Efforts pull together European standards and regs
An overview of the European regulatory bodies affecting standardization and harmonization efforts in the EU
By Carolyn Mathas
When one scans the regulatory and standards landscape in Europe, one can’t help but be overwhelmed with the volume of agencies, regulatory organizations and standards bodies in place that oversee the pharmaceutical and electronics industries. For more than thirty years, regulations have developed throughout Europe to oversee the manufacture, inspection process and delivery of pharmaceuticals. As each country established the guidelines, regulations and standards that it would follow, pharmaceutical companies increasingly met with tremendous bureaucratic red tape, outrageous costs and the inability to bring its products to market in a timely manner worldwide.
The autonomous regulatory efforts of countries comprising the European Union caused myriad duplicated efforts and roadblocks. Today, fortunately, there is a rapid movement towards harmonization of activities, sharing of information and, when possible, reduction of disparity in technical requirements.
Good Manufacturing Practices (GMP)
At the heart of regulations and standards is the concept of Good Manufacturing Practices (GMP). The passage of the Food and Cosmetic Act (FD&C) in 1938 marked the first attempt to regulate production processes in the manufacture of pharmaceuticals. Twenty-four years later, in 1962, the Kefauver-Harris Drug Amendments provided the first legal basis for GMP regulations, and The World Health Organization published the first GMP Guideline in 1968. Today, European Commission Directive 2003/94/EC governs the manufacture of drugs and medical devices, ensuring product quality by regulating and documenting the production environment; 21CFR Part 210 and Part 211 are the equivalent in the United States.
Establishing a basis of good manufacturing practices addresses the fact that end-point testing is inadequate to guarantee quality. Instead, consistent and sound quality principles are used in the manufacture and testing of products to ensure that manufacturing meets quality standards; adequate test measures are used so that product meets quality specs at the time it reaches the market (and throughout its shelf life); and raw materials used in manufacture are standardized and free from contamination.
GMP is not only used in final-product manufacturing, but also for clinical trials. The legal status of investigational pharmaceutical products varies by country. In Germany, for example, these products are manufactured and inspected as licensed products would be. In other countries, legal and regulatory GMP provisions, such as manufacturing practice inspections, do not cover investigative products. The EC guide recommends that the principles of GMP be applied to the preparation of products, and the World Health Organization (WHO) guide on GMP also applies to the preparation of clinical trials supplies. Applying the principles to trials ensures batch-to-batch consistency, adding to the trial’s reliability. It also ensures consistency between an investigational product and the final product, protecting from poor-quality products resulting from manufacturing errors (contamination, cross-contamination, labeling problems, etc.).
In search of consistency
Worldwide standards and regulations seem to boil down to two elements-good manufacturing practice and global consistency. Defined by the European Medicines Evaluation Agency (EMEA), which is charged with the protection and promotion of public and animal health throughout the European Union (EU), GMP is “that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use.”1 Within Europe, there are myriad agencies, standards and regulatory bodies, and groups that establish and defend their version of GMP.
“Each country within the EU has its own agency and regulatory body. ISO and the International Conference on Harmonization (ICH) are standards bodies. The rest of the agencies and regulatory bodies handle implementation. For instance, the MHRA is the British equivalent of the FDA,” explains Dinah Larty, MHRA spokesperson. “These organizations meet regularly, coordinated by the European Medicines Evaluation Agency (EMEA). If the EMEA passes a ruling, it then applies to all of the member states,” Larty adds.
The FDA’s increased collaboration with such international regulatory partners and cooperatives as the ICH and the Pharmaceutical Inspection Cooperation Scheme (PIC/S) is a strong indication that international regulation and standardization is the goal. Recently, the FDA created a working group to analyze internal and external requirements, comparing 21CFR Part 210 and Part 211 against the European Union’s and PIC/S’s GMPs. 21CFR Part 211 includes such issues as microbiological contamination, in-process testing, filters, and equipment cleaning and maintenance. As a result of the analysis, the FDA resolved to modify Part 210 and Part 211 and to harmonize them internationally and with other agencies domestically. What also resulted was a new commitment to share regulatory information with others globally and FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) are now actively coordinating with the ICH and VICH (covering veterinary products).
The European standard-makers
There are several international standards organizations that represent the foundation for technical support in the growth of global markets. Here are a few of the more prominent associations:
International Conference on Harmonization (ICH)
Based in Switzerland at the International Federation of Pharmaceutical Manufacturer’s Associations (IFPMA), ICH has six sponsors: the European Commission; European Federation of Pharmaceutical Industries Associations; Japanese Ministry of Health, Labor and Welfare; Japanese Pharmaceutical Manufacturers Association; Centers for Drug Evaluation and Research and Biologics Evaluation and Research, FDA; and the Pharmaceutical Research and Manufacturers of America. Each of the six has one vote. According to IFPMA, “The countries involved comprise 80 percent of the world market, and are home to the world’s major multinational pharmaceutical companies. The World Health Organization (WHO) and European Free Trade Area and Health Canada are nonvoting observers.”2
The purpose of the ICH is to blend the approval process for new pharmaceutical drugs from Europe, the United States and Japan into one set of standards. The organization was formed in direct response to trade talks in the mid-to-late 1980s between the U.S. and Japan, which involved opening Japan for U.S. pharmaceuticals. The European Commission decided to create a single EU standard for drug approvals to compete with the U.S. and Japanese trade negotiations. IFPMA responded by organizing meetings between the three parties, ultimately resulting in the ICH.
