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International
Pharmaceutical
Academy
Copyright 2011 International Pharmaceutical Academy
Media Sponsors
Wednesday February 2, 2011 Wednesday February 2, 2011
IPA WEBINAR ON IPA WEBINAR ON
Residual Solvents:
Understanding the
Requirements
Residual Solvents:
Understanding the
Requirements
Mr. Gregory P. Martin
Vice Chair, USP General Chapters
Expert Committee
Distinguished Presenter:
2/8/2011
1
Residual Solvents:
Understanding the Requirements
GREGORY P. MARTIN
PRESIDENT
PHARMACEUTICAL ANALYTICAL CHEMISTRY
greg.martin@complectors.com
International Pharmaceutical Academy
Webinar
February, 2011
Complectors Consulting 2011
Agenda
Introductions
Regulatory Landscape
2
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
2/8/2011
2
Goals
Understand the requirements for residual solvents in
the US, EU and Japan
3
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 procedures Select 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
4
Company
How are you involved with residual solvents?
What question would you like to see answered
today?
2/8/2011
3
Regulatory Landscape: History
USP proposed requirements for Organic Volatile
Impurities in 1988
5
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 p
the Pharmacopieal Discussion Group process
USP<467> Residual Solvents
Proposed 2003
Implemented Jul 2008
Regulatory and Guidance Documents
ICH Q3C(R4) Impurities: Guideline for Residual
Solvents
USP <467> 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Products Marketed in the United States (Draft Guidance)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
6
2/8/2011
4
FDA Documents
Guidance for Industry: Residual Solvents in Drug
Products Marketed in the United States (Draft
7
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 li an 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 p
General Chapters
Well discuss some of the differences between USP and EP
later in this presentation
8
2/8/2011
5
Scope of the Requirements
ICH Q3C
Drug substances excipients drug products
9
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
<467> if the subject of a monograph; otherwise ICHQ3C
Approved after July, 2008 required to conform to USP <467>
Includes NDAs, ANDAs, OTC products and Veterinary
products
Classification of Solvents
Solvents were classified after review of available
toxicological and environmental data
10
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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6
Risk-Based
Solvent Classification
Class 1 Solvents to be avoided
Known human carcinogens, strongly suspected human
carcinogens, and environmental hazards carcinogens, 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
11
*All solvent levels should be reduced to the extent possible*
Risk-Based Solvent Classification
12
Class 3 Solvents with low toxic potential
Solvents with low toxic potential to man;
no health based exposure limit is needed no 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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7
13
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)
14
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
2/8/2011
8
Solvent
Concentration
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
15
2-Ethoxyethanol 160 1.6
Ethylene glycol 620 6.2
Formamide 220 2.2
Hexane 290 2.9
Methanol 3000 30.0
Solvent
Concentration
Limit (ppm)
PDE
(mg/day)
2-Methoxyethanol 50 0.5
Class 2 Residual Solvents
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
16
Sulfolane 160 1.6
Tetrahydrofuran 720 7.2
Tetralin 100 1.0
Toluene 890 8.9
Trichloroethylene 80 0.8
Xylenes 2170 21.7
2/8/2011
9
Class 2 Solvents with Poor Volatility
The headspace procedures in <467> are not suitable for the
following compounds when using headspace injection
technique technique
Formamide
2-ethoxyethanol
2-methoxyethanol
Ethylene glycol
N-methylpyrrolidone
Sulfolane
17
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
18
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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10
Acetic acid Heptane
Acetone Isobutyl acetate
A i l I l t t
Class 3 Residual Solvents
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
19
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
20
and excipients
Generally, these are characterized upon
receipt
Role of testing
Role of vendor validation program Role of vendor validation program
Comments on solvates
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11
Solvents from Raw Materials
What does your supplier know about solvents in the
raw materials?
21
raw materials?
How well are these controlled?
Source
Type
Levels
What do you know about solvents in your raw y y
materials?
