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Purity determination of drugs
trends in analytical chemistry, vol. 13, no. 4, 1994
Purity determination
of drugs
A report on the International Symposium on Purity Determination of Drugs, held in Stockholm, Swe-
The International Symposium on Purity Determination of Drugs brought together about 170 scientists. There were three sessions covering the following areas: (I) Registration and Pharmacopoeia1 requirements; (II) Techniques; and (III) Applications The first speaker was Per Sjaberg (Medical Products Agency, Sweden), who talked about toxicological testing of impurities. Presently, regulatory requirements for toxicological testing of drug impurities are decided on a case by case basis. The discussions by the International Conference on Harmonization (ICH) have however resulted in several important considerations relating to the qualification (acceptance) of an impurity. The impurity is considered qualified if it was present in the drug batches used in both preclinical and clinical studies. If the impurity was not present, it is still considered qualified if it is present in the final drug substance bellow an arbitrarily set threshold value. A limit of 0.1% by weight and an intake of less that 0.5 mg/day have been proposed. It has also been suggested that impurities which are also significant metabolites of the drug in animals and/or man do not require toxicological testing. For new, unqualified impurities, he referred to the “Decision tree” for the need of toxicological testing. The ICH document does not cover stereoisomers, biological products, final products and generics. Purity of enantiomers from a regulatory point of view was discussed by Sven-Erik Hillver (Medical Products Agency, Sweden). He pointed out that the presence of a non-wanted enan-
tiomer could in principle be considered as any other impurity and hence, normal regulatory requirements and guidelines would be applicable. Ingvar Sjiiholm (Medical Products Agency, Sweden) talked about Quality requirements for r-DNA derived proteins. Most of the drug regulatory agencies have developed specific, extensive guidelines for the manufacturers and in Europe today, harmonized requirements are applied for the approval of these drugs. In addition to necessary characterization and confirmation and purity tests, studies on the three-dimensional structure are important to foresee any risk for the formation of any untoward antibodies. Moreover, the absence of functioning DNA/RNA is a must, as well as the absence of foreign proteins and virus. During the second session John C. Berridge (Pfizer, UK) gave an overview of analytical techniques. He discussed how to set appropriate specification levels for purity and impurity levels and referred to the ICH deliberations. He pointed out that impurities over 0.1% should be identified. The link to the analytical procedure was discussed as well as the advantages and disadvantages of the different techniques. Douglas Westerlund (Uppsala University, Sweden) talked about selectivity and indirect detection in HPLC and CEFC with the use of different counter- and co-ions as well as micellar agents and other complex-forming compounds. AkosBartha(Astra, Sweden) discussed different methods for selectivity optimization in HPLC and peak purity information based on twodimensional data sets from diode-array detectors, with methods ranging from simple comparison of spectra during peak elution to complex mathematical procedures. Modem thin-layer chromatography
applied to drug analysis was presented by Colin F. Poole (Wayne State University, USA). One of the main advantages of this technique, compared with column chromatography, is the sample integrity. The total sample occupies the chromatogram, not just that portion of the sample that elutes from a chromatographic column. He predicted that in the future the combination of TLC with MS would be a new and very useful detection technique. Jan van der Greef (TN0 Nutrition and Food Res., The Netherlands) discussed impurity profiling and identification by mass spectrometry. To demonstrate the applicability, an example was given where a combination of MS, NIR and NMR was used to monitor the manufacturing process of a polysaccharide. The purity profiles obtained by the three methods were analyzed by pattern recognition techniques. It was found that the batches produced could be classified into two groups depending on the manufacturing route. By using this approach it was also possible to discriminate between accepted and non-accepted batches. NMR spectroscopy for structural determination and purity control was presented by Lennar Kenne (Swedish University of Agricultural Science, Sweden). Modem instrumentation only requires ng-level amounts to obtain valuable NMR data. With this technique it is possible to detect and determine impurities down to about 0.1%. Danielle Giron (Sandoz-Pharma, Switzerland) discussed the use of thermoanalytical methods in pharmaceutical development. Differential scanning calorimetry is a fast and useful screening technique for purity determinations especially in the early development of a synthetic process when chromatographic methods may be inadequate due to lack of selectivity or detectability. Thermoanalytical methods are also useful for the study of polymorphism and pseudo-polymor-
