Global Regulatory Compliance Challenges:
A symposium sponsored by the Regulatory Forum of SQA
26 - 27 October 2009, Philadelphia, PA, USA
ABSTRACTS
The Impact of Cultural Issues on Establishing GLP Programs in Developing Countries
Robert R Stewart PhD
Technology Sciences Group Inc, Washington, DC, USA
The success of Good Laboratory Practices in the OECD countries, and its significance for the acceptance of data for product registration, has resulted in efforts to role these programs out into developing countries. Establishing and maintaining GLP compliance in these countries requires more than just training. Established cultural and operational realities can interfere with a GLP mindset that is so critical to continued compliance. A case history from China will be examined to illustrate some of the issues that arise during the process of setting up and running studies under GLP.
The Current Status and Challenges of Implementing a GLP Program in China
Xiuwen Wang
National Center for Safety Evaluation of Drugs, National Institute for the Control of Pharmaceutical and Biological Products, State Food and Drug Administration, Beijing, P. R. of China
It has been a long and difficult journey for China to build up its GLP program since 1993 when the first draft GLP regulation was issued by the Ministry of Science and Technology. This presentation provides an overview of the history and evolvement of GLP program in China. The challenges and difficulties encountered during this process will be discussed and analyzed from a regulatory agency point of view. The current GLP certification program and status in China will be described. In addition, a brief introduction to Chinese Society of Quality Assurance (CSQA) will be provided.
Establishing a GLP-Certified Laboratory in China: A 15-Year Journey towards GLP Compliance
Xigeng Bai
Safety Evaluation Center, Shenyang Research Institute of Chemical Industry, Shenyang, P. R. of China
How do you establish a GLP laboratory in a country without an OECD membership? What difficulties were met during the process? What embarrassing situations were faced in the long journey towards GLP compliance? More importantly, how to fulfill the final goal of MAD (Mutual Acceptance of Data) with OECD countries? What are the possible solutions for satisfying these issues? This presentation will describe the 15-year endeavor of a laboratory in China towards GLP compliance. The current situation of this laboratory will be provided. In addition, possible solutions to deal with MAD issues will be discussed.
Challenges in Woking Under Both US FDA and China SFDA GLPs
Jinsong Xing
Bioanalytical Services, WuXi AppTec Co., Ltd. Shanghai, China
Any GLP work conducted in China aimed for US FDA submission must comply with both US FDA and China SFDA GLPs. To comply with both sets of GLP regulations can be challenging because of their differences. WuXi Bioanalytical Services just passed a joint inspection by both US FDA and China SFDA without 483. The author will share experiences in working under both FDA and SFDA GLPs and the joint inspection.
GLP Laboratories in China and Their Compliance Status
Joe Zhang
Roche R&D Center (China) Ltd., Shanghai, P. R. China
As a part of strategic growth of its innovative pharmaceutical R&D industry, the Chinese government made GLPs for nonclinical safety studies a law by issuing the Pharmaceutical Administration Law of the People’s Republic of China in 2003. In the same year, the State Food and Drug Administration (SFDA) of China issued the first GLP certificates to four state-owned laboratories. Since then, China has adopted a national GLP certification program, and as of July 31, 2009 there are 33 SFDA-certified laboratories in China. Because more and more pharmaceutical companies have increased their preclinical and clinical drug development activities in China, many private and joint venture preclinical Contract Research Organizations (CROs) have started building/offering GLP services in China to their western clients.
This presentation will provide a comprehensive review of the GLP laboratories in China and their compliance status based on the author’s first-hand experience of building and inspecting GLP laboratories in China. In addition, a brief summary of a recent FDA inspection of four GLP laboratories will be provided.
Multi-Site Study Conduct: The Challenge of GLP Compliance to Conflicting Global Interpretations
Kathrin Ertz1, Martina Preu2
1Bayer CropScience, Monheim, Germany, 2Bayer AnimalHealth, Monheim, Germany
The implementation of GLP on an international level is well advanced. However, the international and national GLP guidelines leave room for interpretation, so that having to work in GLP environments in several countries in parallel can represent a real challenge.
- National GLP interpretation:
- GLP roles, responsibilities and rules in different national guidelines lack consistency.
- Multi-site studies conducted at test sites in different countries cross the "GLP-borders". Encountered issues range from differences in the content of the OECD Guidelines in different language versions to differing interpretation of the OECD GLP Guidelines in the respective national GLP guidelines.
