IPA Webinar -Residual Solvents Understanding the Requirements Feb 2011[1]

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Wednesday February 2, 2011Wednesday February 2, 2011

IPA WEBINAR ONIPA WEBINAR ON

Residual Solvents: Understanding the Requirements


Mr. Gregory P. Martin Vice Chair, USP General Chapters Expert Committee

Distinguished Presenter:

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GREGORY P. MARTIN

PRESIDENT

PHARMACEUTICAL ANALYTICAL CHEMISTRY

[email protected]

International Pharmaceutical AcademyWebinar

February, 2011

Complectors Consulting 2011

Agenda

Introductions Regulatory Landscape

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egu ato y a dscape Classification of Solvents: Class 1, 2 and 3 Solvents from Raw Materials Solvents Introduced During Manufacturing Options for Describing Class 2 Solvents Analytical Procedures Strategies for Compliance Reporting Residual Solvents Questions and Discussion

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Goals

Understand the requirements for residual solvents in the US, EU and Japan

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the US, EU and Japan

Identify the classes of solvents and address sources of solvents

Effectively utilize options for describing Class 2 solvents

Select appropriate analytical proceduresSelect appropriate analytical procedures Utilize strategies to minimize the testing and

resources required to meet the requirements

Report levels of residual solvents appropriately

Introductions

Name Company

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Company How are you involved with residual solvents? What question would you like to see answered

today?

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Regulatory Landscape: History

USP proposed requirements for Organic Volatile Impurities in 1988

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Impurities in 1988 Included 7 solvents, primarily applied to drug substances

ICH Q3C Residual Solvents Concept paper 1994 Implemented 1998

FDA, EMA and MHLW accepted ICH Q3C as part of p Q3 pthe Pharmacopieal Discussion Group process

USP Residual Solvents Proposed 2003 Implemented Jul 2008

Regulatory and Guidance Documents

ICH Q3C(R4) Impurities: Guideline for Residual Solvents

USP Residual Solvents FDA: Guidance for Industry: Residual Solvents in Drug

Products Marketed in the United States (Draft Guidance) August 2008

EU 2.4.24 Identification and Control of Residual Solvents EU 5.4 Residual Solvents

JP 2.46 Residual Solvents Test General Information 7. Guideline for Residual Solvents, Residual

Solvents Test, and Models for the Test in Monographs

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FDA Documents

Guidance for Industry: Residual Solvents in Drug Products Marketed in the United States (Draft

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Products Marketed in the United States (Draft Guidance) August 2008

Residual Solvents in ANDAs: Questions and Answers (October 28, 2008)

Guidance for Industry: Residual Solvents in New Veterinary Medicinal Products, Active Substances y ,and Excipients (Revision) VICH GL18(R) Draft August 2010

Current Regulatory Status

Residual solvents are addressed in the three major compendia (USP, EP and JP) and there is

ICH G id lian ICH Guideline These documents are consistent in identifying

three classes of solvents, and in referring to 59 specific solvents and acceptance criteria for each of them

USP, EP and JP identify procedures in the , y pGeneral Chapters Well discuss some of the differences between USP and EP

later in this presentation

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Scope of the Requirements

ICH Q3C Drug substances excipients drug products

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Drug substances, excipients, drug products Does not apply to investigational or existing products

USP Applies to all monographs

FDA Approved prior to July, 2008 required to conform to USP pp p y q

if the subject of a monograph; otherwise ICHQ3C

Approved after July, 2008 required to conform to USP Includes NDAs, ANDAs, OTC products and Veterinary

products

Classification of Solvents

Solvents were classified after review of available toxicological and environmental data

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toxicological and environmental data

Resulted in a risk-based classification Rules are not absolute Deviations may be acceptable based on justification

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Risk-Based Solvent Classification

Class 1 Solvents to be avoided Known human carcinogens, strongly suspected human

carcinogens, and environmental hazardscarcinogens, and environmental hazards

Class 2 Solvents to be limited 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

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*All solvent levels should be reduced to the extent possible*

Risk-Based Solvent Classification12

Class 3 Solvents with low toxic potential

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

Other Residual Solvents

No toxicological data found upon which to base a PDE?

