Drug safety, drug quality, drug analysis

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<ul><li><p>Available online at www.sciencedirect.com</p><p>Journal of Pharmaceutical and Biomedical Analysis 48 (2008) 247253</p><p>Drug safety, drug quality, d</p><p>Budap2 Octer 200</p><p>Abstract</p><p>Controllin ringproperties of samequality of bu d toare identity, ity iselucidation) cts, tdrug materials can be avoided or at least controlled/minimized.</p><p>The deveand requirePharmacopoare observaused. Sincerecommend</p><p>The effecis that dueattribute for</p><p>It is recomfor more im 2007 Els</p><p>Keywords: D</p><p>1. Introdu</p><p>1.1. Aims</p><p>The aimone senten</p><p>The aianalysis) i</p><p> bulk dru the inter product drug for</p><p> Tel.: +36E-mail ad</p><p>0731-7085/$doi:10.1016/jlopment in the field of chromatographic and spectroscopic methods in the last decades has led to changes in the philosophy, structurements in the monographs of drug materials in the principal pharmacopoeias. Although the approaches of the European and USeias are somewhat different, a common feature is the shift of focal point toward purity tests. In contrast to this, relatively few changes</p><p>ble in the field of the assay methods for bulk drug materials: non-selective titrimetric and spectrophotometric methods are still widelythe results of these do not contribute to the safety issue, the omission of these tests and substitution by the mass balance concept ised.tiveness of the tendency of replacing non-selective methods by selective ones (mainly HPLC) is also questionable. The reason for thisto the limited precision of the HPLC assay the drug content obtained by the mass balance concept is a much better quality controlbulk drug materials than that obtained by HPLC.mended that classical assay methods (including HPLC) be used in exceptional cases only and the time and energy thus spared be used</p><p>portant impurity-related issues that directly contribute to the safety of drug therapy.evier B.V. All rights reserved.</p><p>rug quality; Drug safety; Drug purity; Drug analysis; Assay</p><p>ction</p><p>and scope of drug analysis</p><p>s and scope of drug analysis can be summarized ince as follows:m of drug analysis (with emphasis on industrial drugs the analytical investigation of</p><p>g materials,mediates of their syntheses,s of drug research (potential pharmacons),mulations,</p><p>1 4314620; fax: +36 1 4315284.dress: s.gorog@richter.hu.</p><p> the impurities and degradation products of drugs, biological samples containing the drugs and their metabolites.</p><p>with the aim of obtaining data which can contribute to</p><p> the high quality, the maximum efficacy and maximum safety of drug therapy and the maximum economy of the production of drugs [1].</p><p>This sentence contains the three main issues incorporatedin the title of the paper: safety, quality and analysis of drugs.The aim of this paper is to describe the authors views on thecorrelation of these with the eyes of a pharmaceutical analyst,i.e. how to optimize the contribution of analytical chemistryin assuring maximum safety of drug therapy. The scope of the</p><p> see front matter 2007 Elsevier B.V. All rights reserved..jpba.2007.10.038Sandor Gorog Gedeon Richter Plc., P.O.B. 27, H-1475</p><p>Received 2 October 2007; accepted 1Available online 13 Novemb</p><p>g and minimizing the side effects of drugs are the key issues in assuthe drug material, these cannot be influenced by drug analysts. At thelk drug materials and drug formulations and this is also closely relatestrength and purity. Of these, in the case of bulk drug materials, purand quantitative determination of the impurities and degradation produrug analysis</p><p>est, Hungaryober 20077</p><p>the safety of drug therapy. Since side effects are inherenttime drug analysts play a predominant role in assuring thethe safety issue. The three main attributes of drug qualityof prominent importance: by the identification (structurehe risk of their contribution to the side effect profile of the</p></li><li><p>248 S. Gorog / Journal of Pharmaceutical and Biomedical Analysis 48 (2008) 247253</p><p>paper is restricted to bulk drug materials with small molecules:biomacromolecules and drug formulations will not be dealtwith.</p><p>1.2. Drug</p><p>The Fooships of ththe safety odrugs. . . bemine that thcausing sid</p><p>The efcgists, biolotaking partpharmaceucan only inaiming at in[3].</p><p>So mucanalytical cshows thateffect prolpropertiestheir benefithe duty oftration ageof a new ddecision.</p><p>On thedegradationAvoiding oassuring thtion to toxand regulanant role inmaterial.</p><p>1.3. Drug</p><p>The defiConferencesuitabilityintended usstrength anability of thin the earlytion was bainfrared sping with refnot necessan importaever of prmaterials, icontent is, eically 98.0potentially</p><p>composition of (100 active ingredient content)% = impurities.With other words this means that of the three attributes in</p><p>A/ICH definition purity is of prominent importancemajority of cases the only really important quality</p><p>te.)</p><p>rug</p><p>the t. (1)ventand. Thabovtee tdrugmuc</p><p>f orgpur</p><p>igind ofuritifactothe omendstryuencingpurit) anre e</p><p>es inain,ty pdete</p><p>detaceuationr connsid</p><p>f they.