Test Article Analyses in Compliance with Good Laboratory Practice in Japan: Circumstances and Changes

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1 Test Article Analyses in Compliance with Good Laboratory Practice in Japan: Circumstances and Changes Harumi Namiki 1, *, Tetsuya Shigeta 2, Yoshitaka Ino 3, Kanzo Kimura 4, Katsutoshi Inaba 5, Sachio Kawasaki 6, Yasuhide Kitazaki 7 and Sumi Imada 8 Ad hoc project, GLP Division, Japan Society of Quality Assurance, Tokyo, Japan 1 Kyorin Pharmaceutical Co., Ltd., Japan 2 Wyeth K. K., Japan 3 Japan Tobacco Inc., Japan 4 Sumika Chemical Analysis Service, Japan 5 Terumo Corporation, Japan 6 Fuji Biomedix Co., Ltd., Japan 7 Shin Nippon Biomedical Laboratories, Ltd., Japan 8 Meiji Dairies Corporation, Japan Summary In Japan, many test facilities have been inspected by the monitoring agency since 1984 and inspectors pointed out some issues for improvement. The interest in test article analyses in support of Good Laboratory Practice (GLP)-compliant studies has been rising for the last several years. This paper reports the advice and indications for improvement that were pointed out for test article analyses by the Japanese monitoring agency. In addition, the Japan Society of Quality Assurance (JSQA) conducted surveys using a questionnaire form in 21 and 24 in order to understand the present situation and the changes in Japanese test facilities that belong to the member companies of the GLP division of the JSQA. From the results of surveys, it was found that test article analyses have been performed under GLP, reflecting the requirements of the monitoring agency. Copyright # 27 John Wiley & Sons, Ltd. Key Words: Good Laboratory Practice (GLP); Good Manufacturing Practice (GMP); test article analysis Introduction In Japan, the first Good Laboratory Practice (GLP) regulations for pharmaceuticals (J-GLP) *Correspondence to: H. Namiki, 5, Kanda Surugadai 2- chome, Chiyoda-ku, Tokyo , Japan. harumi.namiki@mb.kyorin-pharm.co.jp came into force in The monitoring agency has inspected test facilities conducting nonclinical laboratory studies for drug safety in compliance with GLP. The Organization for Pharmaceuticals Safety and Research (OPSR/ KIKO) was the monitoring agency following the major amendment of the Pharmaceutical Affairs Law in June The Pharmaceuticals and Copyright r 27 John Wiley & Sons, Ltd. Qual Assur J 27; 11, Published online in Wiley InterScience (

2 Test Article Analyses in Compliance with GLP in Japan 45 Medical Devices Agency ( go.jp/index-e.html) has performed GLP compliance reviews since 1 April 25. There are three status levels for the evaluation of GLP compliance based on the results of inspection and study audit: Status A: Status B: Status C: Compliance with GLP. Some improvements possible but the effects of non-compliance on data reliability are considered tolerable, compliant with GLP if improvements are made. Non-compliance with GLP. If the GLP facility is evaluated as status A or B, the monitoring agency will issue a GLPcompliance certificate. The GLP-compliance certificate is required to support applications for new drug manufacturing or import approval and reexamination in Japan. The certificate for status A assures the GLP compliance for 3 years, and that for status B assures compliance for 2 years. During the GLP compliance reviews, the inspectors point out the key issues they found. Some of these issues are usually documented and released with the certificate of GLP compliance. The following are known requirements with regard to test article analyses [1]: 1. Test article or test article preparation must be analyzed in compliance with GLP. 2. The Study Director should obtain evidence from the sponsor that characterization analysis was performed in compliance with GLP. 3. If test article or test article preparation were not analyzed in compliance with GLP, the facts about non-compliance and the reliability of data must be described in the final report. There was an example of a facility, which was evaluated as status B in 1999 where analyses of test article were conducted in Good Manufacturing Practice (GMP)-compliant laboratories. This case has provoked debates among Japanese Quality Assurance (QA) personnel, including questions such as: why are the analytical data obtained from GMP-compliant systems not sufficient for GLP studies? Why do we have to reanalyze the test article supplied with the GMP-compliant product certificate? Following this we conducted surveys using a questionnaire to understand the situation in Japan. Questionnaire Background of data Data were gathered from the member companies of the GLP division in the JSQA. The first survey was conducted in 21, and produced responses from 1 companies. The follow-up survey was conducted in 24, and 8 companies responded (see Table 1). Table 2 shows the backgrounds of the companies who answered. There were no differences in background between the first survey and the follow-up survey. Therefore, we tried to compare the two surveys. In addition, in the follow-up survey we asked whether GLP-compliant drug safety studies were conducted in-house or outsourced, in order to understand the current situation in detail (see Figure 1). We found that approximately 8% of companies outsourced their GLP studies. Theconductoftestarticleanalysisin supportofglpstudies We asked whether companies analyzed test article in compliance with GLP or not. In the follow-up survey, the results indicated that GLP- Table 1. Background of data Duration First survey March 21 Number of companies Response 1 8 Follow-up survey 21 September October 24

