculate the AI for acrylonitrile; Source of toxicology and carcinogenesis studies
Source for TD50 values
source for TD50 values and carcinogenicity data
Lijinsky study of benzyl chloride
Attributes
10Dose selection criterion for carcinogenicity studies; criteria for adequacy of the rat study; Virtually Safe Dose Based on the Maximum Tolerated Dose.; Based on the Maximum Tolerated Dose for Rodent Bioassays.
Quick Estimate of the Regulatory Virtually Safe Dose.
500 milliliters (mL) for adult males and 400 mL for adult females
The positive dose response was not statistically significant.
No-observed adverse effect level for histological changes
Classification as possibly carcinogenic to humans
WHO defined a TDI for styrene of 7.7 µg/kg/day.
EPA classification for not classifiable as to human carcinogenicity
IARC classification for inadequate evidence of carcinogenicity
IARC classification for glycidol as probably carcinogenic
Technical Details
Substances
10CAS# 75-07-0; Formed endogenously in the human body from metabolism of ethanol; Acetaldehyde is a strong electrophile and is capable of reacting with strong nucleophiles; Pathobiological Effects of Acetaldehyde in Cultured Human Epithelial Cells; Metabolite of vinyl acetate responsible for genotoxicity; oral PDE recommended is based on that derived for acetaldehyde
actuator with formaldehyde as an impurity
Carcinogenicity and Chronic Toxicity of para-Chloronitrobenzene in Rats and Mice.
Breakdown product of vinyl acetate
Main metabolite of styrene, clearly mutagenic; Styrene-7,8-oxide is a metabolite of styrene classified as probably carcinogenic.
Isozyme responsible for methyl chloride metabolism in mouse kidney
Reactive species generated from hydrogen peroxide in the presence of metals
Enzyme that reduces hydrogen peroxide to water and oxygen
administered to mice for 25 weeks in a multidose gavage study
used in the treatment of tuberculosis and sickle cell anemia
Testing Methods
10Ames test used as main criterion for determining mutagenicity; Ames test used to evaluate DMS mutagenicity; Ames test used for mutagenicity testing
Study in Rats and Mice Exposed to Methyl Chloride.
Plotting the results and using the slope to represent beta results in the following graphs.
Quick Estimate of the Regulatory Virtually Safe Dose Based on the Maximum Tolerated Dose for Rodent Bioassays.
IARC concluded there is strong evidence that styrene is genotoxic.
In vitro mammalian gene mutation study
Evaluation of hydrogen peroxide safety
Limit is a linearized multistage extrapolation based on hepatomas
standard long-term carcinogenicity study
In vivo test for glycidol
Processes
9Context where mutagenic chemicals are common
Industrial use of vinyl acetate
method of administration in carcinogenicity bioassays; Method of administration in hamster studies; Studies conducted via oral gavage to assess carcinogenic potency.
Formaldehyde essential for amino acid production
route used in Van Duuren study for DMCC
route of exposure in carcinogenicity studies; route of exposure for DMCC and DMS; exposure route for hydrazine carcinogenicity studies; Separate AI for inhalation exposure was appropriate; Route of administration in 2-year bioassay; Styrene is reported to be carcinogenic in mice via the inhalation route.
Method of oral administration in carcinogenicity studies; oral administration method in Lijinsky study; method of administration in NTP studies for p-chloroaniline; administration in the feed to rats and mice or by gavage; Route of administration in short-term carcinogenicity models; oral route of administration for carcinogenicity studies; Oral gavage study of Wester et al.; Method of administration in carcinogenicity study; Method of administration in NTP studies; Hydrazine sulfate was adminis
An oral carcinogenicity study was conducted in Sprague Dawley rats
In rodents, only inhalation carcinogenicity studies are available
Clinical Concepts
10Human relevance of tumors
Hydrazine calculations were based on female rats
Hydrazine calculations were based on the most sensitive tumor type
P is the proportion of animals with the specified tumor type observed at a certain dose.
calculations were based on the most sensitive tumor type: female rat pheochromocytoma
Observed in Sprague-Dawley rats following inhalation
Styrene-7,8-oxide increased squamous cell tumors in the forestomach.