- From a company point of view, it is desirable to organize test facilities across regional or national "GLP-borders". A more harmonized approach by the international GLP monitoring community would be helpful.
- Archiving: In spite of the new OECD Guidance Document No. 15 on Archiving, some important issues still have not been harmonized on an international level:
- Different required archiving periods in different countries are problematic, especially when working with Contract Research Organizations (CROs) in several countries.
- There is no international systematic approach (or recommendation) for dealing with archived data if CROs close down.
- List of GLP test facilities: Most countries maintain a list of all currently certified GLP test facilities. However, if the GLP certificate of a test facility is not renewed or even revoked, there is no official system in place to circulate this information on an international level.
- Import tolerance studies: Import tolerance studies must be conducted according to GLP (field and analytical part). This rule also applies if the studies are performed in "non-GLP" countries. This entails enormous time, effort and cost for the test facility "exporting" its GLP competence. The complete GLP infrastructure including a Quality Assurance System has to be brought along for each individual study. This study-by-study approach does not contribute to building a sustainable GLP base in these "non-GLP" countries.
GLP Quality Systems and Compliance Monitoring in India
Labhu U Sanghani PhD
Jai Research Foundation, Valvada, Gujarat, India
India has entered the mainstream of the global technological arena with full compliance with the global Intellectual Property Rights (IPR) regime. The “Observer membership” of India in the Organization for Economic Cooperation and Development (OECD), complying with the Mutual Acceptance of Data (MAD) agreement, has made India an attractive destination for outsourcing preclinical studies to India by the European Union, American and other global sponsors. India offers state-of-the-art research facilities for preclinical and chemistry research. The studies are undertaken by highly qualified and GLP-trained researchers whose primary language for communication is English. Additional factors considered by sponsors are a stable democracy and a stable economy, which in turn offer cost arbitrage on account of the strong Indian Rupee. Involvement of the pharmaceutical and agrochemical industries in demanding high-quality, globally acceptable data have been instrumental in the development of global GLP facilities and helped in the development of state-of-the-art toxicology facilities in India.
Strong Government policies, coupled with firm and quick regulation of animal ethics, have led to enhance the confidence level of Indian Contract Research Organization’s (CROs) with the global sponsors. Most of the Indian CROs are certified by the Dutch, German and Indian GLP monitoring authorities. State-of-the-art laboratory equipment and manufacturing/resourcing agencies within the Indian preclinical facilities have led to data generation at par with global pre-clinical CROs. Involvements of Indian scientists and QA professionals with global QA organizations (SQA, BARQA, JSQA), scientific organizations (SOT, ACT, ACS, CIPAC-WHO-FAO) as well as regular interactions with the GLP monitoring authorities and regulators (e.g., FDA, EPA, PSD/CRD, DCGI), have helped the CROs in offering globally comparable and acceptable GLP studies and prompt services to the sponsors. India, being on the forefront of the global information technology (IT) industry, has led to the participation of IT-experienced scientific professionals in the conduct of global GLP studies.
This presentation will present the global quality GLP standards which have formed a backbone by the Indian preclinical facilities. The presentation endeavours to touch upon various GLP issues specific to the subcontinent while conducting the safety studies in India.
The Conduct of Mutli-Site Studies within and across Geographies: Constraints, Complexities and Compliance
Natesan Settiagounder PhD1, William D Barta2
1Advinus Therapeutics Private Ltd, Bangalore, India, 2WDBarta QA Consulting LLC, Lawrenceville, New Jersey, USA
Test facilities and sponsors often decide to engage external laboratories (test sites) for generating regulatory data for different phases of a study. Such studies have been more common earlier for field studies involving agrochemicals. Of late, it is becoming a frequent occurrence for pre-clinical or non-clinical laboratory studies on health and environmental safety as well. Complexities of study design, requirements of specific equipments and expertise for performing specialized phases of studies, experience of certain laboratories during the early phases of R&D work, and business reasons make test facilities and sponsors to look for test sites within and/or across geographies for multi-site studies. Thus, the process of conducting multi-site studies is not only complex but also introduces several constraints as well as compliance related challenges. Current understanding of such challenges and the specifics of carrying out GLP complaint multi-site studies are the focus of this presentation. While the OECD Consensus Document No. 13 provides a great deal of clarity, it remains a challenge to conduct multi-site studies involving multiple test sites, which may have diverse compliance practices such as OECD GLP, FDA GLP and EPA GLP. Creation of a single study plan for multi-site studies, selection of test sites and justification, timely communication, QA inspection at test sites, and generation of GLP complaint phase reports, and finally consolidation of multiple phase reports into a single final report involve tremendous efforts of the study director and lead quality assurance. Test facility and test site management requirements, master schedules, maintaining stability/integrity of samples during transport, archiving of raw data and specimen, etc., are additional compliance related complexities. Based upon hands-on-experience in handling of several multi-site studies within and across geographies over the last 15 years, an attempt is made in this presentation to provide a systematic approach to make the multi-site studies as simple as possible.
