Gas Chromatography -2 OVI

7/27/2019 Gas Chromatography -2 OVI

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Residual solvents

New USP General Chapter

Session II

Mr. Shantanu Chobhe

DGM-Analytical Services

Unichem Laboratories Ltd., Mumbai


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Introduction

..residual solvents in pharmaceuticals aredefined as organic volatile chemicals that areused or produced in the manufacture of drugsubstances or excipients, or in the preparation ofdrug products.

ICH, USP, EP

[Note: residual solvents refers to the amount notremoved during the purification of the product]


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Introduction

Residual solvents are one of the three maintypes of impurities in pharmaceutical articles,the other two being organic and inorganicimpurities.

Therefore, Various Pharmacopeiasfrequentlyinclude a test for residual solvents, together withprocedures for the test and acceptance criteria.


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Introduction

The implementation of modern standards tocontrol these types of impurities has occupiedregulatory agencies, pharmaceuticalmanufacturers, and pharmacopeias for many

years.

Substantial progress in the overall effort camewith development of the ICH Q3C Guideline in

1997 (Impurities: Guideline for Residual Solvents)and subsequent adoption of this Guideline as aFDA guidance.


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History

Chapter of USP was Organic VolatileImpurities(OVI)

Individual monographs specify which method tofollow.

OVIs controlled: Chloroform (60 ppm), Dioxane (380ppm), Methylene Chloride (600 ppm) and

Trichloroethylene (80 ppm) Four methods: I, IV, V, and VI

Standards: reagent grade solvents

Direct injection or Headspace (Method IV) Column: G27 (Method I), G43 (Methods IV and V),

various supports and coatings (Method VI)

Dissolving solvent: water or the solvent specified in the

monograph


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HistoryICH Q3C and EP

ICH Q3C Published in July 1997

Revised in 2002

EP adopts the ICH Q3C guideline in 1999.

General Chapter 5.4. An introductory paragraphand reproduces the ICH Guideline

Chapter 2.4.24 Identification and control of residualsolvents (Test methods for Class 1, 2 and 3Residual Solvents)


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History

USP incorporates ICH Q3Cclassificationand evaluation system and EPprocedures.

USP was not consistent with ICH Q3CImpurity guideline (1997)


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Revision of USP GeneralChapter

First proposal to amend General Chapter and General Notices published in PF 29(4), 2003.

Changes made effective (Mandatory) from 1st

July 2008.


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Changes Done

The requirements have been aligned with the ICHguideline.

The title changed from

Organic volatile Impuritiesto

Residual Solvents.All drug substances, excipients, and products are

subject to relevant control of residual solvents,

even when no test is specified in the individualmonograph.

If solvents are used during production, they are of

suitable quality.


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Contd.. Changes Done

The toxicity and residual level of each solvent are

taken into consideration.

The solvents are limited according to the

principles defined and the requirements specified

in Residual solvents, using the general

methods presented therein or use of othersuitable methods.


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Revised :Main Points

1. Testing is to be performed only for solventslikely to be present

used or produced in the final manufacturingstep

used in previous steps and not removed bya validated procedure.

2. The limits for acceptable concentrations listedin the Chapter are for drug products,not forits components.


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Contd.. Revised :Main Points

4. The concentration in the drug product may be

calculated from the contributions ofcomponents

determined experimentally; mandatory if

solvents are used in its manufacture cumulative calculation exceeds limits

5. Manufacturers of drug products may rely ondata provided by the suppliers of components

6. Provides unambiguous identification andquantification methods


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Contd.. Revised :Main Points

7. Includes options to allow use of materials thatexceed the limits established.

8. The procedures described in this general

chapter are to be applied wherever possible.Otherwise, manufacturers may select the mostappropriate validated analytical procedure fora particular application.


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Risk Based classification of Solvents

Class 1 solvents: Solvents to be avoided

Known human carcinogens, strongly suspectedhuman carcinogens, and environmental hazards.

Class 2 solvents: Solvents to be limitedNon-genotoxic animal carcinogen or possiblecausative agents of others irreversible toxicitysuch as neurotoxicity or teratogenicity.