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
22
knowledge about solvents which are
added.
Often, they are subsequently removed.
Need to characterize the removal process and
resultant levels of solvents resultant levels of solvents.
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12
Options for Characterizing Class 1 Solvents
Should be avoided
What if supplier indicates they are not present?
23
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 ppmand apply to drug product
24
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 ppmlimit, 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
2/8/2011
13
Example: Class 2 Option 2
Consider acetonitrile in a drug product
(concentration limit = 410 ppm PDE = 4 1
25
(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 Passes
Component Amt in
Product
Acetonitrile
Concentration
Daily Exposure
Active ingredient 0.3 g 200 ppm 0.06 mg
Excipient 1 0.9 g 300 ppm 0.27 mg
Excipient 2 3.8 g 200 ppm 0.76 mg
Drug Product 5.0 g 218 ppm 1.09 mg
Example: Class 2 Option 2
Consider acetonitrile in a drug product
(concentration limit = 410 ppm PDE = 4 1
26
(concentration limit = 410 ppm, PDE = 4.1
mg/day). Maximum dose for the drug product is 5
g/day.
Case 2: Drug Product Passes
Component Amt in
Product
Acetonitrile
Concentration
Daily Exposure
Active ingredient 0.3 g 800 ppm 0.24 mg
Excipient 1 0.9 g 400 ppm 0.36 mg
Excipient 2 3.8 g 800 ppm 3.04 mg
Drug Product 5.0 g 728 ppm 3.64 mg
2/8/2011
14
Example: Class 2 Option 2
Consider acetonitrile in a drug product
(concentration limit = 410 ppm PDE = 4 1
27
(concentration limit = 410 ppm, PDE = 4.1
mg/day). Maximum dose for the drug product is 5
g/day.
Case 3: Drug Product Fails
Component Amt in
Product
Acetonitrile
Concentration
Daily Exposure
Active ingredient 0.3 g 800 ppm 0.24 mg
Excipient 1 0.9 g 2000 ppm 1.80 mg
Excipient 2 3.8 g 800 ppm 3.04 mg
Drug Product 5.0 g 1016 ppm 5.08 mg
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
28
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 ), 3
be identified and quantified using procedures similar
to those for Classes 1 and 2
2/8/2011
15
Analytical Procedures
Chromatographic portion of EP and USP
methods are essentially the same
29
methods are essentially the same.
Use of two, orthogonal chromatographic
procedures in both
Sample prep for water insoluble samples is
different
Evaluation criteria are different Evaluation criteria are different
EP states pass if less than 50% of standard area
USP 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 40
o
C: 20 min
10
o
C/min to 240
o
C 20 min
30
10
o
C/min to 240
o
C, 20 min
Injector temp: 140
o
C
FID temp: 250
o
C
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16
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
31
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
32
From USP.org Residual Solvent Mixture Class 1 USP Certificate
2/8/2011
17
Procedure A: Class 2 Mixture A
600.00
700.00
800.00
1 Methanol
2 Acetonitrile
3 Methylenechloride
4 trans-1,2-Dichloroethene
5 cis-1,2-Dichloroethene
6 Tetrahydrofuran
14
7
p
A
10000
200.00
300.00
400.00
500.00
7 Cyclohexane
8 Methylcyclohexane
9 1,4-Dioxane
10 Toluene
11 Chlorobenzene
12 Ethylbenzene
13 m-Xylene& p-Xylene
14 o-Xylene
10
13
4
12
11
5
8
33
0.00
100.00
Minutes
0.00 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
9
6
1
2
I
From USP.org Residual Solvent Class 2 Mixture A USP Certificate
Procedure A: Class 2 - Mixture B
pA
11
FID2 B, (03235A\3235A129.D)
1
5
8
7
8
9
10
artifact
3
7
34
min 0 5 10 15 20 25 30 35
5
6
2
4
6

From USP.org Residual Solvent Class 2 Mixture B USP Certificate
2/8/2011
18
Procedure A Class 3 Mixture
1 Pentane
2 Ethanol
3 Ethyl Ether
4 Acetone
5 Ethyl Formate 5 Ethyl Formate
6 2-Propanol
7 Methyl Acetate
8 t-Butylmethyl Ether
9 1-Propanol
10 Methylethyl Ketone
11 Ethyl Acetate
12 Tetrahydrofuran (THF)
13 2-Butanol
14 2-Methyl-1-propanol
15 Isopropyl Acetate
16 Heptane
17 1-Butanol
18 Propyl Acetate
19 Methylisobutyl Ketone
