PHARMA SCIENCE MONITOR

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 1 Department of Pharmaceutical Analysis, Nethaji Institute of Pharmaceutical sciences, Kazipet, Andhra Pradesh, 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 www.pharmasm.com IC Value 4.01 1756

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 material 4. 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] 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 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 www.pharmasm.com IC Value 4.01 1757

can be justified on the basis of a risk--benefit assessment 2. 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 www.pharmasm.com IC Value 4.01 1758

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 23 rd edition in the general chapter<467> organic volatile impurities 5. 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 sensitivity 3. 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, www.pharmasm.com IC Value 4.01 1759

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 www.pharmasm.com IC Value 4.01 1760

or less) or topical application. Justification for these levels should be made on a case-bycase 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 www.pharmasm.com IC Value 4.01 1761

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 longterm 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 Concern (ppm) Benzene 2 Carcinogen Carbon tetrachloride 4 Toxic and environmental hazard 1,2-Dichloroethane 5 Toxic 1,1 - Dichloroethane 8 Toxic 1,1,1 - Trichloroethane 1500 Environmental hazard B. Solvents to Be Limited Solvents in Class 2 (Table 2) should be limited in pharmaceutical products because of their inherent toxicity. PDEs are given to the nearest 0.1 mg/day, and www.pharmasm.com IC Value 4.01 1762

concentrations are given to the nearest 10 ppm. The stated values do not reflect the necessary analytical precision of determination. Precision should be determined as part of the validation of the method [7]. TABLE 2: CLASS 2 SOLVENTS (SOLVENTS TO BE LIMITED) Solvent PDE (mg/day) Concentration limit (ppm) Acetonitrile 4.1 410 Chlorobenzene 3.6 360 Chloroform 0.6 60 Cyclohexane 38.8 3880 1,2-Dichloroethane 18.7 1870 Dichloromethane 6.0 600 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 Ethyleneglycol 6.2 620 Formamide 2.2 220 Hexane 2.9 290 Methanol 30.0 3000 2-Methoxyethanol 0.5 50 Methylbutyl ketone 0.5 50 Methylcyclohexane 11.8 1180 N-Methylpyrrolidone 48.4 4840 Nitromethane 0.5 50 Pyridine 2.0 200 Sulfolane 1.6 160 Tetralin 1.0 100 Toluene 8.9 890 1,1,2-Trichloroethene 0.8 80 Xylene* 21.7 2170 * Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene C. Solvents with Low Toxic Potential Solvents in Class 3 (Table 3) may be regarded as less toxic and of lower risk to human health. Class 3 includes no solvent known as a human health hazard at levels normally accepted in pharmaceuticals. However, there are no long-term toxicity or carcinogenicity studies for many of the solvents in Class 3. Available data indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies. It is considered that amounts of these residual solvents of 50 mg per day or less www.pharmasm.com IC Value 4.01 1763

(corresponding to 5,000 ppm or 0.5 percent under Option 1) would be acceptable without justification. Higher amounts may also be acceptable provided they are realistic in relation to manufacturing capability and good manufacturing practice (GMP) [7]. D. Solvents for which no adequate toxicological data were found The solvents listed in Table 4 may also be of interest to manufacturers of excipients, drug substances, or drug products. However, no adequate toxicological data on which to base a PDE were found. Manufacturers should supply justification for residual levels of these solvents in pharmaceutical products [7]. TABLE 3: CLASS 3 SOLVENTS (SOLVENTS WITH LOW TOXIC POTENTIAL) Acetic acid Acetone Anisole 1-Butanol 2-Butanol Butyl acetate tert-butylmethyl ether Cumene Dimethyl sulfoxide Ethanol Ethyl acetate Ethyl ether Ethyl formate Formic acid Heptane Isobutyl acetate Isopropyl acetate Methyl acetate 3-Methyl-1-butanol Methylethyl ketone Methylisobutyl ketone 2-Methyl-1-propanol Pentane 1-Pentanol 1-Propanol 2-Propanol Propyl acetate Tetrahydrofuran TABLE 4: SOLVENTS FOR WHICH NO ADEQUATE TOXICOLOGICAL DATA WERE FOUND 1,1-Diethoxypropane 1,1-Dimethoxymethane 2,2-Dimethoxypropane Isooctane Isopropyl ether Methylisopropyl ketone Methyltetrahydrofuran Petroleum ether Trichloroacetic acid Trifluoroacetic acid www.pharmasm.com IC Value 4.01 1764