</p><p>impat in], aa) gee imimpu[15]aperdea] ca], anle ority pticalsafety</p><p>d and Drug Administration (FDA), one of the flag-e drug safety issue describes its own role regardingf drug therapy as follows: . . . FDA. . . requires thatproven safe and effective. . . .FDA. . . must deter-e drug produces the benefits it is supposed to withoute effects that would outweigh those benefits [2].acy of drug therapy depends mainly on pharmacolo-</p><p>gists, biochemists, synthetic chemists, and cliniciansin the development of the drug. Although the role oftical analysts is not negligible even in this field, theydirectly contribute to the success of drug researchtroducing new, highly effective drugs into the therapy</p><p>h the greater is the importance of the activities ofhemists in safety issues. The definition cited above</p><p>the safety of drug therapy mainly depends on the sidee of the drug. As it is known, side effects are inherentof the drug material. The examination of the ratio ofcial actions and the risks caused by the side effects ispharmacologists, toxicologists, clinicians and regis-</p><p>ncies before making decision about the introductionrug: analytical chemists do not play any role in this</p><p>other hand physiologically active impurities andproducts can contribute to the side effect profile.</p><p>r at least minimizing this contribution is a key issue ine reproducibility and safety of drug therapy. In addi-icologists, process chemists, formulation scientiststion agencies, analytical chemists play a predomi-</p><p>this by controlling the quality (purity) of the drug</p><p>quality</p><p>nition of drug quality in a FDA-ICH (Internationalon Harmonisation) document [4] is as follows: The</p><p>of either a drug substance or drug product for itse. This term includes such attributes as the identity,d purity. Of the three attributes improving the reli-e identication tests used to be of great importanceperiod of pharmaceutical analysis when identifica-</p><p>sed on specific colour reactions. Nowadays, however,ectroscopy and/or chromatographic retention match-erence standards create a firm basis for identification</p><p>itating further developments. Strength is of coursent quality attribute of drug formulations. It is, how-actically no importance in the case of bulk drug.e. it is not important whether the active ingredient.g. 98.5 or 99.5% within the acceptance criteria (typ-</p><p>102.0% or even stricter.) The only important pointinfluencing drug safety is the quantity, nature and</p><p>the FD(in theattribu</p><p>1.4. D</p><p>Of[5], i.eual solmetalslimitedin theguaranof the</p><p>Sotion oThe imthe ormethoof impthesecisedrecom</p><p>chemiconseqwhelmthe im(HPLCthese aferencuncertimpuriis thetitativepharmapplic[5] fointo codose otherap</p><p>Thefact th[1114ering (volatilgenicNMRwith ppapers[2325[26,27merabImpurmaceupurity</p><p>hree types of impurities listed in the ICH Guidelinesorganic impurities; (2) inorganic impurities; (3) resid-s, (2) and (3) are easy to control. The number of toxicsolvents that may occur in bulk drug substances is</p><p>eir toxicity is well characterized and the limits set upe-mentioned guidelines and in the pharmacopoeiashat these cannot contribute to the side effect profile.h the more problematic is the potential contribu-anic impurities to the side effects of bulk drugs.</p><p>ity profile of drugs depends on the synthetic route,and purity of the starting materials and reagents,purification and storage conditions: various kindses can originate from differences and changes ofrs. (Note: the author of the present paper criti-fficial classification [5] of organic impurities anded a modified classification better reflecting the</p><p>behind the occurrence of the impurities [6].) As ae of the uncertainties outlined above, in the over-</p><p>majority of cases the pharmacopoeias do not specifyies in the high-performance liquid chromatographicd thin-layer chromatographic (TLC) purity tests;</p><p>xpressed as the main component neglecting the dif-their responses. Of course this can be source of</p><p>moreover sometimes erroneous results. This is whyrofiling, i.e. analytical activities the aim of whichction, identification/structure elucidation and quan-ermination of impurities are key issue in moderntical analysis. This creates the basis for the successfulof the principles outlined in the FDA/ICH documentstrolling the limits of individual impurities takingeration the toxicity of the impurity and the dailydrug thus greatly contributing to the safety of drug</p><p>ortance of impurity profiling is well reflected by thethe recent years four books [710], book chapters</p><p>special issue in Trends in Analytical Chemistry cov-neral aspects, (b) degradation-related impurities, (c)</p><p>purities, (d) TLC aspects, (e) genotoxic and carcino-rities, (f) HPLC aspects and (g) the role of off-line, another one in Advanced Drug Delivery Reviewss on various analytical aspects [16], several reviewling with general [1721], HPLC [22], HPLCMSpillary electrophoresis (CE) and related techniquesd CE-MS [23], chiral CE [28] aspects and innu-dinary papers have been published on this subject.rofiling is a hot topic, indeed, in contemporary phar-analysis!