RESIDUAL SOLVENTS

By Sarvesh Bane
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What is Residual Solvent

Residual solvents in

pharmaceutical are defined as organic volatile chemicals that are used or produced in the manufacture of drug substances or Excipients, or in the preparation of drug products.
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Why Residual Solvent needed

To make Safety of the patient ;

recommends use of less toxic solvents. Testing is to be performed only for solvents likely to be present. Used or produced in the final manufacturing step. Used in previous step and not removed by validated procedure.
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Residual Solvent Classes

As per <467> Their are three classes of Residual solvent based on the toxicity: Class 1 Solvent Solvents to be avoided because it is carcinogens and environmental hazrds.

Residual Solvent Classes

Class 2 Solvents Less toxic, Should be Limited in all drugs. Nongenotoxic animal carcinogens or possible causative agents of other irrversible toxicity, such as neurotoxicity or teratogenicity. Solvent suspected of other significant but reversible toxicity.
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Residual Solvent Classes

Class 3 Solvents with Low toxic potential Solvent with low toxic potential to humans; no health based exposure limit is needed.

Residual Solvent Classes

Other Residual Solvents The residual solvents listed in

Table 4 may also be of interest manufactures of drug substances, excipients, or drug products, However, no adequate toxicology data on which to base a PDE was found.
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New Solvent
New Solvent approved by

competent regulatory agency Manufacturer should notify USP of the identify, the approved limit, the test procedure. USP will address the topic in the individual monograph
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New Solvent
New solvent approved through the

ICH process Solvent will be added to the appropriate list in General Chapter <467>

RS Limits for DP/DS/Excipients

Determining Drug Substance, Drug Product and Excipients Compliance with RS Limits: Option 1: (concentration limits, ppm) for Class 1, 2, & 3 RS Usually applied to Drug Substance ,Drug Product and Excipients.
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RS Limits for DP/DS/Excipients

If Drug Substance ,Drug Product and Excipients meet the RS limits listed in Tables (valid for dose up to 10 grams per day product mass), then Drug Substance ,Drug Product and Excipients meets the test criteria*. Option 1 limits can also be applied to finished Drug Product. *Note: Use of Class 1 solvents must always be justified, even if limits are met .

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RS Limits for DP/DS/Excipients

It is not necessary for each

component of the Drug Substance, Drug Product and Excipients to comply with the limits given under option 1, Hence option 2 is applied.

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RS Limits for DP/DS/Excipients

Option 2: (Permitted Daily Exposure/PDE) for Class 2 & 3 RS: Used when Drug Substance, Drug Product and Excipients exceed Option 1 RS limits, or Drug Product daily dose exceeds 10 g.

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RS Limits for DP/DS/Excipients

A

Daily Exposure is calculated, based on cumulative RS content of all components; If Daily Exposure NMT PDE, then Drug Product meets Option 2. Option 2 cannot be applied to Class 1 RS (no PDE is established).
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Class 1 Solvent General Requirements

Class 1 Solvent ( To be Avoided): All Class 1 Solvents likely to be present in drug product components should be identifeid and quantified. Drug product component manufacturer (API, excipients) should report residual solvent concentration to the Drug product manufacturer/applicant.
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Class 1 Solvent General Requirements

Option 1 concentration limit (ppm)

can be applied to API, excipients, or finished drug product. Option 2 generally may not be applied to class 1 residual solvents.

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Class 2 Solvents General Requirements

Class 2 Solvents (to be Limited): All Class - 2 Solvents likely to be present in drug product components should be identified. Option 1 may be applied if all drug product components have residual solvents concentration below the Table 2 Limits.
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Class 2 Solvents General Requirements

Components residual solvents

concentrations must be reported if Option 1 limits are exceeded. Option 2 applies when option 1 fails Daily exposure calculated to determine if drug product meets the PDE Limits.