THE CURRENT STATUS OF USP, EP AND JP: Although the ICH guideline regarding residual solvents in pharmaceuticals became official in July 1997, USP has not fully adopted it. The current status of each pharmacopeia is different [2]. United States Pharmacopoeia (USP): In 1988, the United States Pharmacopoeia (USP) provided control limits and testing criteria for seven organic volatile impurities (OVIs) under official monograph <467> [8]. According to USP, testing should be conducted only if a manufacturer has indicated the possible presence of a solvent in a product. Testing may be avoided when a manufacturer has assurance, based on the knowledge of the manufacturing process and controlled handling, shipping, and storage of the product, that no potential exists for specific solvents to be present and that the product, if tested, will comply with the accepted limit. Items shipped in airtight containers (such as those used for food additives) can be considered not to have acquired any solvents during transportation [2]. USP <467> recommends testing for seven organic volatile impurities is listed in Table 5 [9]. TABLE 5: ORGANIC VOLATILE IMPURITIES (OVI) OVI Limit Benzene 2 ppm max Chloroform 60 ppm max 1, 4-Dioxane 380 ppm max Methylene Chloride 600 ppm max Trichloroethylene 80 ppm max The compounds were chosen based on relative toxicity and only applied to drug substances and some excipients [8]. In addition; a test for ethylene oxide is conducted if specified in the individual monograph. Unless otherwise specified in the individual monograph, the acceptable limit for ethylene oxide is 10 ppm. USP does not address all other solvents mentioned in the ICH guideline [2]. In an effort to harmonize with the International Conference for Harmonization (ICH), the USP has proposed the adoption of a slightly modified version of ICH (Q3C) methodology, which has been scheduled for implementation on July 1, 2007. The ICH www.pharmasm.com IC Value 4.01 1765

Q3C methodology provides a risk-based approach to residual solvent analysis that considers a patient s exposure to a solvent residue in the drug product. Solvents have been classified based on their potential health risks into three main classes: Class 1: Solvents should not be used because of the unacceptable toxicities or deleterious environmental effects Class 2: Solvents should be limited because of inherent toxicities Class 3: Solvents may be regarded as less toxic and of lower risk to human health Testing is only required for those solvents used in the manufacturing or purification process of drug substances, excipients, or products. This allows each company to determine which solvents it uses in production and develop testing procedures that address their specific needs. It is the responsibility of the drug manufacturer to qualify the purity of all the components used in the manufacturing of the drug product. This would pertain to items such as excipients, of which some contain residual levels of Class 1 solvents by nature of the manufacturing process and/or nature of the starting materials (e.g. ethyl cellulose). The new <467> monograph provides an optional method to determine when residual solvent testing is required for Class 2 solvents. Each Class 2 solvent is assigned a permitted daily exposure (PDE) limit, which is the pharmaceutically acceptable intake level of a residual solvent. The USP has provided a method for the identification, control, and quantification of Class 1 and 2 residual solvents. The method calls for a gas chromatographic (GC) analysis with flame ionization detection (FID) and a headspace injection from either water or organic diluent. The monograph has suggested two procedures: Procedure A G43 (Zebron ZB-624) phase and Procedure B G16 (Zebron ZB-WAXplus) phase. Procedure A should be used first. If a compound is determined to be above the specified concentration limit, then Procedure B should be used to confirm its identity. Since there are known co-elutions on both phases, the orthogonal selectivity ensures that co-elutions on one phase will be resolved on the other. Neither procedure is quantitative, so to determine the concentration the monograph specifies Procedure C, which utilizes whichever phase will give the fewest co-elutions. Class 3 solvents may be determined by <731> Loss on Drying unless the level is expected to be >5000 ppm or 50 mg. If the loss www.pharmasm.com IC Value 4.01 1766