Class 3 solvents: Solvents with low toxic

potentialSolvents with low toxic potential to humanbeings.

f


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Limits of Residual Solvents Class 1:concentration limits, in ppm, are provided in a

Table. They should not be exceeded unless otherwise

stated in the individual monograph.

Class 2:concentration limits are to be calculated fromPDE with the formula:

Concentration (ppm) = 1000 PDE/dose, where PDE is

in mg/day and dose is in g/day.A table is provided, to be used when the daily dose is10 g or less, or when the daily dose is not known orfixed.

Class 3:PDE is 50 mg/day (unless otherwise stated inthe individual monograph.), corresponding to aconcentration of 0.5% for daily doses of 10 g or less.


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Limits of Residual Solvents: Class 1

Class 1 Residual Solvents (Table 1): Shouldnot be used in the manufacturing of drugsubstances, excipients or drug productsbecause of unacceptable toxicities or

deleterious environmental effects of theresidual solvents.

However if their use is unavoidable, theirlevels should be restricted as shown in

Table 1.


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Table 1. Class 1 Residual Solvents

Solvent Limit

(ppm)

Concern

Benzene 2 Carcinogen

Carbon tetrachloride 4 Toxic andenvironmental Hazard

1,2-Dichloroethane 5 Toxic

1,1-Dichloroethene 8 Toxic

1,1,1-Trichloroethane 1500 Environmental Hazard


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Class 2: 27 solvents

Class 2 Residual Solvents: should be limited indrug substances, excipients, and drugproducts because of their inherent toxicities.

Their levels should be restricted as shown in

Table 2. Concentration limits (ppm) varybetween 50 (methylbutylketone) and 3880(cyclohexane).

When Class 2 residual solvents are used (or

produced) in the manufacturing or purificationprocess, they should be identified andquantified


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SolventPDE

(mg/day)Limit (ppm)

Acetonitrile 4.1 410

Chlorobenzene 3.6 360

Chloroform 0.6 60

Cyclohexane 38.8 3880

1,2-Dichloroethene 18.7 1870

1,2-Dimethoxyethane

1.0 100

N,N-Dimethylacetamide

10.9 1090

N,N-Dimethylformamide

8.8 880

1,4-Dioxane 3.8 380

2-Ethoxyethanol 1.6 160

Ethylene glycol 6.2 620

Formamide 2.2 220

Hexane 2.9 290

Methanol 30.0 3000

SolventPDE

(mg/day)Limit (ppm)

2-Methoxyethanol 0.5 50

Methylbutylketone 0.5 50

Methylcyclohexane 11.8 1180

Methylene chloride 6.0 600

N-Methylpyrrolidone 5.3 530

Nitromethane 0.5 50

Pyridine 2.0 200

Sulfolane 1.6 160

Tetrahydrofuran 7.2 720

Tetralin 1.0 100Toluene 8.9 890

Trichloroethylene 0.8 80

Xylenes 21.7 2170


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Options for Determining Levels of Class 2Residual Solvents in Drug Products

Option 1:

All the components of the drug product (drug substancesand excipients) meet the concentration limits (ppm)listed in Table 2, and the daily dose does not exceed 10g: drug product passes.

Option 2:

At least one of the components of the drug productexceeds the concentration limits (ppm), or the dailydose exceeds 10 g: the daily exposure to a solvent

(calculated as the sum of the components contributions)should be less than the PDE (mg).


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Example 1: Option 1 and Option 2,with acetonitrile

PDE acetonitrile = 4.1 mg/day, thus Option 1limit is 410 ppm

(from Table 2). 5.0 g drug product/day. Composed of two excipients

Excipients 1 meets Option 1limit of 410 ppm. Drug substance, excipients 2, and drug product do not meet

Option 1limit of 410 ppm. Drug product however, does meet Option 2limit of 4.1 mg/day.

Component Amount inFormulation

(g)

AcetonitrileContent-Limit

(ppm)

Daily Exposure

(mg)

Drug Substance 0.3 800 (exceeds) 0.24

Excipient 1 0.9 400 (pass) 0.36

Excipient 2 3.8 800 (exceeds) 3.04

Drug Product

Calculated data*

5.0 728 (exceeds)* 3.64 (PASS)*

E l 2 O ti 1 d O ti 2 ith


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Example 2: Option 1 and Option 2, withacetonitrile

PDE acetonitrile = 4.1 mg/day, thus Option 1limit is 410 ppm

(from Table 2). 5.0 g drug product/day. Composed of two excipients

Drug product does not meet Option 1limit (410 ppm) or Option 2limit (4.1mg/day).