3 46 H Namiki et al. compliant analyses increased in outsourcing and non-compliant analysis decreased in-house compared with the first survey (see Figure 2). It seems that these changes resulted from the requirement by the monitoring agency. However, we know that there are some differences between the domestic and overseas situations. We usually receive a certificate of analysis for test articles developed by overseas Table 2. The background of companies Q1: Did your company conduct GLP safety studies? Yes (%) No (%) First survey Follow-up survey 91 9 Q2: Type of business Pharmaceutical company CRO First survey 7 (79%) 19 (21%) Follow-up survey 56 (77%) 17 (23%) companies before the conduct of GLP studies. The results showed that nine companies received analytical results under GLP, and seven companies received them non-glp (Figure 3). Eleven companies answered case-by-case. Seventeen companies answered unknown. To further understand the overseas situation, we made an inquiry to the Society of Quality Assurance (SQA) and the British Association of Research Quality Assurance (BARQA) in January 22. The inquiry revealed that, in both the USA and the UK, test article analysis as a part of a safety study had to be conducted under GLP, as required in Japan. However, we found there is a small difference between both countries in analyses under GMP. The FDA states that test and control article characterization and stability testing conducted as part of a nonclinical laboratory study must be conducted in compliance with the provisions of the FDA-GLP regulations. However, this does not mean that a facility, which normally con- Figure 1. Conduct of GLP safety studies in the follow-up survey (24): in-house or outsourced? 1 8 First (21) Follow-up (24) 6 % 4 2 GLP Non-GLP GLP Non-GLP In-house Out sourcing Figure 2. The conduct of test article analyses in support of GLP safety studies in Japan

4 Test Article Analyses in Compliance with GLP in Japan 47 2 Number of pharmaceutical companies GLP Non-GLP Case by case Unknown Figure 3. Analysis for test article developed by overseas companies in support of GLP studies ducts characterization and stability testing under cgmps, could not also perform characterization and stability testing in compliance with the requirements of the GLP regulations. If a facility that normally conduct testing under cgmps is organized and operates in a manner that satisfies the requirements of the GLPs, we would not object. [2] This explanation was not entirely satisfactory for us as we knew through experience of member companies that the test and control article characterization and stability testing under cgmp, not under GLP, are actually acceptable by the FDA. On the other hand, in the UK, we knew through experience that the results of analyses under GMP could be acceptable when some requirements were fulfilled. In April 23, we had a meeting with KIKO. KIKO declared that they would accept the results of analyses if the analyses under GMP satisfied the requirements of J-GLP. Provision for GLP non-compliant analyses in Japan In many cases, analyses in the primary stage of the development cannot be conducted under GLP. It depends on the stage of the drug development process. These analyses are sometimes conducted in accordance with complete or incomplete standards and test methods under GMP. We asked about the use of analytical results when the specification and test methods are the same as analyses under GMP in pharmaceutical companies. Data were gathered from pharmaceutical companies. In comparison between the first and the follow-up survey, the use of results under GMP decreased and retesting increased (Figure 4). Many companies retested under GLP because of the requirements by the monitoring agency. A stand-alone study or a part of the drug safety study? Next, we asked whether test article analysis in support of GLP studies is conducted as part of studies or as stand-alone studies. As Figure 5 shows, the majority of studies were stand-alone for characterization analyses. In addition, the results were similar for stability testing. Stand-alone study for test article: GLP requirements Final report or certificate? We understand that there are some differences in requirements between GMP and GLP. One of

5 48 H Namiki et al. Percent of pharmaceutical companies (%) Use the results Retest under GLP Other First (21) Follow-up (24) Figure 4. Analyses in support of GLP studies where the specification and test methods are the same as analyses under GMP in pharmaceutical companies Percent of pharmaceutical companies (%) First (21) Follow-up (24) Part of GLPsafety study Stand-alone study Other Figure 5. Performance of characterization analyses for test articles in support of GLP studies them is the final report. Under GMP, results of analysis are usually described in certificates. However, we thought that certificates are not sufficient to satisfy GLP requirements. Then, we asked whether companies preferred a final report or a certificate of analysis. The results are shown in Figure 6. In the first survey, the percentage of answers was 44% for certificate, and 52% for final report. In the follow-up survey, 96% of GLP facilities were preparing final reports, and the percentage of facilities preparing certificates decreased considerably. QAU activity There is also a difference between GLP and GMP with respect to the Quality Assurance Unit