on drying is >0.5 %, then a water determination should be performed using <921> Water Determination. One of the most important considerations is that once implemented, the new method will pertain to all currently marketed drug products as well as those in development and clinical trials [8]. European Pharmacopoeia (EP): EP has fully adopted the ICH guideline regarding residual solvents in 1997. In 2000, they started requiring that all currently marketed drug products, as well as those in development or clinical trial, meet the ICH guidelines [8]. Section 2.4.24 of the 4 th edition of EP describes how to identify and quantify Class 1 and Class 2 residual solvents. The test methods can be used to identify the majority of Class 1 and Class 2 solvents when they are unknown and as limit tests for Class 1 and Class 2 solvents. The methods also can be used for the quantification of Class 2 solvents when the limits are 1000 ppm (0.1%) or for the quantification of Class 3 solvents when required [2]. In 2005 (EP 5 th edition) it has been agreed that acceptance criteria for Class II solvents would not be mentioned in the European Pharmacopoeia monographs and that Class I solvents would be included only where it was known that their use was unavoidable in the manufacturing process for the drug substance using the acceptance criteria laid down in the ICH guidelines. Finally, it is also recognized that some specific substances produce solvated forms for which there are frequently higher levels of solvents, for example, Class III solvents co-crystallising with the active substances for which higher limits than the normal general 0.5% limit may have to be applied. These higher-level Class III solvents would then be named individually on a case-by-case basis where their presence at such levels is considered to be unavoidable. It should be stressed that there is no safety issue relating to such levels since they are low toxicity solvents and the 0.5% threshold is merely a nominal limit [12]. Japanese Pharmacopoeia (JP): The current JP (14 th ) has adopted the ICH guideline. This pharmacopeia defines residual solvents as those residual organic solvents in pharmaceuticals that should be tested using gas chromatography to comply with the limits specified in the ICH Harmonized Tripartite Guideline [2,13]. www.pharmasm.com IC Value 4.01 1767

CASE STUDIES: LIMITS OF RESIDUAL SOLVENT PRESENT IN PFIZER PRODUCTS AS COMPARED TO ICH LIMITS Product (Pfizer centre source) Triamcinolone USP C 21 H 27 FO 6 MW 394.43 Organic Volatile Impurities Of the solvents targeted in USP 26 General Chapter <467>, only methylene chloride may appear in bulk pharmaceutical products manufactured by Pfizer at the Kalamazoo plant. For those products where OVI testing is required, our material will meet the compendial limits for methylene chloride and other solvents that may be added to the target list in the future. No OVI requirement exists in the USP 26 monograph for Triamcinolone, but Triamcinolone from Pfizer meets the requirements of USP 26 General Chapter <467> [14]. ICH Residual Solvents As of 01 July 2000, Pfizer s laboratories began to internally report all solvents that are present above the assay detection limit. During the review of the batch data, it is verified that no solvents are present above the ICH limits. Therefore, all lots of Triamcinolone released after 01 July 2000 will meet the ICH residual solvent guidance. A Comparison of residual solvents content reported by Pfizer and ICH Guideline is listed in Table 6 [14]. www.pharmasm.com IC Value 4.01 1768

