PHARMACEUTICAL REFERENCE STANDARDS

Transcription

1 PHARMACEUTICAL REFERENCE STANDARDS 11 th International Symposium organised by the European Directorate for the Quality of Medicines & HealthCare (EDQM), Council of Europe 3-4 September 2012, Strasbourg, France Poster Abstracts

2 A Case Study for the Development of Stable Solution Reference Standards for Pharmaceutical Applications Matthew Borer, Eli Lilly Other authors : (i.e., M. A. Smith, Paris Laboratory; M. S. Steger and D. M. Viera, Research Center; and A. Power, Paris University) M. McInerney, K. Dancheck, and D. Lytle, Eli Lilly and Company; T. Tarbox, I. Dilek, U. Sreenivasan, K. Gates, and M. Rettinger, Cerilliant Reference Standards are a critical part of the control strategy to ensure the quality, safety, and efficacy of pharmaceuticals. Routine QC of pharmaceuticals requires preparation of working solutions from powder reference material on a routine basis. These solutions are typically prepared in volumetric flasks and stored for short intervals in the laboratory. Weighing of materials for standards in the lab can be time consuming, especially when materials are hygroscopic, toxic or controlled. One source of lot-to-lot discrepancies in release testing is variation in the reference standard working solution which can result from weighing and dilution differences between batches. A solution-based reference standard packaged in a format that preserves concentration and integrity of the material provides a convenient, consistent and cost effective alternative to preparation of working reference standard solutions in the analytical lab. This poster will present information on a high-value pharmaceutical API with a high risk of diversion. Material usage is tightly controlled and requires documentation of secure storage and traceability of usage. The material is electrostatic and requires special handling during the weighing of assay standards. A solution-based assay standard for use in routine QC of this API would provide cost, efficiency, and security benefits. A solution reference standard was prepared in a diluent compatible with the HPLC method and packaged under argon in flame-sealed amber ampoules. Initial stress degradation study of the ampouled product was conducted over 30 days under photo stability and sub freezer to 80 C temperature conditions. Assay and related substances results indicated that the solution standard was stable in the ampouled format. Storage was set to refrigerator conditions based on the stress degradation results. In addition to illustrating the strategy for developing this solution reference standard, this poster will describe the details of the work done to certify the final reference standard for use in QC testing. The official standard has been on stability for 15 months and an identical pilot batch for 2.5 years, both showing excellent stability. This work helps illustrate how solution reference standards offer unique advantages and significant value to laboratory customers in manufacturing and development. 44

3 Solution Reference Standards for Protein Based Pharmaceuticals Matthew Borer, Eli Lilly Other authors: (i.e., M. A. Smith, Paris Laboratory; M. S. Steger and D. M. Viera, Research Center; and A. Power, Paris University) M. McInerney, K. Dancheck, and D. Lytle, Eli Lilly and Company; T. Tarbox, I. Dilek, U. Sreenivasan, K. Gates, and M. Rettinger, Cerilliant The rise of monoclonal antibodies and biopharmaceuticals as drugs and drug candidates presents new challenges in pharmaceutical analysis. Many of these molecules are hygroscopic, air sensitive, highly potent, and can be impossible to isolate as neat powders without loss of biological activity. The traditional approach of using neat powders as the reference standards is therefore not the best practice for most biomolecules. Alternatives, such as lyophilized materials, are generally stable but present issues such as high cost and variability in material content from vial to vial. Lyophilized vial manufacturing can also have a higher rate of failure, which is problematic for high-value source materials such as biologics. Solution based reference standards are an alternative format that mitigates the handling issues associated with these materials and promotes consistency in testing. The ampouled format maintains concentration, protects from air and light, and can promote stability. This poster will present two case studies: a peptide API and a monoclonal antibody. For the peptide API, a solution check standard has been implemented to reduce the use of the reference standard for this purpose. The cost per use of the solution material is a small fraction of the lyophilized reference standard. The solution material has been shown stable for over 100 days and is presented to the labs in a ready-toinject format. The monoclonal antibody example will illustrate how these materials can be stored at deep freezer temperatures as an aqueous solution in flame-sealed glass ampoules. This format allows the solution to be stored for long periods, shipped on dry ice without concern for carbon dioxide entrainment, and offers a lower-cost alternative to polymer cryovials. 45