Navigating Global Registration of GM Crops in Changing Regulatory Environments
Beryl J Packer, PhD
Monsanto Company, St. Louis, Missouri, USA
Regulations for commercial approval and importation of GM crops have undergone major changes in Korea and China over the past two years. Korea is an OECD member nation while China is not. The impact of that fact on the ability of companies to effectively and efficiently obtain regulatory approvals has been surprisingly different than what was expected. The challenges encountered reflect a complex interaction of country-specific regulatory compliance requirements with cultural and political influences, as well as with global economic and trade issues. This discussion includes the various issues raised for both regulators and the regulated community by the most recent changes that have taken place in Korea and China regulatory systems, the approaches that were taken to successfully register Roundup Ready 2 Yield soybean™, and strategic issues to be considered for global harmonization of GM crop registration in the future.
US EPA Technical Cooperation with Asia and Latin America on Good Laboratory Practices
Francisca E Liem
US Environmental Protection Agency, Washington, DC, USA
The Unites States Environmental Protection Agency (EPA) promulgated the Good Laboratory Practice (GLP) Standards for pesticides, under 40 CFR part 160 and chemical substances, 40 CFR part 792 in 1983, amended in 1989. These regulations are to be applied and complied with for studies submitted to the EPA in support of a pesticide registration and pursuant to testing consent agreements and test rules for chemical substances. Since then, many countries in the world has adopted the Organization for Economic Cooperation and Development (OECD) Principles of GLP as their standards for studies in support of registration purposes of pesticides, industrial chemicals and medical products. Most of these countries are in North America, Western Europe, and the Asian Pacific Region. Many more countries, especially in Asia and Latin America are interested in developing their GLP program and adopting the OECD Principles of GLP. This presentation will discuss EPA’s activities in Asia and Latin America on GLP and their status of establishing a recognized GLP program.
Comparison of the Practical GLP Interpretation among US, UK and Japan
Yoshikazu Hasegawa1, Masako Chino1, Kenji Manno1, Vanessa Grant2, Rodney Pateman2,
James McCormack3, Nancy Gongliewski3
1JSQA Special Project team, 2BARQA GLP Committee, 3SQA GLP Specialty Section
In the last decade, the globalization has progressed rapidly in the pharmaceutical industries. It requires the harmonization and mutual understanding among countries in GLP studies. We have recognized some differences of the GLP interpretation among countries through the process of the global development of pharmaceuticals and medical devices. In order to pursue the mutual understanding, we think it is the first step to make the differences clear among United States, United Kingdom and Japan.
There were several investigations about the comparison among GLP articles and the GLP enforcement guidance or ordinance in each other. However, was there any investigation about observations which were issued by an inspection authority based on the GLP interpretation in each country and was the interpretation accorded among countries? This question was not answered yet. Therefore, our project goal was, “Understanding what differences there are in the practical GLP interpretation by the monitoring authority among United States, United Kingdom and Japan.”
We, JSQA Special Team, BARQA and SQA GLP Committee have been investigating the comparison of the practical GLP interpretation among Japanese MHLW GLP, UK GLP and FDA GLP. There were over 300 Q&A cases in the past ten years in the Pharmaceutical GLP Guide Books (Tokyo, YAKUJI NIPPO) before 2008. We have selected 66 Q&A cases to investigate covering all GLP articles and have translated them into English. BARQA and SQA GLP Committees have discussed and prepared their answers for 66 question cases referring to their own databases and past comments and discussion results with their authorities. By comparing the answers of each Quality Assurance Society, we could understand some differences of GLP interpretation among authorities in each country for practical questions.