*All solvent levels should be reduced to the extent possible*

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Limit of Residual Solvents: Class 1

These solvents should be avoided whenever possible

USP allows their use with justification

Levels must be routinely controlled in either:Levels must be routinely controlled in either:

Intermediates, final active substance, or final drug product

Solvent Concentration

Limit (ppm)

Concern

Benzene 2 Carcinogen

Carbon Tetrachloride 4 Toxic,

Env. Hazard

Table 1: Class 1 Residual Solvents

1.2-Dichloroethane 5 Toxic

1,1-Dichloroethene 8 Toxic

1,1,1-Trichloroethane 1500 Env. Hazard

Limit of Residual Solvents: Class 2

Class 2: 27 solvents Class 2 Residual Solvents: should be limited in drug

substances, excipients, and drug products because of their inherent toxicities

Their levels should be restricted as shown in Table 2. Concentration limits (ppm) vary between 50 (methylbutylketone) and 3880 (cyclohexane)

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When Class 2 residual solvents are used or produced in the manufacturing or purification process they should be identified and levels demonstrated to be acceptable

2009

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SolventConcentration

Limit (ppm)PDE

(mg/day)

Acetonitrile 410 4.1

Chlorobenzene 360 3.6

Class 2 Residual Solvents

Chloroform 60 0.6

Cyclohexane 3880 38.8

1,2-Dichloroethene 1870 18.7

1,2-Dimethoxyethane 100 1.0

N,N-Dimethylacetamide 1090 10.9

N,N-Dimethylformamide 880 8.8

1,4-Dioxane 380 3.8

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2-Ethoxyethanol 160 1.6

Ethylene glycol 620 6.2

Formamide 220 2.2

Hexane 290 2.9

Methanol 3000 30.0

SolventConcentration

Limit (ppm)PDE

(mg/day)

2-Methoxyethanol 50 0.5


y 5 5

Methylbutylketone 50 0.5

Methylcyclohexane 1180 11.8

Methylene chloride 600 6.0

N-Methyl-pyrrolidone 530 5.3

Nitromethane 50 0.5

Pyridine 200 2.0

Sulfolane 160 1 6

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Sulfolane 160 1.6

Tetrahydrofuran 720 7.2

Tetralin 100 1.0

Toluene 890 8.9

Trichloroethylene 80 0.8

Xylenes 2170 21.7

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Class 2 Solvents with Poor Volatility

The headspace procedures in are not suitable for the following compounds when using headspace injection techniquetechnique

Formamide 2-ethoxyethanol 2-methoxyethanol Ethylene glycol N-methylpyrrolidone Sulfolane

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These compounds may be detectable if direct injection is used

Residual Solvent Limits: Class 3

Class 3: 27 solvents

Less toxic and of lower risk to human health

LOD i l i l d LOD is most common analytical procedure. 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 of product. Where the limit is NMT 50 mg/day total and an LOD test is included in the monograph, testing for Class 3 solvents can be done by LOD

If the monograph allows for a concentration resulting in more than 50 mg/day (or if there is no LOD test in the

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more than 50 mg/day (or if there is no LOD test in the monograph), Class 3 solvents should be identified and quantified using procedures similar to those for Classes 1 and 2

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Acetic acid Heptane

Acetone Isobutyl acetate

A i l I l t t


Anisole 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

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Ethanol 1-Pentanol

Ethyl acetate 1-Propanol

Ethyl ether 2-Propanol

Ethyl formate Propyl acetate

Formic acid

Solvents from Raw Materials

Raw materials include drug substances d i i t

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and excipients

Generally, these are characterized upon receiptRole of testingRole of vendor validation programRole of vendor validation programComments on solvates

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Solvents from Raw Materials

What does your supplier know about solvents in the raw materials?

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raw materials?

How well are these controlled? Source Type Levels

What do you know about solvents in your raw y ymaterials?

Potential impact of different suppliers, different manufacturers, different grades, etc.

Solvents Introduced During Manufacturing

In a CGMP operation, there should be full k l d b t l t hi h

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knowledge about solvents which are added.

Often, they are subsequently removed.Need to characterize the removal process and

resultant levels of solventsresultant levels of solvents.

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Options for Characterizing Class 1 Solvents

Should be avoided What if supplier indicates they are not present?

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What if supplier indicates they are not present?

