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Stephen 205 (1)

  1. 1. Online Published (2011) ISSN: 0976-7908 Selvan et al PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES REVIEW ON IMPURITIES: A REGULATORY OVERVIEW M.Arulselvan1*, B.Stephen Rathinaraj2,Sirajudeen.M.A.3, Md. Fareedullah2, Farsiya Fatima2, Fatima Shiree21 Department of Pharmaceutical Analysis, Oriental College of Pharmacy.Navi Mumbai,India. Mumbai,India2 Department of Pharmaceutics, Vaagdevi College of Pharmacy, Hanamkonda, Warangal, Andhrapradesh,India.3 Department of Pharmaceutical Biotechnology, Omega College of Pharmacy, Hyderabad, Andhrapradesh,IndiaABSTRACTIncreasing demands of consumers and higher competition in the market emphasize theimportance of drug analysis. The accurate assessment of quality and freshness isespecially important to ease anxiety and to benefit consumers. The quality and stability ofpharmaceutical substances can be affected by the presence of volatile impurities. Volatileimpurities in pharmaceutical products are often residual solvents used in the synthesis,crystallization that escapes during drying or in extraction. This paper reviews the residualsolvents found in the pharmaceuticals, identifying different sources, as well as providingexamples and demonstrating possible measures regarding the control of these organicvolatile impurities in pharmaceuticals.Keywords: Residual solvents; sources of residual solvents; ICH guideline; analysis ofresidual solvents.INTRODUCTION Residual solvents in pharmaceuticals, commonly known as organic volatileimpurities (OVIs), are chemicals that are either used or produced during the manufactureof active pharmaceutical ingredients (APIs), excipients and drug products [1, 2]. Organic solvents play an essential role in drug-substance and excipientmanufacture (e.g., reaction, separation and purification) and in drug-product formulation [3](e.g., granulation and coating) . Some organic solvents are often used during thesynthesis of active pharmaceutical ingredients and excipients or during the preparation of [2]drug products to enhance the yield, increase solubility or aid crystallization . Thesewww.pharmasm.com IC Value – 4.01 1756
  2. 2. Online Published (2011) ISSN: 0976-7908 Selvan et alprocess solvents cannot be completely removed by practical manufacturing practices suchas freeze–drying and drying at high temperature under vacuum. Therefore, some residualsolvents may remain in drug substance material4. Typically, the final purification step inmany pharmaceutical drug-substance processes involves a crystallization step, and thecrystals thus formed can entrap a finite amount of solvent from the mother liquor thatmay cause degradation of the drug, OVIs may also contaminate the products duringpackaging, storage in warehouses and/or during transportation.[3] Sources of residual solvents Used as vehicle Dissolution during Used during during synthesis purification or granulation, coating may remain as crystallization may or any other unit residue remain as residue operation Figure 1 Sources of residual solvents While solvents play a key role in the production of pharmaceuticals, there is alsoa downside, as many of the solvents used have toxic or environmentally hazardousproperties. Complete removal of residual levels of solvents is impractical from amanufacturing 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 theefficacy, safety and stability of the pharmaceutical products. Because residual solventshave 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 belowrecommended acceptable levels. It is a drug manufacturers responsibility to ensure thatany OVIs present in the final product are not harmful to humans and that medicinalproducts do not contain levels of residual solvents higher than recommended safetylimits. Solvents known to cause unacceptable toxicity should be avoided unless their usewww.pharmasm.com IC Value – 4.01 1757
  3. 3. Online Published (2011) ISSN: 0976-7908 Selvan et alcan be justified on the basis of a risk--benefit assessment2. Because of their proven orpotential toxicity the level of residual solvents is controlled through national andinternational guidelines, for example through the FDA and International Conference onHarmonization. "All drug substances, excipients, and products are subject to relevant control ofresidual solvents, even when no test is specified in the individual monograph."REGULATORY AND COMPLIANCE ENVIRONMENT: One of the essential aspects of pharmaceutical manufacturing is regulatorycompliance, which typically encompasses two aspects. The first is compliance withprivate sets of standards based on an applicant filing with a regulatory agency, whichrequires the applicant to report the determined residual solvent levels in a number ofrepresentative batches of pharmaceutical product to establish typical levels of solventcontamination that can routinely be achieved. Based on a statistical evaluation of thereported data, a specification is agreed for solvents used in the final step of the processand a decision made on whether testing is required for solvent used at earlier stages in theprocess. To arrive at a specification that is a measure of the routine performance of theprocess, regulatory agencies require numerical data rather than reporting compliance