In this presentation we will make sure whether there are differences among three countries in the GLP interpretation or not. Additionally, during our investigation, Japanese MHLW GLPs in the Pharmaceuticals and Medical Devices have been revised on June 13, 2008 and come into force as from August 15, 2008. We will try to explain what impacts have been come out mainly and what points have been changed from previous interpretation in this presentation.
African Biosafety Network of Expertise: Building Biosafety Regulatory Programs of African Countries
Allan Liavoga
African Biosafety Network of Expertise, African Union/NEPAD, Pretoria, South Africa
In order to ensure the safe deployment of transgenic crops for the benefit of African farmers and consumers, regulatory systems must be established that are functional in making decisions. However, such decision making systems are largely absent in Africa. The African Biosafety Network of Expertise (ABNE) is an initiative of the African Union and the New Partnership for African Development (NEPAD) mandated to develop and deliver science-based biosafety resources to empower African regulators. This presentation gives a general overview of the current agricultural biotechnology regulatory environment in Africa and the contribution of the ABNE project towards building functional biosafety regulatory systems in African countries.
An Experience in Developing a GLP Operation for Field-based Research in Brazil
Fábio S Tagliaferro1, Wladecir S Oliveira1, Barbara Foy2
1Monsanto do Brasil Ltda., São Paulo, São Paulo State, Brazil, 2Monsanto Company, St. Louis, Missouri, USA
Since 2006, the Regulatory team of Monsanto do Brasil has been developing facilities, research staff, and an infrastructure to support field-based regulatory research for biotech and chemical products. Implementation of a GLP-compliant research system was in the planning, but a new Brazilian law requiring GLP compliance for residue trials that came into force by mid-2008 accelerated the quality system development. Even though the Monsanto GLP Organization located in the US provided strong support, the development of the GLP operation in Brazil was challenging due to limited human resources, relatively reduced time available, and the lack of harmonization among inspectors’ interpretations. Moreover, the multi-site nature of the GLP operation, with distances as long as 1,200 miles between the main test facility and test sites, posed an additional challenge for the development of a unified research and quality system. This presentation will describe the approach adopted for the development of the GLP operation and discuss some peculiarities of the Brazilian model that are critical for recognition by the GLP monitoring authority, INMETRO.
Brazilian System of Agriculture Inputs Inspection: The Official System to Measure the Brazilian Companies Compliance
Luís Eduardo Pacifici Rangel
General Coordination of Pesticides for Ministry of Agriculture, Brazil
The Brazilian process of inspection, executed by the Ministry of Agriculture, Livestock and Food Supply, aims to assure quality for the agriculture inputs offered by pesticide companies. The main inputs regulated by authorities are seeds (genetically modified or not), fertilizers and pesticides. Brazilian legislation is considered modern and follows the most important international protocols on these areas. The main difference is that the official inspection system also assures companies compliance when it comes to information supplied at registration time. The aim of such work is to measure the level of compliance of all agriculture inputs available on the market and of pesticide companies. This system attempts to guarantee consumers rights, developed by authorities, very common in the Brazilian model of law.
Differences in the Interpretation of the GLP Requirements by OECD Monitoring Authorities: The point of view from the pharmaceutical industry
Raymond K Lowing PhD
Sanofi-aventis R&D, Cedex, France
The need to harmonise the GLP principles, their application and their monitoring was seen very early on with the publication of the set of OECD documents, the joint meetings and training of the inspectors and the system of joint mutual visits. Even though some challenges were encountered in the preparation of the text of the initial OECD documents and the update of the principles in 1997, the texts are now, for the most part, aligned. However, often the expectations behind the text are different and sometimes even opposite.
In my company we have an almost unique position having 12 research and development sites in 8 different countries all performing phases of studies which can be used by any of the other sites and all inspected by OECD GLP Monitoring Authorities.
In such a global organization to ensure the maximum quality it is always best to follow the same practices and processes. In this presentation I will identify some of the challenges which are encountered when trying to establish a global system of high quality which will satisfy all the expectations of the multiple monitoring authorities.
I will identify the diversity of origins of the requirements which we need to be aware of including international and national GLP principles, specific guidance documents on GLP, question and answer sessions on GLP interpretations, annexe requirements on specific areas (21 CFR part 11, veterinary legislation etc.) and conference presentations by Regulatory Authorities.