Requirements are stated in ppm Requirements apply to drug product Use algebra

Options for Characterizing Class 2 Solvents

Option 1: ppm Requirements are stated in ppm and apply to drug product

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q pp pp y g p Advantage: since solvents are usually controlled at levels

much lower than the specification, if all raw materials are controlled at levels below the ppm limit, and if the daily dose is not greater than 10 g, may be able to combine raw materials in any ratio

Option 2: PDE (Permitted daily exposure) Requirements are stated in mg per day Requirements are stated in mg per day Advantage: if the daily dose is significantly different from 10 g,

Option 1 may not apply and/or higher concentrations may be acceptable

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Example: Class 2 Option 2

Consider acetonitrile in a drug product (concentration limit = 410 ppm PDE = 4 1

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(concentration limit = 410 ppm, PDE = 4.1 mg/day). Maximum dose for the drug product is 5 g/day.

Case 1: Each Raw Material and Drug Product PassesComponent Amt in

ProductAcetonitrileConcentration

Daily Exposure

Active ingredient 0.3 g 200 ppm 0.06 mg

Excipient 1 0.9 g 300 ppm 0.27 mg


Drug Product 5.0 g 218 ppm 1.09 mg



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Case 2: Drug Product PassesComponent Amt in


Daily Exposure





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Case 3: Drug Product FailsComponent Amt in


Daily Exposure





Options for Characterizing Class 3

Requirements are 5000 ppm or 0.5% or 50 mg/day. Where the limit is NMT 50 mg/day total and an LOD

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Where the limit is NMT 50 mg/day total and an LOD test is included in the monograph, testing for Class 3 solvents can be done by LOD

If the monograph allows for a concentration resulting in more than 50 mg/day (or if there is no LOD test in the monograph), Class 3 solvents should g p ), 3be identified and quantified using procedures similar to those for Classes 1 and 2

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Analytical Procedures

Chromatographic portion of EP and USP methods are essentially the same

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methods are essentially the same.Use of two, orthogonal chromatographic

procedures in both Sample prep for water insoluble samples is

differentEvaluation criteria are differentEvaluation criteria are differentEP states pass if less than 50% of standard areaUSP states pass if less then standard area

USP Method : Procedure A

Headspace

G43 capillary GC column: 6% cyanopropyl phenyl-94% dimethylpolysiloxane 0.32 mm x 30m, 1.8 m 0.53 mm X 30m, 3.0 m

Split ratio: 1:5

Oven 40oC: 20 min

10oC/min to 240oC 20 min

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10oC/min to 240oC, 20 min

Injector temp: 140oC

FID temp: 250oC

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Procedure A: System Suitability

Class 1 Standard Solution Signal-to-Noise (S/N): 1,1,1 trichloroethane > 5

Class 1 System Suitability Solution Signal-to-Noise (S/N): All peaks NLT 3

Class 2 Mixture A Standard Solution Resolution: acetonitrile and methylene chloride > 1.0

If a peak response of any peak in the Test Solution is greater or equal t di k i ith th Cl 1 St d d S l ti Cl

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to a corresponding peak in either the Class 1 Standard Solution, Class 2 Mixture A, or B Standard Solutions, proceed to Procedure B to verify the identity of the peak, otherwise the article meets the requirements of this test

Procedure A: Class 1 Mixture

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From USP.org Residual Solvent Mixture Class 1 USP Certificate

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Procedure A: Class 2 Mixture A

600.00

700.00

800.001 Methanol2 Acetonitrile3 Methylene chloride4 trans-1,2-Dichloroethene5 cis-1,2-Dichloroethene6 Tetrahydrofuran

14

7

pA

100 00

200.00

300.00

400.00

500.007 Cyclohexane8 Methylcyclohexane9 1,4-Dioxane10 Toluene 11 Chlorobenzene 12 Ethylbenzene 13 m-Xylene & p-Xylene14 o-Xylene

10

134

12

115

8

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0.00

100.00

Minutes0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00 30.00

3 961 2I

From USP.org Residual Solvent Class 2 Mixture A USP Certificate

Procedure A: Class 2 - Mixture B

pA

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FID2 B, (03235A\3235A129.D)

