1 Department of Pharmaceutical Analysis, Oriental College of Pharmacy.Navi Mumbai,India. Online Published (2011) ISSN: 0976-7908 Selvan et al www.pharmasm.com IC Value – 4.01 1756 PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES REVIEW ON IMPURITIES: A REGULATORY OVERVIEW M.Arulselvan 1 *, B.Stephen Rathinaraj 2 ,Sirajudeen.M.A. 3 , Md. Fareedullah 2 , Farsiya Fatima 2 , Fatima Shiree 2 Department of Pharmaceutical Analysis, Oriental College of Pharmacy.Navi Mumbai,India 2 Department of Pharmaceutics, Vaagdevi College of Pharmacy, Hanamkonda, Warangal, Andhrapradesh, India. 3 Department of Pharmaceutical Biotechnology, Omega College of Pharmacy, Hyderabad, Andhrapradesh, India ABSTRACT Increasing demands of consumers and higher competition in the market emphasize the importance of drug analysis. The accurate assessment of quality and freshness is especially important to ease anxiety and to benefit consumers. The quality and stability of pharmaceutical substances can be affected by the presence of volatile impurities. Volatile impurities in pharmaceutical products are often residual solvents used in the synthesis, crystallization that escapes during drying or in extraction. This paper reviews the residual solvents found in the pharmaceuticals, identifying different sources, as well as providing examples and demonstrating possible measures regarding the control of these organic volatile impurities in pharmaceuticals. Keywords: Residual solvents; sources of residual solvents; ICH guideline; analysis of residual solvents. INTRODUCTION Residual solvents in pharmaceuticals, commonly known as organic volatile impurities (OVIs), are chemicals that are either used or produced during the manufacture of active pharmaceutical ingredients (APIs), excipients and drug products [1, 2] . Organic solvents play an essential role in drug-substance and excipient manufacture (e.g., reaction, separation and purification) and in drug-product formulation (e.g., granulation and coating) [3] . Some organic solvents are often used during the synthesis of active pharmaceutical ingredients and excipients or during the preparation of drug products to enhance the yield, increase solubility or aid crystallization [2] . These
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1Department of Pharmaceutical Analysis, Oriental College of Pharmacy.Navi Mumbai,India.
Online Published (2011) ISSN: 0976-7908 Selvan et al
www.pharmasm.com IC Value – 4.01 1756
PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES
Department of Pharmaceutical Analysis, Oriental College of Pharmacy.Navi Mumbai,India
2Department of Pharmaceutics, Vaagdevi College of Pharmacy, Hanamkonda, Warangal, Andhrapradesh, India. 3Department of Pharmaceutical Biotechnology, Omega College of Pharmacy, Hyderabad, Andhrapradesh, India
ABSTRACT Increasing demands of consumers and higher competition in the market emphasize the
importance of drug analysis. The accurate assessment of quality and freshness is
especially important to ease anxiety and to benefit consumers. The quality and stability of
pharmaceutical substances can be affected by the presence of volatile impurities. Volatile
impurities in pharmaceutical products are often residual solvents used in the synthesis,
crystallization that escapes during drying or in extraction. This paper reviews the residual
solvents found in the pharmaceuticals, identifying different sources, as well as providing
examples and demonstrating possible measures regarding the control of these organic
volatile impurities in pharmaceuticals.
Keywords: Residual solvents; sources of residual solvents; ICH guideline; analysis of residual solvents. INTRODUCTION
Residual solvents in pharmaceuticals, commonly known as organic volatile
impurities (OVIs), are chemicals that are either used or produced during the manufacture
of active pharmaceutical ingredients (APIs), excipients and drug products [1, 2].
Organic solvents play an essential role in drug-substance and excipient
manufacture (e.g., reaction, separation and purification) and in drug-product formulation
(e.g., granulation and coating) [3]. Some organic solvents are often used during the
synthesis of active pharmaceutical ingredients and excipients or during the preparation of
drug products to enhance the yield, increase solubility or aid crystallization [2]. These
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process solvents cannot be completely removed by practical manufacturing practices such
as freeze–drying and drying at high temperature under vacuum. Therefore, some residual
solvents may remain in drug substance material4. Typically, the final purification step in
many pharmaceutical drug-substance processes involves a crystallization step, and the
crystals thus formed can entrap a finite amount of solvent from the mother liquor that
may cause degradation of the drug, OVIs may also contaminate the products during
packaging, storage in warehouses and/or during transportation.[3]
Figure 1 Sources of residual solvents
While solvents play a key role in the production of pharmaceuticals, there is also
a downside, as many of the solvents used have toxic or environmentally hazardous
properties. Complete removal of residual levels of solvents is impractical from a
manufacturing standpoint, so it is inevitable that traces will remain in the final product.