witha limit test. Internationally, there has been a need to establish regulatory standard guidelines.In 1997, The International Conference on Harmonization of Technical Requirements forRegistration of Pharmaceuticals for Human Use (ICH), through its Q3C Expert workinggroup formed by regulators from the three ICH regions, industry representatives andinterested 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 bejustified by existing safety and toxicity data, and also kept proposed limits within thelevel achievable by normal manufacturing processes and within current analyticcapabilities. The second aspect is compliance with public standards set by Pharmacopoeiasfrom the three ICH regions (United States Pharmacopoeia (USP), EuropeanPharmacopoeia (Ph. Eur.) and Japanese Phamacopoeia (JP)) and also with localpharmacopoeias from countries outside the ICH regions. In the recent past, guidelines forwww.pharmasm.com IC Value – 4.01 1758
  4. 4. Online Published (2011) ISSN: 0976-7908 Selvan et alorganic residual solvents for public standards have generally been vague and not up todate. 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 thegeneral chapter<467> organic volatile impurities5. Very early on, the Ph. Eur. employedthe ICH Q3C regulatory approach and updated the acceptance limits but kept themethodology 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 generalprocedure and describes two complementary gas chromatography (GC) conditions foridentifying unknown solvents. ‘‘System A’’ is recommended for general use and isequivalent 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 ofthis general method is a subject of debate in the pharmaceutical industry due to its limitedselectivity and sensitivity3. Historically, until its 27th edition, the USP restricted itslisting of residual solvents to those of Class 1 and neglected to consider the wide range oforganic solvents used routinely in the pharmaceutical industry. Furthermore, the limitsstated 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 concordancewith the ICH guideline. Residual solvent testing using GC has been included in thepharmacopeias for almost 20 years, while residual solvent-test methods have beenreported in the literature since before that. With USP 28, the public standard for residualsolvents was updated to comply with the ICH Q3C guideline, but the methodology (thesame limit-test approach as Ph. Eur.) and the targeted monographs were not consideredappropriate by industry and regulators, leading to a notice postponing implementation inUSP 29 [6].ICH GUIDELINE: The objective of this guidance is to recommend acceptable amounts for residualsolvents in pharmaceuticals for the safety of the patient. The guidance recommends useof less toxic solvents and describes levels considered to be toxicologically acceptable forsome residual solvents. Residual solvents in pharmaceuticals are defined here as organic volatilechemicals that are used or produced in the manufacture of drug substances or excipients,www.pharmasm.com IC Value – 4.01 1759
  5. 5. Online Published (2011) ISSN: 0976-7908 Selvan et alor in the preparation of drug products. This guidance does not address solventsdeliberately used as excipients nor does it address solvates. However, the content ofsolvents in such products should be evaluated and justified. Since there is no therapeutic benefit from residual solvents, all residual solventsshould be removed to the extent possible to meet product specifications, goodmanufacturing practices, or other quality-based requirements. Drug products shouldcontain no higher levels of residual solvents than can be supported by safety data. Somesolvents that are known to cause unacceptable toxicities (Class 1) should be avoided inthe production of drug substances, excipients, or drug products unless their use can bestrongly justified in a risk-benefit assessment. Some solvents associated with less severetoxicity (Class 2) should be limited in order to protect patients from potential adverseeffects. 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 thescope of this guidance. Therefore, testing should be performed for residual solvents whenproduction 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 orpurification of drug substances, excipients, or drug products. Although manufacturersmay choose to test the drug product, a cumulative method may be used to calculate theresidual solvent levels in the drug product from the levels in the ingredients used toproduce the drug product. If the calculation results in a level equal to or below thatrecommended in this guidance, no testing of the drug product for residual solvents needbe considered. If, however, the calculated level is above the recommended level, the drugproduct should be tested to ascertain whether the formulation process has reduced therelevant solvent level to within the acceptable amount. Drug product should also be testedif a solvent is used during its manufacture. This guidance does not apply to potential new drug substances, excipients, or drugproducts used during the clinical research stages of development, nor does it apply toexisting marketed drug products. The guidance applies to all dosage forms and routes of administration. Higherlevels of residual solvents may be acceptable in certain cases such as short-term (30 dayswww.pharmasm.com IC Value – 4.01 1760