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Class 3 Solvents General Requirements

Class 3 Solvents (Low toxicity): All Class 3 solvents likely to be present should be identified. <731> Loss on drying (LOD) method can be used to demonstrate the drug product component meets option 1 Limit of NMT 0.5 % when referenced in monograph
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Class 3 Solvents General Requirements

FDA recommends the LOD test

when only class 3 residual solvents are present. If Option 1 Limit of NMT 0.5 % is exceeded, residual solvents in

Drug Substance, Drug Product and Excipients should be reported

Option 2 (PDE NMT 50 mg/day for

drug product) can be applied

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USP 30 Second Supplements

This general chapter applies to

existing drug substances, excipients, and Drug products. All Substances and products are to be subject to relevant control of solvents likely to be present in a substance or product.
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USP 30 Second Supplement

Tests for residual solvents are not

generally mentioned in specific monographs because the solvents employed may vary from one manufacturer to another.

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USP 30 Second Supplement

For articles that are designated for

veterinary use only, higher levels for the PDE and concentration limit may be justified in exceptional cases. The procedures described in this general chapter are to be applied wherever possible. Other wise, manufacturers may select the most appropriate validated analytical procedure for a particular application.
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USP 30 Second Supplement

Manufacturers of pharmaceutical

products need information from suppliers about the content of residual solvents in order to meets the criteria of this general chapter. When the information about the presence of specified residual solvents is available, only procedure C is needed to quantify the amount of residual solvents present.
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Responsibility for Reporting RS

Reporting/Documentation of Solvents (all classes): Drug product sponsors are responsible for: Quality and safety of their drug products. Reporting all required RS information to their NDA/ANDA.

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Responsibility for Reporting RS

Keeping

comprehensive, accurate records and documentation of compliance with all applicable GMP and other regulations Drug Substance, Drug Product and Excipients manufacturer can test for RS themselves, or Rely on analysis or certification supplied by the API/excipient supplier, provided that.
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Responsibility for Reporting RS

The Drug Substance, Drug Product and Excipients manufacturer establishes the reliability of such analyses/certification, through verification at appropriate intervals

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Responsibility for Reporting RS

Verification of Vendor Statements:

Drug Substance, Drug Product and Excipients sponsors can submit evidence that the level of process understanding and control are sufficient to conclude that the acceptance criteria will always be met, provided the process is run within the range of the critical parameters (Quality by design/Process Analytical Technology concepts).
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Control of Residual Solvents Summary and Future Plans

Summary and Future Plans Residual Solvents should be controlled in all drug products. USP <467> or ICH Q3C are applicable to many drug product regulatory categories.

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Control of Residual Solvents Summary and Future Plans

Drug

product sponsors are responsible for reporting/documenting control measures for RS and for verifying the RS information they receive from their API and excipient suppliers FDA continues to support Qualityby-Design (QbD) concepts
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Overview
Replaces

USP <467> Organic Volatile Impurities. <467> RS implemented via USP/NF General Notices.

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Overview
USP <467> is based closely on ICH

Q3C Guidance for Industry Impurities: Residual Solvents (Dec. 1997) ICH Q3C still in effect for NDA/ANDA non-compendial drug product. USP <467> RS limits are identical to those in ICH Q3C RS limits directly apply only to finished drug products (Drug Product)
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Overview: USP <467> vs. ICH Q3C

Notable Differences between USP <467> and ICH Q3C : Regulatory Impact: USP <467> Is a mandatory drug product standard per FD&C Act. ICH Q3C Is a guidance/recommendation; nonenforceable (unless included in NDA or ANDA specification).
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Overview: USP <467> vs. ICH Q3C

Scope of Products Affected: USP <467> Applies to all drug products (NDAs, ANDAs, OTCs, and unapproved drugs) with USP monographs ICH Q3C Was applied generally to NDA/ANDA Drug Product approved after 1997; was not made retroactive to cover pre-1997 Drug Product
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Overview: USP <467> vs. ICH Q3C

Analytical: USP <467> Includes analytical methods. (based on EP methods). ICH Q3C Does not include analytical methods.

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