I will then concentrate on some of the more important variations in expectations and interpretations concerning:
- Perimeter of application of GLPs
- Metabolism and Pharmacokinetics
- Multi-site studies
- Metrology
- Computer related systems
- Master schedules
- Quality assurance program and responsibilities
- Control article in bio-analytical phases
- Extra work to signed off studies
- Terminated compounds
In the time given however, it will obviously not be possible to discuss in detail all of the differences in the expectations and unfortunately we will not be able to discuss the very great and interesting variations in the classification of the severity of the same observation by different monitoring authorities which can go from “no criticism” to “critical observation”.
It is important to realize that even though there might be some interpretations that we in the industry have some difficulty in understanding, the objective of this presentation is not to complain or to criticize one or other of the Monitoring Authorities. The objective is to try to be constructive, to show where there are differences so that you can then help us in our goal which is to give you the highest possible level of quality. This obviously will be much easier if we in industry have a single set of expectations to which we need to adhere.
An Update on Health Canada’s Initiative to Establish a GLP Monitoring Authority (GLP-MA)
Paul Sidney
Charles River Laboratories Preclinical Services Montreal Inc, Montreal, Canada
This presentation is an overview on the status of Health Canada’s initiative to establish a GLP Monitoring Authority. As an OECD member state, Canada has an obligation to establish a Monitoring Authority to ensure non-clinical safety studies, conducted in compliance with the OECD GLP Principles, will be accepted internationally. The scope of this update will include an overview of the Canada’s GLP programs, OECD Member state feedback on the status of Health Canada’s OECD obligations, key organizations involved in the establishment of a GLP Monitoring Authority in 2009 and a review of the Draft Guidance published by Health Canada on the Sponsors’ obligations to conduct non-clinical safety studies in accordance with the OECD GLP Principles.
Challenges in Global Software Development and Implementation from a CRO Perspective
Randall Basinger
Quintiles, Durham, North Carolina, USA
This presentation will provide insight into how a global CRO releases software and the challenges of doing so while working in emerging markets such as India, China and Eastern Europe. Having participated in validation efforts and the roll-out of systems that are used in the company’s global offices, Mr. Basinger will provide examples and examples into the issues (cultural differences, technology hurdles, etc.) that companies will likely face in implementing systems across the globe.
Implementing Global GCP Computerized Systems: Preparing and Managing the Global Project
Pat Miller
SAS, Cary, North Carolina, USA
Project management can be challenging under the best circumstances, but managing a global project for a validated software implementation increases the complexity and challenges dramatically. This presentation will look at the points to consider when planning and managing a global, validated implementation project, from seemingly simple issues like time zone differences to cultural differences that can disrupt your project plans and deadlines.
GxP Regulatory Compliance Challenges for Global Data and Document Management
Kim Nitahara
META Solutions, Inc, Somerville, New Jersey, USA
Electronic data, document, and submission management systems have become commonplace throughout our regulated industry over the last few decades. International companies have worked through many of the difficult technological, cross-cultural, and regulatory compliance challenges during the development and implementation of these systems. However, just when we thought we knew all the answers, it seems that many of the original questions have changed.
This presentation will provide an overview of the GxP regulatory compliance requirements and expectations for computerized systems that produce, distribute, archive, and publish electronic data, documents, and regulatory submissions. Specific issues and challenges for global design, development, and implementation will be discussed, including risk-based standards, electronic signatures, Internet security, vendor management, legacy content migration, and archiving. The presentation will include examples from the speaker’s experiences providing audit and consultation services throughout the world.
Helping to Ensure the Integrity of Your Samples during Global Transport
Michael Gordon
World Courier, New Hyde Park, New York, USA
Shipping cold chain samples has become more and more challenging as site locations become even more remote and timelines get tighter. In this session we will discuss the differences in logistic providers and how to overcome some global challenges and examine specific country guidelines. Join us to discuss these and other import/export regulatory demands.
International Shipment of Test Articles and Biological Matrices
Christopher McEvoy
Charles River Laboratories Preclinical Services Montreal Inc, Montreal, Canada
The scope of this presentation will review the challenges of international shipment of Test Article and Biological Matrices for preclinical research. During this session, an overview of the shipment process will be discussed and the key actions to be taken at specific milestones of a preclinical study. There are four key milestones in a preclinical study in which shipment requirements as well as permits and licensing need to be addressed:
1) Inquiry/pre-study start-up process
2) Protocol signed – changes or modifications confirmed
3) First shipment of samples to sponsor or designated sites
4) Return of materials for long-term archiving
A specific case study will be used to demonstrate the challenges posed at each milestone.