Purity determination
of drugs
A report on the International Symposium on Purity Determination of Drugs, held in Stockholm, Swe-
The International Symposium on Purity Determination of Drugs brought together about 170 scientists. There were three sessions covering the following areas: (I) Registration and Pharmacopoeia1 requirements; (II) Techniques; and (III) Applications The first speaker was Per Sjaberg (Medical Products Agency, Sweden), who talked about toxicological testing of impurities. Presently, regulatory requirements for toxicological testing of drug impurities are decided on a case by case basis. The discussions by the International Conference on Harmonization (ICH) have however resulted in several important considerations relating to the qualification (acceptance) of an impurity. The impurity is considered qualified if it was present in the drug batches used in both preclinical and clinical studies. If the impurity was not present, it is still considered qualified if it is present in the final drug substance bellow an arbitrarily set threshold value. A limit of 0.1% by weight and an intake of less that 0.5 mg/day have been proposed. It has also been suggested that impurities which are also significant metabolites of the drug in animals and/or man do not require toxicological testing. For new, unqualified impurities, he referred to the “Decision tree” for the need of toxicological testing. The ICH document does not cover stereoisomers, biological products, final products and generics. Purity of enantiomers from a regulatory point of view was discussed by Sven-Erik Hillver (Medical Products Agency, Sweden). He pointed out that the presence of a non-wanted enan-
tiomer could in principle be considered as any other impurity and hence, normal regulatory requirements and guidelines would be applicable. Ingvar Sjiiholm (Medical Products Agency, Sweden) talked about Quality requirements for r-DNA derived proteins. Most of the drug regulatory agencies have developed specific, extensive guidelines for the manufacturers and in Europe today, harmonized requirements are applied for the approval of these drugs. In addition to necessary characterization and confirmation and purity tests, studies on the three-dimensional structure are important to foresee any risk for the formation of any untoward antibodies. Moreover, the absence of functioning DNA/RNA is a must, as well as the absence of foreign proteins and virus. During the second session John C. Berridge (Pfizer, UK) gave an overview of analytical techniques. He discussed how to set appropriate specification levels for purity and impurity levels and referred to the ICH deliberations. He pointed out that impurities over 0.1% should be identified. The link to the analytical procedure was discussed as well as the advantages and disadvantages of the different techniques. Douglas Westerlund (Uppsala University, Sweden) talked about selectivity and indirect detection in HPLC and CEFC with the use of different counter- and co-ions as well as micellar agents and other complex-forming compounds. AkosBartha(Astra, Sweden) discussed different methods for selectivity optimization in HPLC and peak purity information based on twodimensional data sets from diode-array detectors, with methods ranging from simple comparison of spectra during peak elution to complex mathematical procedures. Modem thin-layer chromatography
applied to drug analysis was presented by Colin F. Poole (Wayne State University, USA). One of the main advantages of this technique, compared with column chromatography, is the sample integrity. The total sample occupies the chromatogram, not just that portion of the sample that elutes from a chromatographic column. He predicted that in the future the combination of TLC with MS would be a new and very useful detection technique. Jan van der Greef (TN0 Nutrition and Food Res., The Netherlands) discussed impurity profiling and identification by mass spectrometry. To demonstrate the applicability, an example was given where a combination of MS, NIR and NMR was used to monitor the manufacturing process of a polysaccharide. The purity profiles obtained by the three methods were analyzed by pattern recognition techniques. It was found that the batches produced could be classified into two groups depending on the manufacturing route. By using this approach it was also possible to discriminate between accepted and non-accepted batches. NMR spectroscopy for structural determination and purity control was presented by Lennar Kenne (Swedish University of Agricultural Science, Sweden). Modem instrumentation only requires ng-level amounts to obtain valuable NMR data. With this technique it is possible to detect and determine impurities down to about 0.1%. Danielle Giron (Sandoz-Pharma, Switzerland) discussed the use of thermoanalytical methods in pharmaceutical development. Differential scanning calorimetry is a fast and useful screening technique for purity determinations especially in the early development of a synthetic process when chromatographic methods may be inadequate due to lack of selectivity or detectability. Thermoanalytical methods are also useful for the study of polymorphism and pseudo-polymor-