The document discusses residual solvents and their testing and limits according to USP <467>. It defines residual solvents as trace organic impurities that are byproducts of manufacturing. There are three classes of residual solvents - Class 1 are toxic and should be avoided, Class 2 should be limited, and Class 3 are less toxic. The method involves three procedures - Procedure A identifies solvents using a G43 column, Procedure B confirms identities using a G16 column, and Procedure C quantifies amounts by comparing to reference standards. The method uses headspace gas chromatography for analysis and has different requirements for water-soluble versus water-insoluble samples.

1. RESIDUAL SOLVENTS
USP <467>
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2. What is Residual Solvent?
 Organic volatile impurities (OVIs), commonly referred to as
residual solvents, are trace level chemical residues in drug
substances and drug products that are byproducts of
manufacturing or that form during packaging and storage.
 Drug manufacturers must ensure that these residues are
removed, or are present only in limited concentrations.
 The International Conference on Harmonization (ICH) Q3C
guideline lists the acceptable amounts of solvent residues that
can be present.
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Why Residual Solvent is important?
 To ensure safety of the patients it is
recommended to use less toxic solvents.
 To prevent any side-effects of drugs by any
carcinogenic or toxic trace elements.
 Testing is to be performed only for solvents
used or produced in the final manufacturing
step, or used in previous step and not
removed by validated procedure. Thus to
maintain quality of drugs.
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Residual Solvent Classes
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5. Class 1 (solvents to be avoided)
 Class 1 residual solvents should not be employed in the
manufacture of drug substances, excipients, and drugproducts
because of the unacceptable toxicities or deleterious
environmental effects of these residual solvents.
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Class 2 Residual Solvents
Class 2 residual solvents should be limited in drug substances,
excipients, and drug products because of the inherent toxicities of
the residual solvents. PDEs are given to the nearest 0.1 mg per
day.
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7. Class 2 Residual Solvents (continued…)
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Class 3 Residual Solvent
Class 3 residual solvents may be regarded as less toxic and of
lower risk to human health than Class 1 and Class 2 residual
solvents. Class 3 includes no solvent known as a human health
hazard at levels normally accepted in pharmaceuticals.
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9. RS Limits for DP/DS/Excipients
 “Option 1”: (Concentration limits, ppm) for Class 1,
2, & 3 Residual Solvents
 “Option 2”: (Permitted Daily Exposure/PDE) for
Class 2 & 3 Residual Solvents
 Option-2 is 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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Class1 Solvent (to be avoided):
General Requirements
 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.
 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 (to be limited):
General Requirements
 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.
 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 (low toxicity):
General Requirements
 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
 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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Responsibility for Reporting RS
Drug product sponsors are responsible for Quality and
safety of their drug products, and Reporting all required
RS information.
Keeping comprehensive, accurate records and
documentation of compliance with all applicable GMP
and other regulations
The Drug Substance, Drug Product and Excipients
manufacturer should establish the reliability of such
analyses, through verification at appropriate intervals
Drug Product manufacturer should verify the Vendor
Statements
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14. Principle for analysis of
residual solvents
 The analysis of residual solvents is commonly performed using
static headspace gas chromatography (HS/GC).
 The basic premise behind headspace analysis begins with the
addition of an exact, known volume or weight of sample into a
closed, sealed vial. This creates two distinct phases in the vial—
a sample phase and a gaseous phase, or “headspace”.
 Volatile components inside the sample phase, whether a solid
or solution, can be extracted, or partitioned, from the sample
phase into the headspace.
 An aliquot of the headspace can then be taken and delivered
into a GC system for separation and detection.
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15.  If we look at the
anatomy of a
headspace vial we
can begin to see the
relationship of the
vial components and
how we can control
these parameters to
create analytical
methods.
 Volatile components
partition from the
sample phase and
equilibrate in the vial
headspace. 15ACI Limited