TABLE 6: COMPARISON OF RESIDUAL SOLVENTS CONTENT REPORTED BY PFIZER AND ICH GUIDELINE Solvent Pfizer specification* ICH class and specification Residual solvents (total) NMT 0.5% Ethyl acetate No individual specification 3 / NMT 0.5% Methylene chloride NMT 600 ppm 2 / NMT 600 ppm Tetrahydrofuran No individual specification 3 / NMT 0.5% Pfizer does not have Registered Specifications for residual solvents, only quality controls Targets. ANALYSIS OF RESIDUAL SOLVENT IN PHARMACEUTICALS: The analysis of residual solvents is an essential part in the quality control of drug substances used in preclinical or clinical trials as well as for use in commercial drug products. Residual solvent analysis of bulk drug substance and finished pharmaceutical products is necessary for a number of reasons: High levels of residual organic solvents represent a risk to human health because of their toxicity Residual organic solvents also play a role in the physicochemical properties of the bulk drug substance. Crystallinity of the bulk drug substance can be affected. Differences in the crystal structure of the bulk drug may lead to changes in dissolution properties and problems with formulation of the finished product. Finally, residual organic solvents can create odor problems and color changes in the finished product and, thus, can lead to consumer complaints [5]. Often, the main purpose for residual solvent testing is in its use as a monitoring check for further drying of bulk pharmaceuticals or as a final check of a finished product. Testing for solvent content in intermediates may need to be performed if a critical amount of residual solvent(s) remaining in the intermediate can alter the next step of the process. Knowledge of the solvent content in the starting materials may help to the development chemist to understand the synthetic routes and predict potential process related impurities. www.pharmasm.com IC Value 4.01 1769

Knowing the solvents used in the process allows the development chemist to look for possible compound- solvent interactions which can lead to the formation of impurities [15]. TABLE 7: LIST OF PHARMACEUTICAL SAMPLE NAMES AND CONTAINED RESIDUAL SOLVENTS [16]. Pharmaceutical sample Residual solvent Class Lidocain Heptane 3 Ethyl aminoben Toluene 2 Antipyrine Methanol 2 Phenacetin Methanol, toluene 2, 2 Cimetidine Ethanol 3 Famotidine Methanol 2 carbamazepine Acetone 3 Residual solvent analysis can be performed with a large array of analytical techniques [17]. The most popular, and the most appropriate, specific solvent analysis is testing by gas chromatography (GC). Modern capillary-column gas chromatographs can separate a large number of volatile components, permitting identification through retention characteristics and detection at ppm levels using a broad range of detectors [5].Gas chromatographic testing can be categorized into three main procedures according to the means of introducing the sample into the instrument. A direct gas chromatographic procedure is one in which a portion of the actual drug substance or formulation is injected into a GC system. The drug substance is usually dissolved in an appropriate solvent and loaded into a syringe and injected. Headspace analysis, on the other hand, is an indirect testing procedure. The analysis is conducted when a volume of gas above the drug substance or formulation is collected and analyzed by a gas chromatograph. Finally, solid-phase microextraction (SPME) is making much progress in recent years for residual solvent testing. In SPME, a silica fiber coated with a sorbent is used to collect and concentrate the volatile solvents. The volatiles are then thermally desorbed in the inlet of the gas chromatograph and analyzed [18]. www.pharmasm.com IC Value 4.01 1770

Many alternatives to gas chromatography have been used to determine the level of residual solvent in pharmaceutical products. Many of these procedures are either nonspecific that is, the solvents are not identified or they have high detection limits, so they are inappropriate for the detailed product characterization required for a regulatory submission. The oldest and simplest method for determining the quantity of volatile residue is measuring the weight loss of a sample during heating. LOD method is widely used, particularly for Class 3 solvents, due to its simplicity and ease of introduction into even the most basic analytical laboratory [5]. Another approach is to use thermogravimetric analysis (TGA), which is a well-known method for the quantitative analysis of the loss of volatile components from a sample [18]. Spectroscopic and spectrometric methods have generally lacked the low detection limits needed for toxic residual solvents, although the detection limits would be applicable for ICH class 2 and 3 solvents. In the case of infrared spectroscopy (IR), a detection limit above 100 ppm and lack of accuracy at low concentrations of residual solvent have been reported. For NMR also high detection limit has been reported [5]. List of pharmaceutical sample names and contained residual solvents is reported in Table 8 [18]. TABLE 8: LIST OF PHARMACEUTICAL SAMPLE NAMES AND CONTAINED RESIDUAL SOLVENTS Pharmaceutical sample Residual solvent Class Lidocain Heptane 3 Ethyl aminoben Toluene 2 Antipyrine Methanol 2 Phenacetin Methanol, toluene 2, 2 Cimetidine Ethanol 3 Famotidine Methanol 2 carbamazepine Acetone 3 CONCLUSION: Whenever organic solvents are used in the production of pharmaceutical products, especially in the last processing steps, the content of residual solvent in the final product should be analyzed. The complete removal of residual level of these solvents is www.pharmasm.com IC Value 4.01 1771

