THE CHALLENGES FOR IMPLEMENTATION OF GOOD MANUFACTURING PRACTICES BY LOCAL PHARMACEUTICAL MANUFACTURES IN VIETNAM

THE CHALLENGES FOR IMPLEMENTATION OF GOOD MANUFACTURING PRACTICES BY LOCAL PHARMACEUTICAL MANUFACTURES IN VIETNAM by Duong To Dung (Ms.) A research report submitted in partial fulfillment of the requirements for the degree of Master of Business Administration. Examination Committee Dr. Do Ba Khang (Chairman) Dr. N. Ramachandran Dr. Sang-kon Lee Nationality: Vietnamese Previous degree: Bachelor of Chemical Engineering Bachelor of Computer Sciences Engineering HCMC University of Technology Ho Chi Minh City, Vietnam Scholarship Donor: Government of Switzerland Asian Institute of Technology School of Management Bangkok, Thailand March, 2001 Acknowledgement First of all, I would like to express my deep gratitude to Dr. Do Ba Khang, who is my advisor for this research paper, for his kindness and willingness as well as valuable comments and advice that help me well in conducting this paper. Moreover, I am also greatly indebted to Dr. Cao Minh Quang and Dr. Pham Thi Binh Minh, who are chief officers of Vietnam’s Ministry of Health for their whole-hearted supports and helps in giving me the necessary and beneficial knowledge and data concerning Vietnam’s pharmaceutical industry. Besides, I truly appreciate the enthusiastic contribution of Dr. Sang-kon Lee and Prof. N. Ramachandran, who are extremely willing to give me helpful advice for improving this research paper. Secondly, without the loves and sacrifices of my parents, I could not be here to have a chance of conducting this research. Thus, it is my full pride to show my everlasting gratitude to them. Thirdly, my acknowledgement is included here to the government of Switzerland, who granted me the scholarship for finishing my MBA at AIT. And finally, I would like to send my thanks to all of my teachers as well as friends, who make my life - not only in AIT but everywhere - more valuable and enjoyable. Abstract Good Manufacturing Practices (GMP) guidelines or regulations for pharmaceutical, food, cosmetic, and some other industries aim at ensuring that products are consistently produced and controlled to the quality standards appropriate to their intended uses and as required by the marketing authorizations or product specifications. In pharmaceutical industry, GMP is the most fundamental element of Quality Assurance and internationally recognized. Basic standards of GMP have been published by the World Health Organization (WHO). Nevertheless, many multi-national companies normally work to the more demanding standards of GMP imposed by regulatory agencies in the European Union and the United States Food and Drug Administration (FDA) as well as their own internal or national GMP guidelines. In most developed countries, GMP has become force of law, while in Vietnam, GMP guidelines that based on ASEAN GMP guidelines are not enforceable. Therefore, putting GMP into regulation is the concern of Vietnam’s Ministry of Health, as there are existed constraints relating to the current local circumstances as well as local pharmaceutical manufacturers’ capabilities. Thus, this research identifies and describes the challenges and difficulties faced by pharmaceutical manufacturers, especially local firms in Vietnam towards implementing GMP. These challenges can be classified into two categories: internal factors and external factors. Internal factors comprise the financial shortage, qualified-personnel shortage and inability in information accessing. External factors include government lagged and inappropriate policies, customer attitudes and behaviors, and rivals’ influences. Table of Contents Chapter Title Page Title Page i Acknowledgement ii Abstract iii Table of Contents iv List of Abbreviations v 1. Introduction 1 2. Theoretical Review 6 2.1 Quality Assurance in Pharmaceutical industry 6 ASEAN GMP 10 GMP in comparison with ISO 9000 series 12 2.4 Pros and cons in implementing quality standards 17 3. Pharmaceutical Industry and GMP implementation in Vietnam 19 3.1 Overview of pharmaceutical industry in Vietnam 19 Government policies towards GMP implementation 22 Vietnam GMP guidelines 24 Major challenges faced by firms towards implementing GMP 24 Government's responsibilities in supporting firms’ GMP compliance 30 Conclusions and Recommendations 31 Conclusions 31 Recommendations 32 To firms 32 To government 39 To further studies 42 5. References 43 6. Appendices A. ASEAN GMP 44 B. A typical Organizational Structure of GMP-approved firm 51 C. ASEAN and other National GLP and GMP Authorities 52 D. Web-sites relating to some of GMP regulations 54 List of local pharmaceutical manufacturers and 55 their relevant data55 Circular 12 BYT-QD providing a guide 64 for implementing ASEAN GMP G. Interviewees 67 List of Abbreviations GMP Good Manufacturing Practices WHO World Health