15

8

7

8

9

10

artifact

3

7

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min0 5 10 15 20 25 30 355

6

24

6

From USP.org Residual Solvent Class 2 Mixture B USP Certificate

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Procedure A Class 3 Mixture

1 Pentane2 Ethanol3 Ethyl Ether4 Acetone5 Ethyl Formate5 Ethyl Formate6 2-Propanol7 Methyl Acetate8 t-Butylmethyl Ether9 1-Propanol10 Methylethyl Ketone11 Ethyl Acetate12 Tetrahydrofuran (THF)13 2-Butanol14 2-Methyl-1-propanol15 Isopropyl Acetate16 Heptane17 1-Butanol18 Propyl Acetate19 Methylisobutyl Ketone20 3-Methyl-1-butanol

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20 3 Methyl 1 butanol21 Isobutyl Acetate22 1-Pentanol23 Butyl Acetate24 Cumene25 Anisole26 Dimethyl Sulfoxide (solvent)

From Phenomenex GC Application ID NO. 16006

USP Method: Procedure B

Headspace

G16 capillary GC column: P l h l Gl l C d M Polyethylene Glycol Compound 20M

0.32 mm x 30m, 0.25 m 0.53 mm X 30m, 0.25 m

Split ratio: 1:5

Oven 50oC: 20 min

6oC/min to 165oC 20 min

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6oC/min to 165oC, 20 min

Injector temp: 140oC

FID temp: 250oC

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Procedure B: System Suitability

Class 1 Standard Solution S/N: Benzene > 5 S/N: Benzene > 5

Class 1 System Suitability Solution S/N: All peaks > 3

Class 2 System Suitability Solution Resolution: Resolution between Acetonitrile & cis-

dichloroethene > 1

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If the peak response(s) in the Test Solution in the peaks identified in Procedure A is/are greater than or equal to a corresponding peak(s) in either the Class 1 Standard Solution, Class 2 Mixture A, or B Standard Solutions, proceed to Procedure C to quantify the peak(s), other wise the article meets the requirements of this test

Procedure B: Class 1 Mixture

From USP.org Residual Solvent Mixture Class 1 USP Certificate

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Procedure B: Class 2 Mixture A

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From USP.org Residual Solvent Class 2 Mixture A USP Certificate

Procedure B: Class 2 Mixture B

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From USP.org Residual Solvent Class 2 Mixture B USP Certificate

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Procedure B: Class 2 Mixture C (by direct injection)

pA

1400

FID1 A, (03-252\03252028.D)

6

DMSO 1. 2-Methoxyethanol2. 2-Ethoxyethanol3 N N-Dimethylformamide

400

600

800

1000

1200

* Additional peak from DMSO

3

4 5

8

3. N,N-Dimethylformamide4. N,N-Dimethylacetamide5. Ethyleneglycol6. N-Methylpyrrolidone7. Formamide8. Sulfolane

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min0 10 20 30 40 50

0

200

400

12

3

7

8

*

*

From USP.org Residual Solvent Class 2 Mixture C USP Certificate

USP Method: Procedure C

Procedure A conditions Headspace Headspace G43 capillary GC column:

6% cyanopropyl phenyl-94% dimethylpolysiloxane 0.32 mm x 30m, 1.8 m 0.53 mm X 30m, 3.0 m

Split ratio: 1:5 Oven 40oC: 20 min

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10oC/min to 240oC, 20 min Injector temp: 140oC FID temp: 250oC

If results from Procedure A are inferior to B, use Procedure B conditions

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Preparations for Procedure C

Same as for Procedure A plus:

S d d l i ( ) Standard solution(s): For each peak identified and verified by Procedures A

and B by dilution of the respective USP Residual Solvent Reference Standard

Spiked Test Solution A Mixture of Test Solution and Standard solution

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A Mixture of Test Solution and Standard solution

Procedure C: System Suitability

Class 1 Standard Solution S/N: 1,1,1 trichloroethane > 5

Class 1 System Suitability Solution S/N: All peaks > 3

Class 2 Mixture A Standard Solution Resolution: Acetonitrile and methylene chloride > 1.0

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If Procedure B is used, follow those system suitability requirements

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Water-soluble vs. Water-insoluble

Water-soluble: solutions are prepared using water as diluent (with some DMSO)

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as diluent (with some DMSO)

Water-insoluble: solutions are prepared using dimethylformamide or dimethyl sulfoxide as diluent

Methodology Options

Use the compendial methodology Requires verification

Use the compendial methodology with minor changes as defined in General Chapter Chromatography Requires verification

Use a modified version of the compendial methodology Requires validation, but may be able to take advantage of existing q y g g

validation

Develop an Alternative Procedure Requires full validation

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Adjustments of Compendial Methods

USP and FDA indicate that adjustments of operating conditions to meet the operating conditions to meet the requirements may be necessary and acceptable without re-validation, while modifications are not acceptable without re-validation

What constitutes an adjustment or modification?

