Review Article A Comparative Study of Registration Procedure for Submission of Generic Drug in Brunei Darussalam and Malaysia *Gopal Patel, Dilip Maheshwari Department of Quality Assurance & Pharm Regulatory Affairs, L. J. Institute of Pharmacy, Ahmedabad, Gujarat, India. ABSTRACT Present study was focused on the regulatory requirements for submission of Generic Drugs in Brunei Darussalam & Malaysia. In present scenario the Market for generic drugs of the ASEAN (Association of South East Asian Nations) countries are growing day by day, so it is necessary to regulate the drug product for its Safety, Efficacy and Quality. There are ten member countries under the ASEAN declaration, where certain guidelines are country specific like their registration process, labelling requirements whereas certain regulatory requirements are harmonized as the ASEAN guidelines. These ASEAN guidelines are derived from the ICH guidelines. Under the ASEAN declaration ACCSQ-PPWG (ASEAN Consultative Committee for Standard & Quality Pharmaceutical Product Working Group) was established for the Harmonization for the pharmaceutical regulation. Generic drugs are more economical than the new or innovator drugs and the quality of the generics are same as the innovator drug products, so the use of the Generic drug products is increased. In present study comparison of the registration process of the generic drug products is carried out. In the comparison mainly application procedure and its handling till the approval of the generic drug product is carried out. This comparison of the registration procedure is helpful to the new manufacturer to globalize their business in the concern countries. Keywords: ACCSQ-PPWG, ASEAN, generic drug application, marketing authorization approval Received 21 March 2014 Received in revised form 05 April 2014 Accepted 07 April 2014 *Address for correspondence: Gopal Patel, Department of Quality Assurance & Pharm Regulatory Affairs, L. J. Institute of Pharmacy, Ahmadabad, Gujarat, India. E-mail: gopal16690@gmail.com INTRODUCTION [1-8] In current scenario, for registration of any pharmaceutical products in any country it is necessary to comply with the regulatory requirements of that particular country. The regulatory requirements in the various countries around the world are still quite different. Therefore, it is very difficult especially for companies, to develop a regulatory approach for a marketing approval for a generic drug. On this background, it is very important to know in detail the regulatory requirements in each concerned country where Generic drug application should be submitted. So it is necessary to establish a suitable regulatory strategy before the submission in order to avoid any major difficulties and unexpected surprises. Brunei Darussalam and Malaysia are the countries which are harmonized through the Declaration known as ASEAN (Association of South East Asian Nations). Hence it is necessary to go through the ASEAN guidelines before develop any strategy for marketing approval of generic drug, though the requirements for application of generic drug is different for each of the member country. About ASEAN The Association of Southeast Asian Nations, or ASEAN, was established on 8 August 1967 in Bangkok, Thailand, with the signing of the ASEAN Declaration (Bangkok Declaration) by the Founding Fathers of ASEAN, namely Indonesia, Malaysia, Philippines, Singapore and Thailand. Brunei Gopal Patel et.al, IJPRR 2014; 3(5) 52
Darussalam then joined on 7 January 1984, Vietnam on 28 July 1995, Lao PDR (People s Democratic Republic) and Myanmar on 23 July 1997, and Cambodia on 30 April 1999, making up what is today the ten Member States of ASEAN. In 1999 a harmonization initiative was started among the 10 ASEAN countries. One aim of this harmonization should be to harmonize quality guidelines that are valid for all countries involved. Another focus lies in the technical co-operation. Therefore the ASEAN Consultative Committee for Standards and Quality - Pharmaceutical Product Working Group (ACCSQ-PPWG) was established. The objective of the ACCSQ-PPWG is the development of harmonization schemes of pharmaceuticals' regulations of the ASEAN member countries to complement and facilitate the objective of ASEAN Free Trade Area (AFTA), particularly, the elimination of technical barriers to trade posed by these regulations, without compromising on drug quality, safety and efficacy. ASEAN An Emerging Pharmaceutical Market The Southeast Asian pharmaceuticals industry is in a state of flux, and the generic drug market is slowly gaining more attention from both patients and governments. To grow, companies are reorganizing and reinventing themselves. In South East Asia region, the pharmaceutical trends and developments vary from one market to another i.e. different speed. Despite the negative impact of the global recession, the ASEAN markets have a pharmaceutical market value of US$ 23.1 billion in 2009, and are expected to continue to grow.these markets are projected to have a total pharmaceutical market value of US$ 77.4 billion in 2016. MATERIALS AND METHODS COMPARATIVE ANALYSIS OF REGULATION OF GENERIC DRUG SUBMISSION IN BRUNEI DARUSSALAM AND MALAYSIA Regulatory Authorities[1-2] Regulatory authorities for the concern countries are given in (Table 1). Table 1: Regulatory Authorities of Brunei Darussalam and Malaysia Brunei Darussalam Malaysia Ministry of