Organization FDA U.S Food and Drug Administration GLP Good Laboratory Practices GSP Good Storage Practices GDP Good Distribution Practices GPP Good Pharmacy Practices Good Prescribing Practices GCP Good Clinical Practices SOP Standard Operating Procedures FIP International Pharmaceutical Federation CFR Code for Federal Regulations CHAPTER 1 INTRODUCTION Background Facing the increasingly fierce competition and rapid globalization trend, companies around the world have to ensure their products’ quality by complying with some types of quality assurance standards or regulations, which are internationally or globally recognized. In pharmaceutical, food, cosmetic, and some other industries, the Good Manufacturing Practices (GMP) regulations are mostly used. What is GMP? In pharmaceutical industry, GMP is a quality assurance system for ensuring that products are consistently produced and controlled according to quality standards, and it is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product. Those main risks are: Unexpected contamination of product, causing damage to health or even death. Incorrect labels on containers, which could mean that patients receive the wrong medicines. Insufficient or too much active ingredients, resulting in ineffective treatment or adverse effects. GMP covers all aspects of production, from starting materials, premises and equipment, to the training and personal hygiene of staff. Detailed, written procedures are essential for each process that could affect the quality of the finished product. Furthermore, there must be systems to provide documented proofs that correct procedures are consistently followed at each step in the manufacturing process - every time a product is made. The figure hereunder illustrates the ten major components of GMP. Production General Quality control Personnel Self-inspection Premises Handling of complaint and recall Equipment Documentation Sanitation Figure 1.1: Ten major contents of GMP Why GMP? Two levels are mentioned hereunder as the reasons for implementing GMP standards: the macro level relating to the national policies and benefits, while the micro level concerns the firm’s benefits. Macro level: F Economic aspects: + Most countries will only accept import and sales of medicine that have been manufactured to internationally recognized GMP. + Governments seeking to promote their countries’ export of pharmaceuticals can do so by making GMP mandating for all pharmaceutical production. F Social and humane aspects: + Implementation of GMP is an investment in good quality medicine, that helps improve the health of individual patients as well as the community in terms of patient safety, recovery times and the like. Micro level (firm-level): + Making poor quality products does not reduce costs. In the long run, it is more expensive in finding mistakes after they have been made than preventing them in the first place and first time. GMP is designed to ensure that mistakes do not occur, thus, helps firms reduce production costs significantly in the long term. + Making and distributing poor quality medicines leads to loss of credibility for everyone: both public and private health care as well as the manufacturers. GMP helps firms build their credibility through producing quality products. In Asian region, many countries have not enforced the GMP compliance of pharmaceutical manufacturers while merely encourage them to implement the GMP guidelines for their own competitive advantages. Moreover, there is not a mutual recognition for national GMP guidelines and regulations among members of ASEAN, which is a considering obstacle to the pharmaceutical market opening process in the region. In Vietnam, the Drug Administration formed in August 1997 is responsible for establishing the GMP guidelines and granting the GMP - compliance certificates. However, these certificates are effective only in Vietnam, as they are not recognized in other countries. From 30 October to 1 November, 2000, there is a meeting of ASEAN members in Hanoi – Vietnam, relating to pharmaceutical issues, includes a discussion of approaches to the mutual recognition of ASEAN GMP certificates in the region. However, this issue is out of this research’s scope, hence, it is not mentioned in detail herein. Problem Statement As aforementioned, the ongoing challenges faced by Vietnam’s Ministry of Health are: How to establish or amend GMP guidelines and regulations, which are both appropriate to the domestic conditions and agreed with ASEAN GMP guidelines, that will become the regulations in the near future. What can the government do to promote pharmaceutical firms’ GMP compliance. What can the government do to support and reinforce the domestic pharmaceutical firms’ capabilities in order to sustain and develop in the on-going boundless market. Objectives In this research paper, the following objectives are