Problem: You have an impurity that goes out of specification during a stability study
In the pharmaceutical industry, active substance or pharmaceutical product specifications are established according to criteria governed by old guidance (ICH Q3A(R2) and ICH Q3B(R2)) and do not reflect the state of the art of the development of toxicological expertise (ICH Q6 and ICH M7(R1)) in the industry.
You need to have information on the quantity of impurities detected in the current stability study "stability threshold".
Latest effective regulatory landscape governing the specifications limits
ICH Q3A (R2): Impurities in New Drug Substances – Step 5 CPMP/ICH/2737/99
This document provides guidance on the content and qualification of impurities in new drug substances for registration applications.
§ It applies to drug substances produced by chemical synthesis and not previously registered in a region or Member State.
§ It is not intended to apply to new drug substances used during the clinical research stage of development.
§ Types of drug substances not covered in the guideline: biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation product and semi-synthetic products derived therefrom, herbal products, and crude products of animal or plant origin
ICH Q3B (R2): Impurities in New Drug Products – Step 5 CPMP/ICH/2738/99
This document provides guidance on the content and qualification of impurities in new drug products for registration applications.
§ It applies to drug products produced from chemically synthesized new drug substances not previously registered in a region or Member State.
ICH Q6A: Specifications: Tests Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances – Step 5 CPMP/ICH/367/96
This guideline is intended to assist to the extent possible, in the establishment of a single set of global specifications for new drug substances and new drug products.
§ It provides guidance on the setting and justification of acceptance criteria and the selection of test procedures.
§ It applies to new drug substances of synthetic chemical origin, and new drug products produced from them, which have not been registered previously in the United States, the European Union, or Japan.
ICH Q6B: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products – Step 5 CPMP/ICH/365/96
This document proposes a uniform set of international specifications for biotechnological and biological products to support new marketing applications. The principles adopted and explained in this document apply to proteins and polypeptides, their derivatives, and products of which they are components.
ICH M7 (R1): Guideline on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risks – Step 5 EMA/CHMP/ICH/83812/2013
This guideline emphasizes considerations of both safety and quality risk management in establishing levels of mutagenic impurities that are expected to pose negligible carcinogenic risk.
It outlines recommendations for assessment and control of mutagenic impurities that reside or are reasonably expected to reside in the final drug substance or product, taking into consideration the intended conditions of human use.
A draft version of the Addendum of this guideline is also available: Guideline on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risks – Addendum – Step 2b EMA/CHMP/ICH/272147/2021
The ICH M7 document was physically separated into a main Guideline and a separate Addendum including the monographs. The revision adds 7 new monographs to the Addendum.
Additionally, various pharmacopoeias (US Pharmacopeia, European Pharmacopeia, Japanese Pharmacopeia or Chinese Pharmacopeia) are product focused and supersede all above guidelines.
And knowing the Maximum Daily Dose ("MDD") of the drug, compare the value of the stability threshold to the ICH Q3B limit.
- If % stability< % ICH Q3B limit → no evaluation
- If % stability >% ICH Q3B limit → toxicological evaluation
Specification is based on a general purpose limit - It does not take into account toxicity.
Toxicological evaluation and risk analysis
Determination of the toxicological profile of the impurity (CMR, acute toxicity, chronic toxicity, etc.) by studying bibliographic data or using in silico models (QSAR, Read-across): a NOAEL or LOAEL value will be chosen.
Calculation of the toxicological limit, Permitted Daily Exposure ("PDE")
Knowing the toxicological threshold (PDE) and the MDD, the new specification can be calculated as follows:
You can check Tox by Design methodology for Out of Specification reassessment, signed by an European Registered Toxicologist
In the event you are performing this exercise for innovative compounds GMP scale up manufacturing, please be noted Tox by Design is duly accredited for the French Research Tax Credit CIR.
Feel free to contact us using this email link to receive a quotation for Out of Specification reassessment, before or after Marketing Authorisation.