Healthis established under Sub-Decree 67 ANKr.BKof Govt. of Brunei, dated 22 nd October, 1997 as the government ministry. MoH is solely responsible for all aspects related to health including development of strategic plan, implementation and evaluation of the public health services in Brunei. Biro Pengawalan Farmaseutikal Kebangsaan (BPFK)also known as National Pharmaceutical Control Bureau (NPCB),Ministry of Health Malaysia, is the executive body established under the Control of Drugs and Cosmetics Regulations 1984. The main task of this Authority is to ensure the safety, quality and efficacy of pharmaceuticals, health and personal care products that are marketed in Malaysia. Dossier Requirement [9-10] Dossier Requirement of Brunei Darussalam- The data requirements will be based on the following criteria as shown in (Table 2). Table 2: Dossier Requirement of Brunei Darussalam Application Type Data requirements 1) Innovator product Innovator product- registered for < 5 years in at least one benchmark Parts I, II, III and IV country Innovator product- registered for < 5 years in at least one benchmark Parts I, Part II and country containing existing chemical/biological entity(s) in a new pharmacokinetic data dosage form Innovator product- registered > 5 years in 3 benchmark countries Parts I and II 2) Generic product* Parts I and II 3) Abridged application Part I only Gopal Patel et.al, IJPRR 2014; 3(5) 53
Dossier Requirement of Malaysia: Data to be submitted as general requirement to support an application for product registration is based on the product category as shown below in (Table 3). Table 3: Dossier Requirement of Malaysia (A) FULL EVALUATION (based on ACTD/ ACTR) No. Product Category Part I Part II Part III Part IV 1. New Drug Products 2. Biologics 3. Generics Not Applicable Not Applicable (B) ABRIDGED EVALUATION No. Product Category 1. * Generics (Non-Scheduled Poison) - Only Part I Flow chart for registration of generic drug in Brunei Darussalam [9] Registration procedure for generic drug submission is given as follows as shown in (figure 1). Figure 1: Flow chart for registration of generic drug in Brunei Darussalam Flow chart for registration of generic drug in Malaysia [10] Registration process for generic drug submission is given as follows as shown in (figure 2). Gopal Patel et.al, IJPRR 2014; 3(5) 54
Figure 2: Flow chart for registration of generic drug in Malaysia * Good Manufacturing Practice (GMP) Certification ** For natural products only *** Application for manufacturer, import and/or wholesale license RESULTS AND DISCUSSION COMPARISON [9-13] From this present work by reviewing the different Guidelines the differences of regulatory requirements between two countries were found and it should be discussed as shown in (Table 4). CONCLUSION From the Comparison it is found that registrations of both the countries are different from each other for the submission of generic drugs. Also we discussed the major differences between the registration processes of the generic drugs in both the countries. In the Brunei Darussalam once the application is rejected the applicant should file the new application from the beginning where as in case of Malaysia applicant can appeal the decision of the authority for the rejection of the application. Also the time and cost require to obtain the marketing authorisation approval is less in Malaysia than the Brunei Darussalam. This work may have importance for the small pharmaceutical companies who wants to globalize their business. From the present work it is also found that the marketing of the generic drug in Malaysia is easier than to market in the Brunei Darussalam. Gopal Patel et.al, IJPRR 2014; 3(5) 55
Table 4: Comparison of regulatory parameters of Brunei Darussalam and Malaysia Parameter Brunei Darussalam Malaysia Application Submission Application Screening Application Evaluation By providing letter of intent and by using the prescribed forms issued by the Department of Pharmaceutical Services(DPS). Application forms can either be obtained from Drug Registration Unit, Drug Administration Section DPS, or downloaded from the following website: http://www.moh.gov.bn/ pharmacyservices/forms.htm For submission, hard copies for Part I and II are required to be submitted. Submission of Part III and IV may be submitted in a CD/DVD. Applications are to be submitted by the person responsible for the company or its representative to: Drug Registration Unit Drug Administration Section Department of Pharmaceutical Services The submitted application will be screened and validated for completeness within 10 working days. DRU may request for further information and additional supporting documents from the applicant through the query letter. Applicant should make available such information or documentation required for each correspondence within 60 calendar days from the date of the screening query letter. During product evaluation, DRU may request for further information and additional supporting documents from the applicant. Applicant should make available such information or documentation required for each correspondence within 60 calendar days from the date of the request. Application of product registration shall be submitted with letter of intent via the online QUEST system at www.bpfk.gov.my. Applicant shall ensure all data requirements needed to support the application is fulfilled before submission. Hard