16. Headspace Vial
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17. Principle for analysis of residual solvents
(continued…)
 Residual solvent analysis by static HS/GC can be enhanced by careful
consideration of two basic concepts—partition coefficient (K) and phase
ratio (β).
 Partition coefficients and phase ratios work together to determine the
final concentration of volatile compounds in the headspace of sample
vials.
 The partition coefficient (K) is defined as the equilibrium distribution of
an analyte between the sample and gas phases. Compounds that have
low K values will tend to partition more readily into the gas phase, and
have relatively high responses and low limits of detection.
 The phase ratio (β) is defined as the volume of the headspace over the
volume of the sample in the vial. Lower values for β (i.e., larger sample
sizes) will yield higher responses for compounds with inherently low K
values.
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18. Principle for analysis of residual solvents
(continued…)
 Striving for the lowest
values for both K and
β when preparing
samples will result in
higher concentrations
of volatile analytes in
the gas phase and,
therefore, better
sensitivity
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19. Overview of Method for Residual
Solvent Testing
 USP <467> is divided into two separate sections based upon
sample solubility: water-soluble and water-insoluble articles.
The methodology for both types of articles is similar, but the
diluent used in both standard and sample preparations differs
based upon the solubility of the test article.
 The test method consists of three procedures (A, B, and C), that
are designed to identify, confirm, and then quantify residual
solvents in drug substances and products .
 The revised USP <467> method consists of a static headspace
extraction coupled with a gas chromatographic separation and
flame ionization detection.
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21. Procedure A - Identification
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 Procedure A is the first step in the identification process and is
performed on a G43 column to determine if any residual solvents are
present in the sample at detectable levels.
 First, Class 1 standard and system suitability solutions and Class 2 Mix
A standard solutions are assayed under the method-specified operating
conditions to establish system suitability.
 All peaks in the Class 1 system suitability solution must have a signal-to-
noise ratio not less than 3, the Class 1 standard solution must have a
1,1,1-trichloroethane response greater than 5, and the resolution of
acetonitrile and dichloromethane must be not less than 1 in the Class 2
Mixture A solution.
 When system suitability has been achieved, the test solutions are
assayed along with the Class 1 and Class 2 Mixtures A and B standard
solutions. If a peak is determined in the sample that matches a retention
time and has a greater response than that of a corresponding reference
material, then Procedure B is performed for verification of the analyte.

22. a G43 Column
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23. Identification of residual solvent in sample by
comparing with reference standard
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24. Procedure B - Confirmation
 Once a residual solvent is identified and found to be above the percent
daily exposure limit, Procedure B is performed to confirm analyte
identity.
 A G16 capillary column is used here as a confirmation column, because
it yields an alternate selectivity compared to a G43 column. The same
standard and system suitability preparations are used in Procedures A
and B.
 The system suitability requirements differ here in that the Class 1
standard solution must have a benzene response greater than 5 and
the resolution of acetonitrile and cisdichloroethene must not be less
than 1 in the Class 2 Mixture A solution, a change from the original
version.
 If the analyte identified in Procedure A again matches the retention time
and exceeds the peak response of the reference materials (with the
same exception to 1,1,1-trichloroethane), the analyst must quantify the
analyte using Procedure C.
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25. Confirmation of residual solvent in sample by
comparing retention time and peak response
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26. Procedure C – Quantification
 Once a residual solvent has been identified and verified,
Procedure C is used to quantify the analyte by analyzing the
sample against compound-specific reference materials.
 Individual standards are prepared by diluting the analyte in
solution to a concentration of 1/20 of the concentration limit
given under concentration limit Table 1 or 2 of the method.
 Following the procedure and instrument conditions in either
Procedure A or B (whichever provides the most definitive
results), a quantifiable result is produced.
 For water-insoluble articles, the same procedure is followed,
except dimethylformamide or dimethylsulfoxide is used as the
diluent.
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27. Confirmation of residual solvent in sample by analyzing the
sample against compound-specific reference materials.
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28. ACI Limited 28
QUESTIONS ?

29. THANK YOU
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By
Hasan Al Banna
Quality Control Officer
Quality Assurance Department
ACI Limited (Pharma Plant)