  6. 6. Online Published (2011) ISSN: 0976-7908 Selvan et alor 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 thedegree to which they can be considered an environmental hazard. The list provided in theguideline is not exhaustive, and one should evaluate the synthesis and manufacturingprocesses for all possible residual solvents. The term tolerable daily intake (TDI) is used by the International Program onChemical Safety (IPCS) to describe exposure limits of toxic chemicals and the termacceptable daily intake (ADI) is used by the World Health Organization (WHO) andother national and international health authorities and institutes. The new term permitteddaily exposure (PDE) is defined in the present guidance as a pharmaceutically acceptableintake of residual solvents to avoid confusion of differing values for ADIs of the samesubstance [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 PDEs 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 ofpharmaceuticals are listed as toxic chemicals in Environmental Health Criteria (EHC)monographs and in the Integrated Risk Information System (IRIS). The objectives ofwww.pharmasm.com IC Value – 4.01 1761
  7. 7. Online Published (2011) ISSN: 0976-7908 Selvan et alsuch 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 ofhuman health and maintenance of environmental integrity against the possible deleteriouseffects of chemicals resulting from long-term environmental exposure. The methodsinvolved 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 beused with modification of the approach such as use of larger safety factors. The approachdescribed therein relates primarily to long-term or lifetime exposure of the generalpopulation in the ambient environment (i.e., ambient air, food, drinking water, and othermedia) [7].LIMITS OF RESIDUAL SOLVENTS:A. Solvents to Be Avoided Solvents in Class 1 (Table 1) should not be employed in the manufacture of drugsubstances, excipients, and drug products because of their unacceptable toxicity or theirdeleterious environmental effect. However, if their use is unavoidable in order to producea drug product with a significant therapeutic advance, then their levels should berestricted 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 statedlimit 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 hazardB. Solvents to Be Limited Solvents in Class 2 (Table 2) should be limited in pharmaceutical productsbecause of their inherent toxicity. PDEs are given to the nearest 0.1 mg/day, andwww.pharmasm.com IC Value – 4.01 1762
  8. 8. Online Published (2011) ISSN: 0976-7908 Selvan et alconcentrations are given to the nearest 10 ppm. The stated values do not reflect thenecessary analytical precision of determination. Precision should be determined as part ofthe 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 benzeneC. Solvents with Low Toxic Potential Solvents in Class 3 (Table 3) may be regarded as less toxic and of lower risk tohuman health. Class 3 includes no solvent known as a human health hazard at levelsnormally accepted in pharmaceuticals. However, there are no long-term toxicity orcarcinogenicity studies for many of the solvents in Class 3. Available data indicate thatthey are less toxic in acute or short-term studies and negative in genotoxicity studies. It isconsidered that amounts of these residual solvents of 50 mg per day or lesswww.pharmasm.com IC Value – 4.01 1763
  9. 9. Online Published (2011) ISSN: 0976-7908 Selvan et al(corresponding to 5,000 ppm or 0.5 percent under Option 1) would be acceptable withoutjustification. Higher amounts may also be acceptable provided they are realistic inrelation 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 ofexcipients, drug substances, or drug products. However, no adequate toxicological dataon which to base a PDE were found. Manufacturers should supply justification forresidual levels of these solvents in pharmaceutical products[7].TABLE 3: CLASS 3 SOLVENTS (SOLVENTS WITH LOW TOXIC POTENTIAL)  Acetic acid  Heptane  Acetone  Isobutyl acetate  Anisole  Isopropyl acetate  1-Butanol  Methyl acetate  2-Butanol  3-Methyl-1-butanol  Butyl acetate  Methylethyl ketone  tert-Butylmethyl ether  Methylisobutyl ketone  Cumene  2-Methyl-1-propanol  Dimethyl sulfoxide  Pentane  Ethanol  1-Pentanol  Ethyl acetate  1-Propanol  Ethyl ether  2-Propanol  Ethyl formate  Propyl acetate  Formic acid  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 acidwww.pharmasm.com IC Value – 4.01 1764
  10. 10. Online Published (2011) ISSN: 0976-7908 Selvan et alTHE CURRENT STATUS OF USP, EP AND JP: Although the ICH guideline regarding residual solvents in pharmaceuticalsbecame official in July 1997, USP has not fully adopted it. The current status of eachpharmacopeia is different [2].United States Pharmacopoeia (USP): In 1988, the United States Pharmacopoeia (USP) provided control limits andtesting criteria for seven organic volatile impurities (OVIs) under official monograph [8]<467> . According to USP, testing should be conducted only if a manufacturer hasindicated the possible presence of a solvent in a product. Testing may be avoided when amanufacturer has assurance, based on the knowledge of the manufacturing process andcontrolled handling, shipping, and storage of the product, that no potential exists forspecific solvents to be present and that the product, if tested, will comply with theaccepted 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 [8]substances and some excipients . In addition; a test for ethylene oxide is conducted ifspecified in the individual monograph. Unless otherwise specified in the individualmonograph, the acceptable limit for ethylene oxide is 10 ppm. USP does not address allother 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 ICHwww.pharmasm.com IC Value – 4.01 1765