Oral exposure to styrene increased incidence of these tumors in mice.
Observed in male mice at high exposure levels
Statistically significant increases in tumors of the duodenum observed in mice; Tumors observed in mouse drinking water studies
Identified Hazards
Hazards
9The primary safety concern addressed by AI and PDE calculations
Hydrogen peroxide is mutagenic and genotoxic in vitro
Limited the exposure concentration in NTP studies
Epichlorohydrin is probably carcinogenic to humans
Increases in micronucleated cells that do not indicate hazards
risk assessment for pharmaceuticals affecting the immune system
nonlinear dose response associated with the genotoxicity and carcinogenicity of acetaldehyde; Historical perception of aniline; Potential for a mutagenic mode of action
nasal tumors in inhalation carcinogenicity studies were only found at inhalation doses also associated with cytotoxicity
Endpoint used to calculate TD50
Standards & References
External Standards
4OECD 453 Guideline for the Testing of Chemicals: Combined Chronic Toxicity/Carcinogenicity Studies
TD50 reported in Carcinogenic Potency Database
Standard followed for carcinogenicity study
Guidelines for genotoxicity assays
Specifications
6Derived for mutagenic impurities with positive carcinogenicity data
concentration limit of formaldehyde in air
A limit of 60 ppm styrene into foods is permissible in the EU.
Upper limit for acceptable intakes
Calculated using uncertainty factors for threshold-based compounds
Default basis for acceptable intakes when specific data is lacking
ICH References (5)
Application of the Principles of the ICH M7 Guidance to Calculation of Compound-Specific Acceptable Intakes; Application of the principles of the ICH M7 guideline to calculation of compound-specific acceptable intakes; principles applied to calculation of compound-specific AIs; application of principles to calculation of compound-specific acceptable intakes; Application of the principles of the ICH M7 guideline to calculation of compound-specific acceptable intakes.
Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk; Application of the principles of the ICH M7 guideline to calculation of compound-specific acceptable intakes; ICH guidance for industry M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities; Document title and version; Document title and addendum reference; Guidance for assessment and control of DNA reactive impurities.; Assessment and Control of DNA Reactive Impu
Impurities: Guidance for Residual Solvents; Guidance for Industry Q3C(R8) Impurities: Guidance for Residual Solvents used to calculate PDE; ICH guidance for industry Q3C(R8) Impurities: Guidance for Residual Solvents; Used to define the process for deriving the PDE for aniline.; Guidance for Residual Solvents used for breathing volume assumptions; Used for human breathing volume assumptions (28,800 liters/day).; Guidance for Residual Solvents used for calculations
Elemental Impurities; PDE methodology is further explained in ICH Q3D(R2)
Dose Selection for Carcinogenicity Studies of Pharmaceuticals
Related CFR Sections (1)
- 21CFR182.60§ 182.60 Synthetic flavoring substances and adjuvants.
Synthetic flavoring substances and adjuvants that are generally recognized as safe for their intended use, within the meaning of section 409 of the Act, are as follows:Read full regulation →
See Also (8)
- Guidance for Industry: Preparation of Premarket Submissions for Food Contact Substances (Chemistry Recommendations) (Status: Final)
- Guidance for Industry: Preparation of Food Contact Substance Notifications (Toxicology Recommendations) (Status: Final)
- CPG Sec 562.550 Safety and Labeling of Waxed (Coated) Fruits and Vegetables (Status: Final)
- CPG Sec 500.200 Food Additives -"GRAS" (Status: Final)
- Guidance for Industry: Estimating Dietary Intake of Substances in Food (Status: Final)
- Guidance for Industry: Recommendations for Submission of Chemical and Technological Data for Direct Food Additive Petitions (Status: Final)
- Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting: Guidance for Industry (Status: Final)
- Guidance for Industry: Assessing the Effects of Significant Manufacturing Process Changes, Including Emerging Technologies, on the Safety and Regulatory Status of Food Ingredients and Food Contact Substances, Including Food Ingredients that Are Color Additives (Status: Final)