supposed to be attained: To review the general concepts of quality assurance as well as ASEAN GMP guidelines for pharmaceutical industry. To compare GMP standards and ISO 9000 series of standards To present a broad view of the current situation of Vietnamese pharmaceutical industry and GMP compliance of pharmaceutical companies in Vietnam To outline pharmaceutical manufacturers’ difficulties and constraints relating to the GMP compliance in Vietnam Based on external benchmarking and internal auditing, to propose recommendations to: Firms for overcoming the challenges and successfully implementing GMP Government for promoting pharmaceutical firms’ GMP compliance Scope of study This research paper focuses only on the GMP guidelines and regulations for pharmaceutical industry in general, as well as the GMP implementation situations in Vietnam, which concentrated on finding out both internal and external challenges faced by firms in the process of obtaining GMP conformity. Methodology This research is conducted based on three critical tasks: Theoretically reviewing the quality assurance in pharmaceutical industry in general, Data collecting about Vietnamese pharmaceutical manufacturers in terms of revenues, GMP compliance, labor forces, capitals as well as the Vietnamese government’s policies towards firms’ GMP conformity, and Finally, basing on the collected information, recommendations are made to firms, government (Ministry of Health) and further studies. The research methodology framework is presented in the following diagram: Describe general concepts of Quality Assurance in Pharmaceutical Industry From Internet, books, journals Theoretical Review Review ASEAN GMP From Internet, books, journals Compare GMP vs. ISO From Internet, books, journals Review and describe the current situations of pharmaceutical industry in Vietnam, focusing on GMP compliance Actualities of pharmaceutical industry and GMP Implementation in Vietnam From secondary data, available at the Drug Administration of Vietnam Find out challenges faced by firms in implementing GMP Personal interviews Recommen- -dations For firms, for government, and for further studies Figure 1.2: Research framework of this paper Overview The entire research paper is divided into four chapters as the following: Chapter 1: presents a general overview of the background information, current problems, objectives and scope of the research study as well as the methodology for conducting this research paper. Chapter 2: discusses briefly the quality assurance concept in pharmaceutical industry and ASEAN GMP guidelines. A comparison of GMP versus ISO 9000 series standards is included as well. Last but not least, some pros and cons of quality standards are also considered. Chapter 3: outlines the actualities of pharmaceutical industry in Vietnam in terms of market structure and governmental policies. Moreover, the GMP compliance in Vietnam, as well as governmental policies relating to GMP implementation is also included. Aside from those, the internal and external challenges faced by firms in implementing GMP are also presented. Chapter 4: presents the recommendations to firms for overcoming the challenges and better practicing in implementing GMP standards. Also the recommendations to government for speeding up the GMP compliance of pharmaceutical manufacturers are addressed. CHAPTER 2 THEORETICAL REVIEW 2.1 Quality Assurance in Pharmaceutical Industry Quality assurance in pharmaceutical industry is a broad concept embracing research and development through manufacturing, quality control, storage and distribution, to the information provided to the prescribers and the patients. It is the sum total of the organized arrangements made with the objective of ensuring that medicinal products are of the quality required for their intended use. Quality assurance therefore incorporates GMP plus other factors illustrated by 5g-P principle mentioned hereafter. According to Kathy Constantine (2000), the system of quality assurance appropriate for the manufacture of medicinal products should ensure that: medicinal products are designed and developed in a way that takes account of the requirements of GMP and GLP (Good Laboratory Practices); production and control operations are clearly specified and GMP adopted; managerial responsibilities are clearly specified; arrangements are made for the manufacture, supply and use of the correct starting and packaging materials; all necessary controls on intermediate products, and any other in-process controls and validation are carried out; the finished product is correctly processed and checked, according to the defined procedures; medicinal products are not sold or supplied before a qualified person has certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorization and any other regulations relevant to the production, control and release of medicinal