  11. 11. Online Published (2011) ISSN: 0976-7908 Selvan et alQ3C methodology provides a risk-based approach to residual solvent analysis thatconsiders a patient’s exposure to a solvent residue in the drug product. Solvents havebeen classified based on their potential health risks into three main classes:• Class 1: Solvents should not be used because of the unacceptable toxicities ordeleterious 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 orpurification process of drug substances, excipients, or products. This allows eachcompany to determine which solvents it uses in production and develop testingprocedures that address their specific needs. It is the responsibility of the drugmanufacturer to qualify the purity of all the components used in the manufacturing of thedrug product. This would pertain to items such as excipients, of which some containresidual levels of Class 1 solvents by nature of the manufacturing process and/or natureof the starting materials (e.g. ethyl cellulose). The new <467> monograph provides anoptional method to determine when residual solvent testing is required for Class 2solvents. Each Class 2 solvent is assigned a permitted daily exposure (PDE) limit, whichis the pharmaceutically acceptable intake level of a residual solvent. The USP has provided a method for the identification, control, and quantificationof 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 eitherwater or organic diluent. The monograph has suggested two procedures: Procedure AG43 (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 specifiedconcentration limit, then Procedure B should be used to confirm its identity. Since thereare known co-elutions on both phases, the orthogonal selectivity ensures that co-elutionson one phase will be resolved on the other. Neither procedure is quantitative, so todetermine the concentration the monograph specifies Procedure C, which utilizeswhichever 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 losswww.pharmasm.com IC Value – 4.01 1766
  12. 12. Online Published (2011) ISSN: 0976-7908 Selvan et alon drying is >0.5 %, then a water determination should be performed using <921> WaterDetermination. One of the most important considerations is that once implemented, the newmethod will pertain to all currently marketed drug products as well as those indevelopment and clinical trials [8].European Pharmacopoeia (EP): EP has fully adopted the ICH guideline regarding residual solvents in 1997. In2000, they started requiring that all currently marketed drug products, as well as those indevelopment or clinical trial, meet the ICH guidelines [8]. Section 2.4.24 of the 4th editionof EP describes how to identify and quantify Class 1 and Class 2 residual solvents. Thetest methods can be used to identify the majority of Class 1 and Class 2 solvents whenthey are unknown and as limit tests for Class 1 and Class 2 solvents. The methods alsocan 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 5th edition) it has been agreed that acceptance criteria for Class IIsolvents would not be mentioned in the European Pharmacopoeia monographs and thatClass I solvents would be included only where it was known that their use wasunavoidable in the manufacturing process for the drug substance using the acceptancecriteria laid down in the ICH guidelines. Finally, it is also recognized that some specificsubstances produce solvated forms for which there are frequently higher levels ofsolvents, for example, Class III solvents co-crystallising with the active substances forwhich higher limits than the normal general 0.5% limit may have to be applied. Thesehigher-level Class III solvents would then be named individually on a case-by-case basiswhere their presence at such levels is considered to be unavoidable. It should be stressedthat there is no safety issue relating to such levels since they are low toxicity solvents andthe 0.5% threshold is merely a nominal limit [12].Japanese Pharmacopoeia (JP): The current JP (14th) has adopted the ICH guideline. This pharmacopeia definesresidual solvents as those residual organic solvents in pharmaceuticals that should betested using gas chromatography to comply with the limits specified in the ICHHarmonized Tripartite Guideline [2,13].www.pharmasm.com IC Value – 4.01 1767