Manufacturer could test to see if manufacturing reduced the level ofacetonitrile in the drug product below 410 ppm; if so it passes.

Component Amount inFormulation

(g)

Acetonitrile Content-Limit

(ppm)

Daily Exposure

(mg)

Drug Substance 0.3 800 (exceeds) 0.24



Drug Product

Calculated data*

5.0 1016 (exceeds)* 5.08 (FAIL)*


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Class 3: 27 solvents

Less toxic and of lower risk to human health Unless otherwise stated in the individual

monograph, PDE is NMT 50 mg/day,corresponding to a concentration limit of 5000

ppm for daily doses not greater than 10 g ofproduct.

Use Loss on Drying in NMT 0.5%.

If the monograph allows for a concentration

resulting in more than 50 mg/day, Class 3solvents must be identified and quantified.


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Acetic acid Heptane

Acetone Isobutyl acetateAnisole Isopropyl acetate

1-Butanol Methyl acetate

2-Butanol 3-Methyl-1-butanol

Butyl acetate Methylethylketone

tert-Butylmethyl ether Methylisobutylketone

Cumene 2-Methyl-l-propanol

Dimethyl sulfoxide Pentane

Ethanol 1-Pentanol

Ethyl acetate 1-Propanol

Ethyl ether 2-Propanol

Ethyl formate Propyl acetate

Formic acid

O h id l l


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Other Residual solvents No adequate toxicological data on which to base a PDE

was found.

Residual levels of these solvents in drug products shallbe justified.

Table 4.Other Residual Solvents1,1-Diethoxypropane Methyl isopropyl ketone

1,1-Dimethoxypropane Methytetrahydrofuran

2,2-Dimethoxypropane Petroleum ether

Isooctane Trichloroacetic acid

Isopropyl ether Trifluroacetic acid


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Analytical Procedures (ICH, EP)

ICH:Any harmonized procedures for

determining levels of residual solvents asdescribed in the pharmacopoeias should beused, if feasible. Otherwise, manufacturerswould be free to select the most appropriate

validated analytical procedure . . . EP:. . . The methodology in the general

analytical method (2.2.24)is to be appliedwherever possible. Otherwise an appropriate

validated method is to be employed.


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Analytical Procedures USP

USP:. . . The procedures described in . . . Thisgeneral chapter are to be applied wheneverpossible. Otherwise manufacturers mayselect the most appropriate validatedanalytical procedure for a particularapplication . . .

Id tifi ti C t l d


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Identification, Control, andQuantification of Residual Solvents

Class 1 and Class 2 Residual Solvents Procedure A-Identification and Limit Test

Procedure B-Confirmatory Test

Procedure C-Quantitative Test

Class 3 Residual Solvents LOD, followed if necessary by Gas

Chromatography analysis if it exceeds0.5%.

Manufacturers statement regarding


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Manufacturers statement regardingResidual solvents

Statement/Declaration shall include-

All Class 1 solvents used or generated

All Class 2 solvents "likely to be present

Whether Class 3 solvents are" likely to be present" andidentity of all Class 3 solvents present at greater than 0.5%

All other solvents "likely to be present, as applicable.

The expected control limits for the solvents identifiedabove

C l l i f S d d i


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Calculation of Standard concentrationSample containing Methanol as a residual solvent

Limit as per ICH: 3000 ppm

Sample concentration: 500 mg of sample in 5 mL of DMF(diluent)

Factor is (5ml / 0.5g) = 10

Standard concentration:

Absolute concentration = ICH limit / Factori.e. 3000 / 10 = 300 ppm


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Calculation of residual solvent

Standard preparation: 30mg of Methanol to 100mL with

DMF

Calculations: Methanol content in ppm

Area in sample Wt of Std (g) 5---------------------- X -------------- X --------------- X 106

Area in std 100 Wt of spl (g)


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Thank You !

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Gas Chromatography -2 OVI