20 3-Methyl-1-butanol
35
20 3 Methyl 1 butanol
21 Isobutyl Acetate
22 1-Pentanol
23 Butyl Acetate
24 Cumene
25 Anisole
26 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 50
o
C: 20 min
6
o
C/min to 165
o
C 20 min
36
6
o
C/min to 165
o
C, 20 min
Injector temp: 140
o
C
FID temp: 250
o
C
2/8/2011
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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
37
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
2/8/2011
20
Procedure B: Class 2 Mixture A
39
From USP.org Residual Solvent Class 2 Mixture A USP Certificate
Procedure B: Class 2 Mixture B
40
From USP.org Residual Solvent Class 2 Mixture B USP Certificate
2/8/2011
21
Procedure B: Class 2 Mixture C (by direct injection)
pA
1400
FID1A, (03-252\03252028.D)
6
DMSO
1. 2-Methoxyethanol
2. 2-Ethoxyethanol
3 NN-Dimethylformamide
400
600
800
1000
1200
* Additional peak fromDMSO
3
4
5
8
3. N,N-Dimethylformamide
4. N,N-Dimethylacetamide
5. Ethyleneglycol
6. N-Methylpyrrolidone
7. Formamide
8. Sulfolane
41
min 0 10 20 30 40 50
0
200
400
1
2
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 40
o
C: 20 min
42
10
o
C/min to 240
o
C, 20 min
Injector temp: 140
o
C
FID temp: 250
o
C
If results from Procedure A are inferior to B, use Procedure B
conditions
2/8/2011
22
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
43
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
44
If Procedure B is used, follow those system suitability requirements
2/8/2011
23
Water-soluble vs. Water-insoluble
Water-soluble: solutions are prepared using water
as diluent (with some DMSO)
45
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 <621> 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
46
2/8/2011
24
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?
47
Any changes to operating parameters which are not listed in <621>, or
are greater in magnitude than those listed in <621> are considered
Modifications
48
are greater in magnitude than those listed in <621> 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
2/8/2011
25
What are some reasons it may be desirable to use alternative
procedures?
Alternative Procedures
49
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 <467>
A laboratory is having difficulty getting the compendial procedures to work
Alternative procedures must be validated in accordance with
<1225>
USP: . . . The procedures described in . . . this general chapter are to
be applied whenever possible. Otherwise manufacturers may select
Alternative Procedures Permitted
50
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.
2/8/2011
26
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
51
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 <621> 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)
52
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)
2/8/2011
27
To Test or Not to Test
Full testing
Where you would probably start without additional
53
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:
54
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 d submission should include a finished product
specification stating compliance with USP <467>
2/8/2011
28
Reporting Residual Solvents
For each residual solvent identified by the drug
substance manufacturer, excipient manufacturer,
55
, p ,
or used by the ANDA sponsor:
A statement that indicates which option was used to
demonstrate compliance with USP <467> 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 g
product, 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
Reporting Residual Solvents
Information of residual solvents in coati ng materi als, colorants,
fl l d i i ti i k i ll t d d
56
flavors, capsules, and i mpri nti ng i nks is generally not needed
unless Class 1 solvents are used in the manufacture of these
components.
2/8/2011
29
Recap
Regulatory Landscape
Cl ifi ti f S l t Cl d
57
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
58

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