  13. 13. Online Published (2011) ISSN: 0976-7908 Selvan et alCASE STUDIES: LIMITS OF RESIDUAL SOLVENT PRESENT IN PFIZERPRODUCTS AS COMPARED TO ICH LIMITSProduct (Pfizer centre source)Triamcinolone USPC21H27FO6 MW 394.43Organic Volatile Impurities Of the solvents targeted in USP 26 General Chapter <467>, only methylenechloride may appear in bulk pharmaceutical products manufactured by Pfizer at theKalamazoo plant. For those products where OVI testing is required, our material willmeet the compendial limits for methylene chloride and other solvents that may be addedto the target list in the future. No OVI requirement exists in the USP 26 monograph for Triamcinolone, butTriamcinolone 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 solventsthat are present above the assay detection limit. During the review of the batch data, it isverified that no solvents are present above the ICH limits. Therefore, all lots ofTriamcinolone 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 listedin Table 6 [14].www.pharmasm.com IC Value – 4.01 1768
  14. 14. Online Published (2011) ISSN: 0976-7908 Selvan et alTABLE 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 drugsubstances used in preclinical or clinical trials as well as for use in commercial drugproducts. Residual solvent analysis of bulk drug substance and finished pharmaceuticalproducts 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
  15. 15. Online Published (2011) ISSN: 0976-7908 Selvan et al  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 [17]techniques . The most popular, and the most appropriate, specific solvent analysis istesting by gas chromatography (GC). Modern capillary-column gas chromatographs canseparate a large number of volatile components, permitting identification throughretention characteristics and detection at ppm levels using a broad range of detectors[5] .Gas chromatographic testing can be categorized into three main procedures accordingto the means of introducing the sample into the instrument. A direct gas chromatographicprocedure is one in which a portion of the actual drug substance or formulation is injectedinto a GC system. The drug substance is usually dissolved in an appropriate solvent andloaded into a syringe and injected. Headspace analysis, on the other hand, is an indirecttesting procedure. The analysis is conducted when a volume of gas above the drugsubstance or formulation is collected and analyzed by a gas chromatograph. Finally,solid-phase microextraction (SPME) is making much progress in recent years for residualsolvent testing. In SPME, a silica fiber coated with a sorbent is used to collect andconcentrate the volatile solvents. The volatiles are then thermally desorbed in the inlet ofthe gas chromatograph and analyzed [18].www.pharmasm.com IC Value – 4.01 1770
  16. 16. Online Published (2011) ISSN: 0976-7908 Selvan et al Many alternatives to gas chromatography have been used to determine the level ofresidual solvent in pharmaceutical products. Many of these procedures are eithernonspecific—that is, the solvents are not identified—or they have high detection limits,so they are inappropriate for the detailed product characterization required for aregulatory submission. The oldest and simplest method for determining the quantity ofvolatile residue is measuring the weight loss of a sample during heating. LOD method iswidely used, particularly for Class 3 solvents, due to its simplicity and ease ofintroduction into even the most basic analytical laboratory [5]. Another approach is to usethermogravimetric analysis (TGA), which is a well-known method for the quantitative [18]analysis of the loss of volatile components from a sample . Spectroscopic andspectrometric methods have generally lacked the low detection limits needed for toxicresidual solvents, although the detection limits would be applicable for ICH class 2 and 3solvents. In the case of infrared spectroscopy (IR), a detection limit above 100 ppm andlack of accuracy at low concentrations of residual solvent have been reported. For NMRalso high detection limit has been reported [5]. List of pharmaceutical sample names and [18]contained residual solvents is reported in Table 8 .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 3CONCLUSION: 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 productshould be analyzed. The complete removal of residual level of these solvents iswww.pharmasm.com IC Value – 4.01 1771
  17. 17. Online Published (2011) ISSN: 0976-7908 Selvan et alimpracticable and traces always remain in the final products. The presence of theseresidual solvents even in small amounts has a negative influence not only on the qualityof products but also on human health. Acceptability of residual solvents seems to be bestjudged following the ICH residual solvent guideline which is adopted by the USP, EPand JP; it classifies the solvent into four groups. In class 1 are included the most toxicsolvents which, unless strongly justified, should be avoided. For the toxic solvents ofclass 2, the limits are expressed as concentrations (ppm) and additionally in the case ofknown daily drug intake, by the very important ‘permitted daily exposure’ (PDE). Theclass 3 includes the solvents with low toxic potential for which the general limit is set at0.5%. 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 inwww.pharmasm.com IC Value – 4.01 1772
  18. 18. Online Published (2011) ISSN: 0976-7908 Selvan et al 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; 5th 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;5th 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, 14th 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.comwww.pharmasm.com IC Value – 4.01 1773

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