ICH Q3A(R2) GUIDELINE: IMPURITIES IN NEW DRUG SUBSTANCES

ICH Q3A(R2) GUIDELINE: IMPURITIES IN NEW DRUG SUBSTANCES

This article is a summary of ICH Q3A(R2) guideline.

What is this guideline about?

This guideline is about guidance for registration applications on the content and qualification of impurities in new drug substances produced by chemical syntheses.

What kind of drug substances this guideline does not cover?

This guideline does not cover new drug substances used during the clinical research stage of development, biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation product and semi-synthetic products derived therefrom, herbal products, and crude products of animal or plant origin.

CLASSIFICATION OF IMPURITIES

Impurities are classified as follows:

classification flowchart of impurities

What are the reasons or what is the need for reporting these impurities and to have a control over them?

·         Organic impurities:

As the API is manufactured, it has to pass through various stages of manufacturing like synthesis, purification, storage etc. so there is a huge possibility that impurity might arise through these stages. These impurities need to be presented supported by scientific data of the chemical reactions involved in the synthesis, impurities associated with raw materials that could contribute to the impurity profile of the new drug substance, and possible degradation products.

Also it is expected that summary that of laboratory studies conducted to detect impurities in the new drug substance should be presented. This summary should include test results of batches manufactured during the development process and batches from the proposed commercial process, as well as the results of stress testing used to identify potential impurities arising during storage. The impurity profile of the drug substance batches intended for marketing should be compared with those used in development, and any differences discussed.

What kind of impurities should be reported under organic impurities?

When any impurity is observed to be greater than (>) the identification threshold, then it should be reported.

Where can such condition be observed?

• üStudies conducted to characterize the structure of actual impurities present in the new drug substance.
• ü  Any batch manufactured by the proposed commercial process.
• ü  Any degradation product observed in stability studies at recommended storage conditions

What if identification of an impurity is still not feasible in spite of many trials and efforts?

In that case, a summary of the laboratory studies demonstrating the unsuccessful effort should be included in the application. Where attempts have been made to identify impurities present at levels of not more than (≤) the identification thresholds, it is useful also to report the results of these studies. Identification of impurities present at an apparent level of not more than (≤) the identification threshold is generally not considered necessary. However, analytical procedures should be developed for those potential impurities that are expected to be unusually potent, producing toxic or pharmacological effects at a level not more than (≤) the identification threshold.

·       Inorganic Impurities

Inorganic impurities are normally detected and quantified using pharmacopoeial or other appropriate procedures. Carry-over of catalysts to the new drug substance should be evaluated during development. The need for inclusion or exclusion of inorganic impurities in the new drug substance specification should be discussed. Acceptance criteria should be based on pharmacopoeial standards or known safety data.

·         Solvents

The control of residues of the solvents used in the manufacturing process for the new drug substance should be discussed and presented according to the ICH Q3C Guideline for Residual Solvents.

 ANALYTICAL PROCEDURES

As per this guideline, whatever analytical procedures or methods are being used for determining the impurities, they should be validated and be in line with ICHQ2A and Q2B guidelines.

How to report impurity content of batches?

• Quantitative results should be presented numerically and not in general terms like “complies”, “meets the limit”, “meets the requirement” etc.

• Any impurity at a level greater than (>) the reporting threshold and total impurities observed in the batches of the new drug substance should be reported with the analytical procedures indicated.

• If results are occurring below 1.0%, then such results should be reported to two decimal places (e.g., 0.06%, 0.13%);

• If results are observed above 1.0%, then such results should be reported to one decimal place (e.g., 1.3%).

• Results should be rounded using conventional rules. (E.g. 0.066 can be rounded off to 0.07; 0.124 can be rounded off to 0.12)

• Impurities should be designated by code number or by an appropriate descriptor, e.g., retention time.  If a higher reporting threshold is proposed, it should be fully justified. All impurities at a level greater than (>) the reporting threshold should be summed and reported as total impurities.
• Representative chromatograms from analytical validation studies showing separation and detectability of impurities (e.g., on spiked samples), along with any other impurity tests routinely performed should be provided.

LISTING OF IMPURITIES IN SPECIFICATIONS

Those individual impurities with specific acceptance criteria included in the specification for the new drug substance are referred to as "specified impurities". Specified impurities can be identified or unidentified.

specified impurities classification

A rationale for the inclusion or exclusion of impurities in the specification should be presented.

Specified identified impurities should be included along with specified unidentified impurities estimated to be present at a level greater than (>) the identification threshold

For unidentified impurities, the procedure used and assumptions made in establishing the level of the impurity should be clearly stated.

Specified, unidentified impurities should be referred to by an appropriate qualitative analytical descriptive label (e.g., “unidentified A", “unidentified with relative retention of 0.9”).

A general acceptance criterion of not more than (≤) the identification threshold for any unspecified impurity and an acceptance criterion for total impurities should be included.

While summarizing new drug substance specification, following list of impurities should be included:

• v Organic Impurities

§  Each specified identified impurity

§  Each specified unidentified impurity

§  Any unspecified impurity with an acceptance criterion of not more than (≤) the identification threshold

§  Total impurities

• v  Residual Solvents

• v  Inorganic Impurities

QUALIFICATION OF IMPURITIES

Qualification is the process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified. It is best explained in “Decision Tree for Identification and Qualification” mentioned in ICH Q3A(R2) guideline.