API – Impurity Profile Generation

  • Published on: Oct 27, 2017

I.INTRODUCTION

This SOP addresses those impurities in drug substances classified as degradation products of the active ingredient, impurities present in the drug substance as part of the manufacturing/storage process or reaction of the drug substance with an immediate container/closure system.

II.DEFINITIONS

A. Foreign substances: Materials introduced by contamination or cross contamination and are not consequences of the preparation of the drug substance.

B. Residual Solvents: Organic volatile chemicals that are used or produced in the manufacturing process. The solvents are not completely removed by practical manufacturing methods. Drug products should contain no higher a level of residual solvents than can be supported by safety data. For a classification of residual solvents, refer to the current USP <467>.

C. Toxic Impurities: Impurities that have significant undesirable activity. These require individual identification and quantitation by specific tests.

D. Concomitant Components: These are characteristic of many drug substances. Examples may include, but are not limited to, geometric and optical isomers or racemates.

E. Signal Impurities: Impurities that require individual identification and quantitation by specific tests. Signal impurities may include some process related impurities or degradation products that provide key information about the process.

F. Ordinary Impurities: Impurities that are innocuous by virtue of having no significant, undesirable activity in the amounts present. These impurities may arise out of the synthesis, preparation or degradation of the drug substance. For further information, refer to the current USP <466>.

G. Related Substances: These impurities may be identified or unidentified degradation products or impurities arising from the manufacturing process.

H. Degradation Study: A means of degrading a drug substance via several routes, usually involving acids, temperature, light, etc., in order to evaluate the routes and base of impurities. This information is used to generate the impurity profile of the product.

III.PROCEDURE

A. A protocol will be developed outlining the process for compiling an impurity profile for the drug substance. Included in the protocol will be the following information, at a minimum:

  • a. Process description
  • b. Drug Substance name
  • c. Finished substance or compendia specifications
  • d. Methodology for testing
  • e. Process for degradation
  • f. Any limits for identification

B. Once an impurity has been detected, it becomes necessary to estimate its content. Detectability equates to a given component providing a signal at least twice that of the background noise or baseline. If the estimations indicate that a given impurity content is greater than 0.1%, then the impurity must be characterized.

C. Stability testing program of raw materials will be based upon the impurity profile. Exposure of the drug substance to likely storage conditions and stressed storage conditions to identify any material susceptibilities that may impact product quality should be conducted.

D. Degradation products that appear should be identified, isolated and assessed for interactive effects and/or toxicity.

E. Degradation material should be evaluated with developed assays – typically HPLC or TLC.

F. Degradation can be carried out via any one or combination of the following processes:

  • a. Oxidation
  • b. Hydrolysis
  • c. Racemization
  • d. Photo-chemical reactions
  • e. Denaturation
  • f. Temperature
  • g. Humidity

Note: Rationale as to the selection of these degradation mechanisms should be documented in the protocol.

G. The analysis will be carried out via the applicable analytical methodology.

H. The limits for impurities must be established based upon the scientific judgments of the manufacturer, compendia requirements and any applicable regulatory requirements.

I. Establishing limits may be based upon the following:

    • a. The toxicology of the drug substance containing typical levels of impurities
    • b. The toxicology of the impurities relative to the drug substance
    • c. The route of administration
    • d. The daily dose of the drug substance
    • e. The target population
    • f.  The pharmacology of an impurity, if appropriate
    • g. The source of the drug substance
    • h. Duration of administration
    • i.  Capability of removal

Leave a Reply

Your email address will not be published. Required fields are marked *