The presence of these unwanted chemicals even in small amounts may influence the
efficacy, safety and stability of the pharmaceutical products. Because residual solvents
have no therapeutic benefits but may be hazardous to human health and the environment,
it must be ensured that they are either not present in products or are only present below
recommended acceptable levels. It is a drug manufacturer's responsibility to ensure that
any OVIs present in the final product are not harmful to humans and that medicinal
products do not contain levels of residual solvents higher than recommended safety
limits. Solvents known to cause unacceptable toxicity should be avoided unless their use
Sources of residual solvents
Used as vehicle during synthesis may remain as
residue
Dissolution during purification or
crystallization may remain as residue
Used during granulation, coating
or any other unit operation
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can be justified on the basis of a risk--benefit assessment2. Because of their proven or
potential toxicity the level of residual solvents is controlled through national and
international guidelines, for example through the FDA and International Conference on
Harmonization.
"All drug substances, excipients, and products are subject to relevant control of
residual solvents, even when no test is specified in the individual monograph."
REGULATORY AND COMPLIANCE ENVIRONMENT:
One of the essential aspects of pharmaceutical manufacturing is regulatory
compliance, which typically encompasses two aspects. The first is compliance with
private sets of standards based on an applicant filing with a regulatory agency, which
requires the applicant to report the determined residual solvent levels in a number of
representative batches of pharmaceutical product to establish typical levels of solvent
contamination that can routinely be achieved. Based on a statistical evaluation of the
reported data, a specification is agreed for solvents used in the final step of the process
and a decision made on whether testing is required for solvent used at earlier stages in the
process. To arrive at a specification that is a measure of the routine performance of the
process, regulatory agencies require numerical data rather than reporting compliance with
a limit test.
Internationally, there has been a need to establish regulatory standard guidelines.
In 1997, The International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH), through its Q3C Expert working
group formed by regulators from the three ICH regions, industry representatives and
interested parties/observers, finalized the Q3C guideline on residual solvents. Essentially,
ICH has consistently proposed that limits on organic solvents be set at levels that can be
justified by existing safety and toxicity data, and also kept proposed limits within the
level achievable by normal manufacturing processes and within current analytic
capabilities.
The second aspect is compliance with public standards set by Pharmacopoeias
from the three ICH regions (United States Pharmacopoeia (USP), European
Pharmacopoeia (Ph. Eur.) and Japanese Phamacopoeia (JP)) and also with local
pharmacopoeias from countries outside the ICH regions. In the recent past, guidelines for
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organic residual solvents for public standards have generally been vague and not up to
date. The pharmacopoeial approach was typically a limit test for residual solvents,
employing standard addition[3]. The USP set the official limits in USP 23rd edition in the
general chapter<467> organic volatile impurities5. Very early on, the Ph. Eur. employed
the ICH Q3C regulatory approach and updated the acceptance limits but kept the
methodology as a limit test based on standard addition. The general method in Ph. Eur.
for Identification and Control of Residual Solvents in drug substances defines a general
procedure and describes two complementary gas chromatography (GC) conditions for
identifying unknown solvents. ‘‘System A’’ is recommended for general use and is
equivalent to ‘‘Methods IV and V’’ of the USP for analysis of volatile organic impurities
‘‘System B’’ is used to confirm identification and to solve co-elutions. Implementation of
this general method is a subject of debate in the pharmaceutical industry due to its limited
selectivity and sensitivity3. Historically, until its 27th edition, the USP restricted its
listing of residual solvents to those of Class 1 and neglected to consider the wide range of
organic solvents used routinely in the pharmaceutical industry. Furthermore, the limits
stated for Class 1 solvents benzene, chloroform, 1, 4-dioxane, methylene chloride, and 1,
1, 1-trichloroethane are in the range 2–600 (ppm) and are therefore not in concordance
with the ICH guideline. Residual solvent testing using GC has been included in the
pharmacopeias for almost 20 years, while residual solvent-test methods have been
reported in the literature since before that. With USP 28, the public standard for residual
solvents was updated to comply with the ICH Q3C guideline, but the methodology (the
same limit-test approach as Ph. Eur.) and the targeted monographs were not considered
appropriate by industry and regulators, leading to a notice postponing implementation in
USP 29 [6].
ICH GUIDELINE:
The objective of this guidance is to recommend acceptable amounts for residual
solvents in pharmaceuticals for the safety of the patient. The guidance recommends use
of less toxic solvents and describes levels considered to be toxicologically acceptable for
some residual solvents.
Residual solvents in pharmaceuticals are defined here as organic volatile
chemicals that are used or produced in the manufacture of drug substances or excipients,
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or in the preparation of drug products. This guidance does not address solvents
deliberately used as excipients nor does it address solvates. However, the content of
solvents in such products should be evaluated and justified.