4 International standards and secondary working reagents for Blood Virology Nucleic acid Techniques Ms Clare Morris, E Wigglesworth, National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar. Hertfordshire. EN6 3QG The National Institute for Biological Standards and Control (NIBSC) is a World Health Organisation (WHO) Collaborating Centre that produces a majority of the world s International Standards and reference reagents as well as a large number of secondary references and working reagents. WHO International Standards and Reference Regents The primary gold standard in biological reference materials terms is a WHO International Standard (IS) or Reference Reagent (RR), from which laboratories can calibrate their own reference materials for biological testing. This set of common standards is essential if testing results from different parts of the world are to be comparable and to reduce variability between in-house and commercial assays between laboratories. Each IS must be assessed via an international collaborative study to establish performance and assign an International Unitage (IU). Each standard must be fully characterized and have proven stability prior to establishment. The standard is endorsed by a WHO committee Expert Committee on Biological Standardisation and Control (ECBS). Secondary Working Reagents Secondary working reagents are produced for frequent use in assays as daily run controls and indicators of performance. They can be used to monitor the consistency of assays or system performance over time using statistical process control on a daily basis, over a period of time, or as a retrospective monitor of assay lot variance. Data from the same batches of working reagent can also be used to compare performance between laboratories. NIBSC have a variety of International Standards and secondary working reagents for blood viral markers such as HIV, HCV, HBV, HAV and B19, these are designed for use in nucleic acid techniques. In some cases the secondary reagent is calibrated in IU s against the corresponding IS. Most of the working reagents are CE marked and are suitable for in vitro diagnostic use within Europe. The poster will elaborate on the process of establishing a biological international standard, how secondary working reagents are made, and what it means for a working reagent to be suitable for in vitro diagnostic use. 46

5 Development of the National System of Medicine Reference Substances in Ukraine Leontiev Dmytro, Deputy Director (on Science), Group Manager Validation and Reference Substances Gryzodoub O.I., Director Ukrainian Scientific Pharmacopoeial Center for Quality of Medicines (Kharkov ) For creation of a modern pharmaceutical reference substance (RS) system in Ukraine it was required to develop theoretical basis for metrological criteria. The principle of insignificancy was elaborated (enabling use for any selected level of confidence): (confidence level Р = 5%), where 1 for example, maximal permitted uncertainty of a analysis result ( As), and 2 - maximal permitted uncertainty of RS assigned value ( RS). The systematic application of the given principle results in developing metrological criteria for pharmaceutical RS, analytical validation, evaluation of results of inter-laboratory testing and suitability of the analytical equipment for the pharmaceutical analysis. On basis of this principle and destination of pharmaceutical tests requirements for As was elaborated. Assay for preparations: As 0.32 B, where ±B - symmetrical content limits (assay for substances - European Pharnacopoeia approach exploits: As B, where B - excess of the upper content limit over 100 %). Tests Uniformity of Content and Dissolutions: As 3%. Based on this requirements approaches for Ukrainian Pharmacopoeal RS elaboration were developed (criteria for RS, uniformity and stability testing). Certified value must be determined by a direct method (titration, generally) and by subtraction of the obtained content of impurities from 100 %. The balance is confirmed, if difference not exceeds RS. Now about 500 various RS of the Ukrainian Pharmacopoeia were certified: - for Assay (chemical tests, microbiological and biological ones), Identification and another tests; - for Impurities control (synthesized); - as herbal markers (isolated from herbal material); - as standardized herbal extracts (this permits the use of one summary extract in substitution of several individual herbal markers); - instead of RS, specific for USSR (in a majority, of herbal origin); - other use. Ukrainian Pharmacopoeia RS are used in most Commonwealth of Independent States (CIS) by pharmaceutical manufacturers, State Inspection laboratories, and in pre-registration researches. The principles developed for the Pharmacopoeial RS certification were applied successfully to the working RS (WRS) certification. Since 2003 the Pharmacopoeial Center of Ukraine is an organizer of the Ukrainian Proficiency Testing Program (PPT). Laboratories of quality control of medicines of Ukraine, CIS countries and some European Union countries participated in different rounds (1164 labs in all). For TS elaboration and participant results assessment the next approach was developed. The uncertainty of certified TS values ( TS ) should be insignificant compared to the As : TS (%) 0.32 As ; the result of the participant (X i ) is satisfactory, if X i deviates from the certified values of TS (X Att ) not more than the As : X i X Att As. The same principles were used for the elaboration of other RS: - RS for validation/verification of test procedures (for direct methods); - RS for analytical equipment qualification (pharmaceutical tests); - RS for in-laboratory quality assurance. At the present time, Ukraine is the only country of the CIS, that has own National Pharmaceutical RS System and which RS are widely used in the other CIS countries. 47