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Any changes to operating parameters which are not listed in , or are greater in magnitude than those listed in are considered

Modifications48

are greater in magnitude than those listed in are considered modifications

Modifications generally require additional validation

It may not be necessary to perform a complete revalidation of the modified compendial procedure, depending on the nature of the

difi ti i d i t f b k t th lid t d modifications, using good science to refer back to the validated compendial procedure

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What are some reasons it may be desirable to use alternative procedures?

Alternative Procedures49

p A laboratory has an existing procedure which is working well and well

suited to its needs

A laboratory desires a shorter run time and only needs to address a few specific solvents

A laboratory has a need to address a solvent not included in A laboratory is having difficulty getting the compendial procedures to work

Alternative procedures must be validated in accordance with

USP: . . . The procedures described in . . . this general chapter are to be applied whenever possible. Otherwise manufacturers may select

Alternative Procedures Permitted50

the most appropriate validated analytical procedure for a particular application.

ICH: Any harmonized procedures for determining levels of residual solvents as described in the pharmacopoeias should be used, if feasible. Otherwise, manufacturers would be free to select the most appropriate validated analytical procedure .

EP: . . . The methodology in the general analytical method (2.2.24) is to be applied wherever possible. Otherwise an appropriate validated method is to be employed.

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Approaching Alternative Procedures

Always evaluate benefit vs. cost If an alternative procedure is necessary (e.g. addressing a

new solvent) options are limited and validation will be

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new solvent), options are limited and validation will be required

If the alternative procedure is optional (e.g. to reduce run time), consider the overall benefit and costs, including development, validation (and possibly revalidation for additional materials), documentation and filing implications.

It may be beneficial to consider a minor adjustment (within the scope of allowances) or a modification of compendial procedures (which may reduce validation efforts) before pursuing an alternative procedure

Strategies for Compliance

Components (active ingredients, excipients) Limit test, then quantitative test (if necessary)

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Limit test, then quantitative test (if necessary) Concentration limits (ppm)

Assumes maximum dose of 10 g/day Absolute amounts (PDE)

Dependent on amount in final daily dose

Drug products Algebra

i i h i i (if ) Limit test, then quantitative test (if necessary) Concentration limits (ppm)

Assumes maximum dose of 10 g/day Absolute amounts (PDE)

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To Test or Not to Test

Full testing Where you would probably start without additional

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Where you would probably start without additional information and lab studies

Reduced testing Purchased materials

Vendor validation

Manufactured materials Knowledge of solvents used and process

QbD approach Understanding and control of process

Reporting Residual Solvents

For each excipient used in the formulation, information in the submission should include:

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Excipient manufacturers statement regarding residual solvents

ANDA sponsor's verification of excipient manufacturers statement

For the drug product, information in the b i i h ld i l d fi i h d dsubmission should include a finished product

specification stating compliance with USP

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For each residual solvent identified by the drug substance manufacturer, excipient manufacturer,

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, p ,or used by the ANDA sponsor: A statement that indicates which option was used to

demonstrate compliance with USP and a summary of the appropriate calculation, if Option 2 was used, indicating the source of data used in the calculation

The results of any residual solvent testing on the drug y g gproduct, if applicable

Suitable information to support the safety of residual solvents that are not defined as being Class 1, Class 2, or Class 3 solvents


Information of residual solvents in coating materials, colorants, fl l d i i ti i k i ll t d d

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flavors, capsules, and imprinting inks is generally not needed unless Class 1 solvents are used in the manufacture of these components.

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Recap

Regulatory LandscapeCl ifi ti f S l t Cl d

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Classification of Solvents: Class 1, 2 and 3 Solvents from Raw Materials Solvents Introduced During Manufacturing Options for Describing Class 2 Solvents

A l ti l P d Analytical Procedures Strategies for Compliance Reporting Residual Solvents

Questions and Discussion

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IPA Webinar -Residual Solvents Understanding the Requirements Feb 2011[1]

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