Since there is no therapeutic benefit from residual solvents, all residual solvents
should be removed to the extent possible to meet product specifications, good
manufacturing practices, or other quality-based requirements. Drug products should
contain no higher levels of residual solvents than can be supported by safety data. Some
solvents that are known to cause unacceptable toxicities (Class 1) should be avoided in
the production of drug substances, excipients, or drug products unless their use can be
strongly justified in a risk-benefit assessment. Some solvents associated with less severe
toxicity (Class 2) should be limited in order to protect patients from potential adverse
effects. Ideally, less toxic solvents (Class 3) should be used where practical [7].
SCOPE OF THE GUIDANCE:
Residual solvents in drug substances, excipients, and drug products are within the
scope of this guidance. Therefore, testing should be performed for residual solvents when
production or purification processes are known to result in the presence of such solvents.
It is only necessary to test for solvents that are used or produced in the manufacture or
purification of drug substances, excipients, or drug products. Although manufacturers
may choose to test the drug product, a cumulative method may be used to calculate the
residual solvent levels in the drug product from the levels in the ingredients used to
produce the drug product. If the calculation results in a level equal to or below that
recommended in this guidance, no testing of the drug product for residual solvents need
be considered. If, however, the calculated level is above the recommended level, the drug
product should be tested to ascertain whether the formulation process has reduced the
relevant solvent level to within the acceptable amount. Drug product should also be tested
if a solvent is used during its manufacture.
This guidance does not apply to potential new drug substances, excipients, or drug
products used during the clinical research stages of development, nor does it apply to
existing marketed drug products.
The guidance applies to all dosage forms and routes of administration. Higher
levels of residual solvents may be acceptable in certain cases such as short-term (30 days
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or less) or topical application. Justification for these levels should be made on a case-by-
case basis [7].
CLASSIFICATION OF RESIDUAL SOLVENTS:
OVIs are classified into three classes on the basis of their toxicity level and the
degree to which they can be considered an environmental hazard. The list provided in the
guideline is not exhaustive, and one should evaluate the synthesis and manufacturing
processes for all possible residual solvents.
The term tolerable daily intake (TDI) is used by the International Program on
Chemical Safety (IPCS) to describe exposure limits of toxic chemicals and the term
acceptable daily intake (ADI) is used by the World Health Organization (WHO) and
other national and international health authorities and institutes. The new term permitted
daily exposure (PDE) is defined in the present guidance as a pharmaceutically acceptable
intake of residual solvents to avoid confusion of differing values for ADI's of the same
substance [7].
Residual solvents are classified on the basis of risk assessment:
Class 1 solvents: Solvents to be avoided-
Known human carcinogens, strongly suspected human carcinogens, and
environmental hazards.
Class 2 solvents: Solvents to be limited-
Nongenotoxic animal carcinogens or possible causative agents of other
irreversible toxicity such as neurotoxicity or teratogenicity.
Class 3 solvents: Solvents with low toxic potential-
Solvents with low toxic potential to man; no health-based exposure limit is
needed. Class 3 solvents have PDE's of 50 milligrams (mg) or more per day.
Class 4 solvents: Solvents for which no adequate toxicological data was found
No adequate toxicological data on which to base a PDE (permitted dose
exposure) was found [7].
ENVIRONMENTAL REGULATION OF ORGANIC VOLATILE SOLVENTS
Several of the residual solvents frequently used in the production of
pharmaceuticals are listed as toxic chemicals in Environmental Health Criteria (EHC)
monographs and in the Integrated Risk Information System (IRIS). The objectives of
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such groups as the International Programme on Chemical Safety (IPCS), the U.S.
Environmental Protection Agency (EPA), and the U.S. Food and Drug Administration
(FDA) include the determination of acceptable exposure levels. The goal is protection of
human health and maintenance of environmental integrity against the possible deleterious
effects of chemicals resulting from long-term environmental exposure. The methods
involved in the estimation of maximum safe exposure limits are usually based on long-
term studies. When long-term study data are unavailable, shorter term study data can be
used with modification of the approach such as use of larger safety factors. The approach
described therein relates primarily to long-term or lifetime exposure of the general
population in the ambient environment (i.e., ambient air, food, drinking water, and other
media) [7].
LIMITS OF RESIDUAL SOLVENTS:
A. Solvents to Be Avoided
Solvents in Class 1 (Table 1) should not be employed in the manufacture of drug
substances, excipients, and drug products because of their unacceptable toxicity or their
deleterious environmental effect. However, if their use is unavoidable in order to produce
a drug product with a significant therapeutic advance, then their levels should be
restricted as shown in Table 1, unless otherwise justified. The solvent 1, 1, 1-
Trichloroethane is included in Table 1 because it is an environmental hazard. The stated
limit of 1,500 ppm is based on a review of the safety data.
TABLE 1: CLASS 1 SOLVENT (SOLVENTS THAT SHOULD BE AVOIDED)
Concentration limit (ppm)
Concern
Benzene 2 Carcinogen Carbon tetrachloride 4 Toxic and