impracticable and traces always remain in the final products. The presence of these residual solvents even in small amounts has a negative influence not only on the quality of products but also on human health. Acceptability of residual solvents seems to be best judged following the ICH residual solvent guideline which is adopted by the USP, EP and JP; it classifies the solvent into four groups. In class 1 are included the most toxic solvents which, unless strongly justified, should be avoided. For the toxic solvents of class 2, the limits are expressed as concentrations (ppm) and additionally in the case of known daily drug intake, by the very important permitted daily exposure (PDE). The class 3 includes the solvents with low toxic potential for which the general limit is set at 0.5%. The class 4 includes solvents for which no adequate toxicological data was found. REFERENCES 1. Michulec M., Wardenki, W. Development of headspace solid- phase microextraction-gas chromatography method for the determination of solvent residues in edible oils and pharmaceuticals. J. Chromatogr 2005; 1071: 119-124. 2. Dwivedi A. M. Residual solvent analysis in pharmaceuticals. Pharmaceutical technology 2002; 42-46. 3. Camarasu C. Unknown residual solvents identification in drug products by headspace solid phase microextraction gas chromatography- mass spectroscopy. Chromatographia 2002; 56: S131-S135. 4. Rocheleau M J. Measuring residual solvents in pharmaceutical samples using fast gas chromatography techniques. J. Chromatogr. B 2004; 805: 77-86. 5. B Hymer C. Residual solvent testing: A review of gas chromatographic and alternative techniques, Pharm. Res. 2003; 20, 337-343. 6. Otero, R., Carrera, G., Static headspace gas chromatographic method for quantitative determination of residual solvents in pharmaceutical drug substances according to European pharmacopoeia requirements. J. Chromatogr. A 2004; 1057: 193-201. 7. ICH Q3(C). Impurities: residual solvents 1997. 8. Countrymen, S. Understanding the revision to USP monograph <467>: residual solvents, phenomenex Inc. Torrance, CA, USA, 2007. 9. General chapters <466>. "Ordinary impurities" and <1086>, "Impurities in www.pharmasm.com IC Value 4.01 1772

official articles," in USP 28--NF 23. US Pharmacopoeia. 12601 Twin brook Parkway, Rockville, Maryland 20852, USA, 2004. 10. European pharmacopoeia. Identification and control of residual solvents (2.4.24), directorate for the quality of medicines of the council of Europe, Strasbourg, France, 2005; 5 th edition, pp. 96. 11. European Pharmacopoeia. General chapter 5.10, Control of impurities in substances for pharmaceutical use and general monograph: 2034, substances for pharmaceutical use, 2005;5 th edition. pp 559-561, 586-587. 12. Morris, J. M. Regulation of residual solvents in medicinal products in the European Union, Irish medicines board, 2007. 13. Japanese Pharmacopoeia. Residual solvent testing, society of Japanese pharmacopoeia, 14 th edition. 14. Pfizer centre source. Triamcinalone, Pfizer.inc 2004. 15. Ahuja S. Residual solvents. Handbook of modern pharmaceutical analysis. Marcel Dekker publications, 2003; pp. 86-87. 16. Wood, D. C., Miller, J. M. Headspace liquid microextraction. LC-GC Europe 2004; 17: 573-579. 17. Ahuja S. Gas chromatography, Handbook of modern pharmaceutical analysis. Marcel Dekker publications, 2003; pp.375-377. 18. Madichie C., Camarasu C. Recent progress in the determination of volatile impurities in pharmaceuticals. Trends in analytical chemistry 2006; 25: 768-777. For Correspondence: M.Arul Selvan Email: steaje@gmail.com www.pharmasm.com IC Value 4.01 1773