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Residual solvent in pharmaceuticals is defined here as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products.

LIMIT OF RESIDUAL SOLVENTS IN DRUG PRODUCT

1.0   Purpose:

• • The purpose of this Standard Operating Procedure (SOP) is to describe the limit of residual solvent. 

2.0   Scope:

• • This SOP is applicable to the limit of residual solvent in case of raw materials at the Quality Control Department.

3.0   References and Annexures – Limit of Residual Solvent:

• • References:

• • IP: Indian pharmacopoeia

• • BP: British pharmacopoeia

• • USP: United States pharmacopoeia

• • ICH Q3C(R5) :Impurities: Guideline for Residual Solvents

• • IH: In house

• • Annexures:

• • IP – Limit of Residual Solvent (Annexure-1)

• • USP – Limit of Residual Solvent (Annexure-2)

• • BP – Limit of Residual Solvent (Annexure-3)

• • ICH – Limit of Residual Solvent (Annexure-4)

4.0   Responsibilities – Limit of Residual Solvent:

• • Analyst :

• • To check the manufacturer COA with SOP Annexures.

• • Inform about the abnormalities to section head or designee.

• • To make entry of residual solvent result in the Analytical template.

• • Quality Control Head or Designee :

• • Ensure practice is being followed as per SOP.

• • To provide training to all concerns.

• • Quality Assurance :

• • Check the SOP.

• • To ensure the implementation of the system as per SOP.

• • Quality head, Regulatory Affairs, and Plant Head or designee :

• • To review and approve the SOP.

5.0   Abbreviations and Definition and of terms used in Limit of Residual Solvent:

• • Abbreviations:

• • STP: Standard Testing Procedure.

• • B.No.:Batch Number.

• • PDE: Permitted Daily Exposure

• • COA: Certificate Of Analysis

• • GIM: Goods Inward Memo

• • Definition and of terms :

• • Residual solvents:-Residual solvents in pharmaceuticals are defined here as organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products.

6.0   Procedure – Limit of Residual Solvent:

• • After receiving of raw material GIM along with COA, QC Officer shall check the grade of material(IP, BP, USP, or Inhouse) as per manufacturer’s COA.

• • QC Officer shall review the residual solvent limit and result for the pharmacopeia limit with respective Annexures and from manufacturers COA.

• • For in house material ICH residual solvent limit shall be considered for reference.

• • If the residual solvents result of the manufacturer is higher side than the respective Annexures limit then reject the material.

• • If results are within the respective Annexures limit then release the batch.

• • Classification of Residual Solvents by Risk Assessment:

• • Residual solvents are evaluated for their possible risk to human health and classified three classes as follows as per ICH Guideline:

• • Class 1 solvents:

• • Solvents to be avoided known human carcinogens, strongly suspected human carcinogens, and environmental hazards.

• • Class 2 solvents:

• • Solvents to be limited for Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity.

• • Solvents suspected of other significant but reversible toxicities.

• • Class 3 solvents:

• • Solvents with low toxic potential to man; no health-based exposure limit is needed.

• • Class 3 solvents have PDEs of 50 mg or more per day.

Annexure 1 – Limit of Residual Solvent as per IP

• Class -1: Residual Solvents –

• Class -2: Residual Solvents –

• Class -3: Residual Solvents –

  • These solvents are less toxic and of lower risk to human health.

• • Nevertheless, they need to be limited by good manufacturing practices or other quality-based requirements,

• • The concentration limits of 5000ppm would be acceptable for the solvents in the below table.

Annexure 2 – Limit of Residual Solvent as per USP

• Class -1: Residual Solvents –

• Class -2: Residual Solvents –

• Class -3: Residual Solvents –

  • These residual solvents are less toxic and of lower risk to human health.

• • Nevertheless, they need to be limited by good manufacturing practices or other quality-based requirements,

• • The concentration limits of 5000ppm would be acceptable for the solvents in below table-3

• • The residual solvent listed below table may also be of interest to manufacturers of drug substances, Excipients, or drug products.

• • However, no adequate toxicological data on which to base a PDE was found and mention as follows.

Annexure 3 – Limit of Residual Solvent as per BP

• Class -1: Residual Solvents –

• Class -2: Residual Solvents –

• Class -3: Residual Solvents –

  • These solvents are less toxic and of lower risk to human health.

• • Nevertheless, they need to be limited by good manufacturing practices or other quality-based requirements,

• • The concentration limits of 5000ppm would be acceptable for the solvents in the below table.

• • The residual solvent listed in the below table may also be of interest to manufacturers of drug substances, Excipients, or drug products.

• • However, no adequate toxicological data on which to base a PDE was found.

Annexure 4 – Limit of Residual Solvent as per ICH

• Class -1: Residual Solvents –

• Class -2: Residual Solvents –

• Class -3: Residual Solvents –

  • These solvents are less toxic and of lower risk to human health.

• • Nevertheless, they need to be limited by good manufacturing practices or other quality-based requirements.

• • The concentration limits of 5000ppm would be acceptable for the solvents in the below table.

• • The residual solvent listed in table-4 may also be of interest to manufacturers of drug substances, Excipients, or drug products.
  • However, no adequate toxicological data on which to base a PDE was found.

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