copies of Part I & II are required to be submitted. And Part III and IV should be submitted by CD for the New Drug. Applications are submitted to BIRO PENGAWALAN FARMASEUTIKAL KEBANGSAAN Pusat Pembangunan Organisasi Lot, 36, JalanUniversiti, 46200, Petaling Jaya, SELANGOR After an online submission of the product registration application has been done, the application shall be undergone an initial evaluation. o Satisfactory- Only complete application shall be accepted and approved for payment. o Non-satisfactory- If the application is found incomplete during the screening process, the application shall be rejected and the applicant shall be notified via the system Initiation of review Upon confirmation of payment, the application with the submitted data shall be evaluated. Review of applications shall follow a queue system. Correspondence Correspondence via the system shall be sent to the applicant if there is any clarification and further supplementary data/ information, documentation or samples pertaining to the application, if deemed necessary by the Authority. Stop clock Timeline for product Registration a) Full Evaluation Generics 210 working days b) Abridged Evaluation Gopal Patel et.al, IJPRR 2014; 3(5) 56
Fees Authority Decision Processing fee- B$200 payable at the point of submission of the application for a medicinal product registration Product License fee- Product License is valid for 5 years. There is no charge in the first year and the fee of B$50 for each subsequent year. Amendment fee- The amendment fee is payable upon approval of the amendment. The major and minor amendment fees are B$150 and B$50 respectively. The applicant will be informed on the decision of the BDMCA in writing as to whether the application has been approved or rejected. Product Registration Number Product License Certificate Rejection, cancellation, suspension of registration Appeal against the BDMCA s decision ACKNOWLEDGEMENT The authors are thankful to Dr. K. Pundarikakshudu, Director of L. J. Institute of Pharmacy for providing us facilities and guidance. REFERENCES 1. Association of South East Asian Nations [online]. [cited 2014 Mar 1]; Available from: URL: http://www.aseansec.org/14903.html 2. Ministry of Health Brunei Darussalam [online]. [cited 2014 Mar 15]; Available from: URL: http://www.moh.gov.bn/about/organisation.htm 3. National Pharmaceutical Control Bureau, Introduction to DCA [online]. [cited 2014 Mar 15]; Available from: URL: http://portal.bpfk.gov.my/index.cfm?menuid =9 4. Southeast Asian Pharmaceuticals Industry: Generic Drug Market Frost & Sullivan research service [online]. [cited 2014 Feb 25]; Available from: URL: http:// www.frost.com/prod/servlet/reportbrochure.pag?id=p458-01-00-00-00 Generics (Non- Scheduled poison) Single Active ingredient 116 working days Two or more Active ingredient 136 working days Generic Drug: - Single API- 2200.00 RM - Two/more API- 3000.00 RM Decisions of the Authority A regulatory decision shall be made based on the outcome of the evaluation of the submitted documentation, and samples (if applicable). Product Registration Number The product registration holder shall be notified by the Authority and a product registration number (i.e. MAL number) shall be assigned to the registered product via the system. 5. The Asian Pharmaceutical Industry Outlook 2012 [online]. 2012 [cited 2014 Feb 25]; Available from: URL:http://resources. tectura.com/life-science-insights/doccenter/ ASEAN-LifeScienceInsights-AsiaPharma IndustryOutlook012012.pdf 6. The Outlook for Pharmaceuticals in South East Asia Aug 03 [online]. 2011. [cited 2014 Mar 2]; Available from: URL: http://www.articlesbase.com/medicinearticles/the-outlook-for-pharmaceuticals-insouth-east-asia-5092325.html 7. Bernard E., Michael D., Deborah J. The Asia- Pacific Profile [online]. [cited 2014 Mar 5]; Available from: URL: http://books.google. com.au/books?id=l07ak-d6dac&q=asean+ market#v=s nippet&q= ASEAN%20market &f=false 8. Ruth Lätzel. Development of the ASEAN Pharmaceutical Harmonisation Scheme - An Example of Regional Integration -. dermathematischnaturwissenschaftlichenfa kultät der Rheinischen Friedrich-Wilhelms- Universität Bonn. 2007. 11-13 9. Guide To Application For Registration of Medicinal Products, 3 rd Edition (Dec Gopal Patel et.al, IJPRR 2014; 3(5) 57
2012),Department of Pharmaceutical Services, Ministry of Health, Brunei Darussalam; http://www.moh.gov.bn/ pharmacyservices/download/guide%20to% 20Application%20for%20registration%20of %20Medicinal%20Products.pdf 10. Drug Registration Guidance Document (DRGD) First Edition, February 2014; http://portal.bpfk.gov.my/newsmaster.cfm? &menuid=52&action=view&retrieveid=364# sthash.l88pbyfv.dpuf 11. Priyank Sharma, Rajendra Kr. Songara, Vipin Mishra, MayankTripathi. Procedure for Pharmaceutical Generic Dossier Filling of Solid Oral Dosage Forms for ASEAN Countries &A Comparative Study of ASEAN CTD & ICH CTD. Asian Journal of Pharmaceutical Sciences And Research. 2012 may; 2(5); 1-53. 12. Vipin Mishra*, BirendraSrivastava. Study of multisource medicinal product registration procedure of marketing authorization in ASEAN (Singapore). Asian Journal of Pharmaceutical Sciences and Research. 2012 jul; 2(7); 15-38. 13. Sauwakon R.: Drug Regulations and Incentives and Innovation: The Case of ASEAN ; http://www.who.int/intellectualproperty/st udies/drugregulationincentives.pdf Gopal Patel et.al, IJPRR 2014; 3(5) 58