6 Test Article Analyses in Compliance with GLP in Japan 49 Percent of pharmaceutical companies (%) Final Report Certificate Other 2 5 First (21) Follow-up (24) Figure 6. Documentation of test article analysis: final report or certificate? (more than one category could be selected) 4 Table 3. Changes in QAU activities of pharmaceutical companies between surveys Item Answers (% of total) First survey (21) Follow-up survey (24) Protocol " Study-based inspection and process-based inspection 6 8 " Raw data " Final report " Facility-based inspection Inspection/audit report QA statement " Others 24 6 (QAU). Table 3 shows survey results on QAU actions in pharmaceutical companies to satisfy the GLP requirements for test article analyses. In the follow-up survey, there was an increase in the incidence of protocol and final report review, and study-based inspection compared with the first survey. Outsourcing Domestic situation We asked what information was given as the evidence of GLP-compliant analysis from sponsors to CROs. Data were gathered from pharmaceutical companies. As shown in Figure 7, sponsors have started to give final reports and QA statements as evidence of GLP-compliant analysis. In the follow-up survey, there was an apparent increase in the use of certificates. Currently, a final report often includes a certificate as one of its attachments. It is suggested that this has led to increased use of certificates. We asked CROs how GLP compliance was confirmed (Figure 8). This question is based on the monitoring agency requirement that the Study Director must confirm that the test article

7 5 H Namiki et al. First (21) Follow-up (24) Other 6 6 , etc 2 13 Certificate 21 3 SD or FMstatement 1 6 QA Statement 1 15 Final Report Number of answers Figure 7. Information about the results of test article analyses provided from sponsors (pharmaceutical companies) to CROs (more than one category could be selected) SD ¼ Study Director; FM ¼ Facility Manager First (21) Follow-up (24) Other 3 3 Records ( , etc) 5 9 Visit the sponsor's facility 1 FR, Statement, etc Number of answers Figure 8. Confirmation that that test article analyses were conducted under GLP at CROs (more than one category could be selected) FR ¼ Final Report was analyzed under GLP. There has been an increase in final reports and QA statements, and has decreased. As shown here, CROs confirmed GLP compliance of analytical results by receiving final reports and QA statements. These results show the improvements by both sponsors and Japanese CROs. Outsourcing to overseas CROs For global research and registration, Japanese companies are outsourcing many of their studies. Therefore, we investigated outsourcing to overseas CROs. The results showed that 58% of companies outsourced their GLP studies to various countries (Table 4).

8 Test Article Analyses in Compliance with GLP in Japan 51 Table 4. Outsourcing to overseas CROs in Japanese pharmaceutical industries Country UK 28 USA 32 Canada 12 Netherlands 6 France 4 Germany 2 Switzerland 1 Austria 1 Philippines 1 We asked whether characterization analyses and stability testing in support of overseas GLP studies were conducted in Japan or other countries. As shown in Figure 9, eight companies conducted all analyses in other countries, and 29 companies conducted analyses in Japan. Six companies conducted their characterization analyses in Japan and their stability testing in other countries. Conclusion Answers Test article analyses in support of GLP safety studies must be conducted under J-GLP in Japan. Therefore, if analytical testing is not conducted under GLP, Japanese companies will retest under J-GLP. This is the same for products developed by overseas companies. In addition, when Japanese companies outsource their GLP studies to other countries, test article analysis is still conducted in Japan. To satisfy the GLP requirements, final reports and QA statements are prepared, and the incidence of QA audits has increased during the years between our surveys. Not all test article analyses in support of GLP studies have to be conducted in compliance with GLP. If analyses under GMP satisfy the GLP requirements, they will be accepted; however, this may be difficult in Japan. In outsourced GLP studies, sponsors now provide CROs with the necessary information about GLP compliance, and more CROs have started to confirm that the analysis was performed in compliance with GLP as a result of the monitoring agency s requirements. These results lead us to the conclusion that the current situation for test article analyses in Japan reflects the requirements by the monitoring agency. We hope this article will be useful for understanding the current situation in Japan Numbers of companies A B C D Figure 9. Choice of facility for test article analyses in support of GLP-compliant studies A: all analyses are conducted in foreign country; B: all analyses are conducted in compliance with GLP in Japan; C: characterization analyses are conducted in Japan and stability analyses are conducted overseas; D: others

9 52 H Namiki et al. Acknowledgements We very much appreciate the assistance of Ms Etsuko Kokubunji, Ms Junko Hara and the members of the JSQA GLP-ad hoc committee (21 23) for the analyses of the first and follow-up surveys. We express our sincere gratitude to SQA and BARQA. The research was supported by the GLP Steering Committee of the JSQA. References 1. Japan Pharmacists Education Center (eds). Iyakuhin GLP Guide Book 24. Yakuji Nippo: Tokyo, 24 (Japanese). 2. Ad hoc project, GLP division in JSQA (eds). Concept of Test Article Analysis in Support of GLP-Compliant Studies. Japan Society of Quality Assurance: Tokyo, 23 (Japanese).