products; satisfactory arrangements exist to ensure, as far as possible, that the medicinal products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life; and there is a procedure for self-inspection and (or) quality audit which regularly appraises the effectiveness and applicability of the quality assurance system. The figure hereunder is the 5g-P principle or 5gxP principle developed by WHO in 1998 (GMP – Good Manufacturing Practices, GLP – Good Laboratory Practices, GSP – Good Storage Practices, GDP – Good Distribution Practices, and GPP – Good Pharmacy Practices) in quality assurance for pharmaceutical products (Cao Minh Quang, 2000). To ensure the quality of medicinal products from the starting materials through many other processes or stages, to the consumer, a good and cooperative relationship is needed between the manufacturer, whole-sellers, pharmacists and the like. Hence, the focus on only GMP while neglecting other four good practices (GLP, GSP, GDP, and GPP) is ineffectual to the product’s quality. The brief concepts of the other four good practices are explained hereunder. Quality Assurance in Pharmaceutical Industry Quality Assurance of Pharmaceutical products GPP Good Pharmacy Practices GDP Good Distribu-tion Practices GSP Good Storage Practices GLP Good Labora-tory Practices GMP Good Manufac-turing Practices Quality Assurance of Clinical Therapy GPP Good Prescri-bing Practices GCP Good Clinical Practices Figure 2.1: 5g-P Principle in Quality Assurance of Pharmaceutical products Source: Dr. Cao Minh Quang, 2000. It should be noticed as well that the quality assurance of clinical therapy (including Good Clinical Practices and Good Prescribing Practices) is not less important than the 5g-P principle in quality assurance of pharmaceutical products in offering the best services to the patients. What are the other four Good Practices (GLP, GSP, GDP, and GPP)? Good Laboratory Practices: GLP regulations set forth in either Title 21 Code for U.S. Federal Regulations (CFR) Part 58, Title 40 CFR Part 160 or Title 40 CFR Part 792. GLP conditions are required for conducting studies that support or are intended to support applications for research or marketing permits for products regulated by the FDA or the Environmental Protection Agency (EPA). It is a method to ensure that the quality and integrity of data generated in the course of a study are adequate to meet the Federal requirements. In brief, a study is in compliance with GLP regulations when it has a sound protocol, qualified personnel to run the study, standard operation procedures, proper and adequate facilities, calibrated and maintained equipment, fully retrievable raw data and overviewed by all independent quality assurance officer. Pharmaceutical manufacturers are required that all non-clinical studies submitted for the development of a new drug to be conducted under GLP conditions. Good Storage Practices: it is not an enforceable regulation at this moment, however, it is now been considering by drug administrations in many countries. For instance, in Vienna FIP (International Pharmaceutical Federation) Congress 2000, from 26 to 31 August 2000, Good Storage Practices is one of the topics discussed. The following is an illustration of the GSP guidelines for storing and handling vaccines. Designate one person within each clinic or office to coordinate storage and documentation of vaccines. Provide information to all personnel handling vaccines regarding appropriate storage and documentation practices. Check all vaccine shipments for any evidence of heat damage upon receipt; check cold chain monitor cards if appropriate. Routinely check all refrigerators or freezers to ensure proper working order. Place a thermometer in the refrigerator and maintain a daily log of refrigerator temperatures to document compliance with manufacturers' recommendations. Avoid storing any food in the same area with vaccines. Store vaccines in an area away from refrigerated or frozen medications to avoid confusion. Do not store vaccines in the refrigerator door shelf where temperature fluctuations may be greater. If possible, store bottles of chilled water in refrigerators and ice in freezers to minimize temperature fluctuations in the event of brief electrical power outages. Perform a monthly inspection of opened and unopened vials for out-of-date vaccines. When opening or reconstituting a vial, note the date and time it was prepared; check the manufacturer's recommendations for storage of reconstituted vaccines. Perform a "shake test" for products containing tetanus toxoid; if the product has been allowed to freeze, an insoluble precipitate will form in clumps that cannot be dissolved with vigorous shaking of the vial. Good Distribution Practices: as GSP, GDP is not a regulation. Moreover, there is no official GDP guidance. However, it is one of the issues to be considered b