</p></li><li><p>S. Gorog / Journal of Pharmaceutical and Biomedical Analysis 48 (2008) 247253 249</p><p>2. The safety issue and the pharmacopoeias</p><p>2.1. Historical overview</p><p>Pharmacopoeias are traditionally considered to be the safe-guards and guarantee for the quality of drugs. As shown inTable 1, the principal national pharmacopoeias (and in addi-tion that of the authors country) were first published at varioustimes in the 19th century. Due to the globalisation of the phar-maceutical market, the pharmacopoeias of the countries in theEuropean Union are now under the umbrella of the EuropeanPharmacopoeia (Ph. Eur.) [29], moreover further harmonisa-tion of these standards has been in progress since 1990 amongPh. Eur., the United States Pharmacopoeia (USP) [30] and theJapanese Pharmacopoeia (JP) [31] in the framework of the Inter-national Conference on Harmonisation (ICH).</p><p>Table 1 the mission of pharmacopoeias is . . .to maintain andimprove health. . .by disseminating authoritative standards. . .formedicines.pharmacopcan be consetting thesto) reflect tthe currentopment incontributeously increthe era of c</p><p>If we coing, e.g. UUSP 30 (20</p><p> The strumore or</p><p>constant As alrea</p><p>tion are band chrodards.</p><p> The greaof imme</p><p>Table 1Principal phar</p><p>Pharmacopoe</p><p>United States</p><p>EuropeUnited KinFranceGermany</p><p>Italy</p><p>Hungary</p><p>Japan</p><p>i.e. in the field of impurity-related tests. In 1960 HPLC didnot yet exist and TLC was at its beginnings. For this reasonimpurityof ignitiity of thcarbonizpoint, etterize theand hencdrugs. Thas beenopmentmajoritychromatcharacte</p><p> The pictis notsion of</p><p>er.</p><p>ssayacop</p><p>Dedefi: Toent ollowion a</p><p>Nonecti50sere</p><p>tterre n</p><p>puritthodgroul wiethoespey ared cote hof prod of</p><p>ace</p><p>y thd inn th</p><p>name</p><p>let a30a]sodiend</p><p>thazi. . [30]. It has to be added to this quotation that theoeias are not only disseminating the standards butsidered to be flagships of the drug quality issue bye standards. These standards should (or at least oughthe state-of-the-art of the possibilities represented bystate of analytical chemistry. The tremendous devel-analytical instrumentation enables drug analysts toat a higher level and more effectively to the continu-asing demands as regards the safety of drugs than inlassical analysis.mpare the changes within half a century by compar-SP 16, published in 1960 with the currently official07), some conclusions can be drawn:</p><p>cture of the monographs for bulk drug materials isless the same: description, identication, physicals, impurity-related tests, assay.dy mentioned, classical colour tests for the identica-eing step-by-step replaced by infrared spectroscopy</p><p>matographic retention matching with reference stan-</p><p>test development is observable in the field which isnse importance from the point of view of drug safety,</p><p>macopoeias</p><p>ia First volume Present volume</p><p>1820 United States Pharmacopeia (USP)30, 2007</p><p>19641971 European Pharmacopoeia 5, 2007gdom 1864 British Pharmacopoeia (BP) 2007</p><p>1837 Pharmacopee Francaise 10, 20051872 Deutsches Arzneibuch (DAB) 10,</p><p>Nachtrag 8, 20051892 Farmacopea Italiana XI, 2002,</p><p>Suppl. 1, 20051871 Pharmacopoeia Hungarica VIII,</p><p>200320061874 Japanese Pharmacopoeia XIV,</p><p>2001, Suppl. 2006</p><p>pap</p><p>2.2. Apharm</p><p>2.2.1.The</p><p>AssaystatemThe fodefinit</p><p>2.2.2.Refl</p><p>late 19[33] w(the lathese atial imthe metionalare stiltion m70%, rtometroutdatillustracase o</p><p>methotion bybase bmethobetwee16 istal vioblue [0.1 Mmetricprome-related tests were restricted to tests such as residueon, loss on drying, completeness, colour and clar-e solution, chloride, sulphate, heavy metals, easilyable substances, range and sharpness of the meltingc. It is needless to say that these tests did not charac-</p><p>purity of the drug material at a sufficiently high levele only very moderately contributed to the safety ofhe development in this field in the last few decades</p><p>very rapid and substantial. Thanks to the devel-in chromatographic technology, the overwhelmingof monographs in modern pharmacopoeias contain</p><p>ographic (usually HPLC or TLC) tests suitable for therisation of the impurity profile of the drug material.ure as regards the development of assay methodsas clear as with the impurities. The discus-this will be the subject of Section 2.2 in this</p><p>methods for bulk drug materials inoeias</p><p>nitionnition of assay in ICH documents [32] is as follows:provide an exact result which allows an accurate</p><p>f the content or potency of the analyte in a sample.ing sections will show how the requirements in thisre fulfilled in the current pharmacopoeias.</p><p>-selective methodsng the state-of-the-art of analytical chemistry in theand early 1960s, the principal methods in USP 16titration and ultraviolet-visible spectrophotometrybeing often based on colour reactions). Althoughon-selective methods, i.e. the majority of the poten-ies are likely to contain the same moieties on whichs are based as the drug itself: acidic or basic func-ps and chromophores, respectively, these methodsdely used in the pharmacopoeias. The share of titra-ds in the current USP and Ph. Eur. is about 40 andctively, while the same figures for UV spectropho-e about 10% in both pharmacopoeias; the ro...</p></li></ul>

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