The functions of the ICH include:
• Agreement on one set of scientific rules for clinical trials
• Reducing the number of animals and human test subjects
• Creating one set of standards for the manufacturing of new drugs
• Ensuring similar application processes for drug approval in all countries
• Ensuring that other countries accept research findings
In November 2003, ICH created two expert working groups (EWGs) focusing on pharmaceutical development. The first, ICH Q8, focuses on product life-cycle risk and quality by design. It articulates the “desired state” for pharmaceutical manufacturing in the 21st century as: “Product quality and performance achieved and assured by design of effective and efficient manufacturing processes.”3 The group is developing a guidance for a pharmaceutical development section that will help apply knowledge gained through the application of scientific approaches and risk management strategies directly to the development and review of a product and its manufacturing process. Today, uncertainty during the review process accounts for considerable delays. The emerging Q8 will enable regulatory agencies to develop:
• Risk-based reviews and inspections
• Manufacturing process improvements without the need for regulatory review
• Real-time quality control to reduce end-product release testing
The second EWG, ICH Q9, is charged with defining principles by which risk management will be integrated into decisions by regulators and industry regarding quality and compliance with current good manufacturing practice (cGMP). The two groups work in parallel and share information.
A more recently formed ICH Q10 will cover life-cycle management for process and system control and will promote post-approval improvements to manufacturing processes. It addresses the challenges of post-approval changes since, specifically for manufacturers, the regulatory process should not delay implementation of improvements in manufacturing processes once a product is approved for marketing.
In the past few years, the U.S. FDA has actively embraced the concept of harmonization to promote technical innovation for enhanced public health promotion and protection. In November 2003, an agreement was reached by ICH to work on an internally harmonized plan to develop a pharmaceutical quality system based on an integrated approach to risk management and science.
ICH’s M4 Common Technical Document (CTD) guidance describes a harmonized format for new product applications. The CTD is intended to reduce time and resources necessary to compile applications; ease the use of electronic submissions; facilitate regulatory reviews and communication with the applicant; and simplify the exchange of regulatory information.
International Organization for Standardization (ISO)
The International Organization for Standardization (ISO) is the world’s largest technical standards development body. ISO is a network of the national standards institutes of 148 countries, made up of one member per country. Founded in 1946, when delegates from twenty-five countries met in London and created a new international organization to “facilitate the international coordination and unification of international standards,”4 ISO acts as a bridge between private industry and government regulators where solutions that meet both needs can be found. The organization officially began operations on February 23, 1947. Since then, ISO has published more than 13,700 International Standards covering screw threads, freight containers, bankcards, and performance and safety requirements. Standards ensure cleanliness, interoperability of equipment and technologies, test method agreement and safety standards, with the majority of standards being applicable to any organization, or industry segment, worldwide.
Headquartered in London, the MHRA is the British equivalent of the FDA, charged with the safety, quality and efficacy of drugs sold or supplied in the UK. Source: MHRA
According to Dave Schmidt, Plastic Shop Manager at Imtec Acculine (Sunnyvale, Calif.), manufacturer of wet-processing modules and systems for the semiconductor industry, “Imtec initially applied for ISO 9001 to secure itself in the marketplace and elevate the company above the ‘mom and pop’ shops. ISO certification guarantees our customers internationally and domestically that Imtec goes the extra mile to provide quality and repeatability in its products.” Under ISO, companies such as Imtec inspect all incoming materials, throughout the process, and conduct 100 percent final testing to demonstrate that each test was implemented and passed, ensuring a high level of quality.
“We went through the certification process initially in 1994 and upgraded to ISO 9001-2000 in 2003. The entire process from the time we expressed interest to completion was approximately eighteen months. In the beginning, it was extremely difficult for our employees to understand the benefits of all the added work and the seemingly endless documentation. However, as we worked through the four levels of the quality system, from quality manual, operating procedures, work instructions, to quality records, it began to make sense why the process was so important. Now, it’s like clockwork and second nature,” added Schmidt. “ISO allowed us to get our foot in the door with international customers that we might never have attracted without the certification. It assures them that we follow strict guidelines and conduct internal audits. Today, our customers include every major U.S. semiconductor manufacturer, along with those in the United Kingdom, Europe, Japan, Korea, Singapore, Taiwan and China.”
ISO certification assures Imtec???s customers that they are receiving a high-quality product and attracts new customers worldwide. Source: Imtec Acculine
Based on a foundation of “equal footing,” each ISO member takes part in the development of any standard it feels is important and each member retains one vote. Based on this framework, each member country has the ability to strategically influence the direction of ISO.
ISO collaborates with more than 500 international and regional organizations, including nearly 30 international standards-developing bodies However powerful, ISO standards are voluntary; ISO does not regulate or legislate. It has no legal authority to enforce implementation. Many countries have adopted ISO standards as part of their regulatory framework or as a technical basis for legislation. As such, they may become a market requirement, such as ISO 9000 quality management. ISO requires a review of its standards every five years at minimum to establish whether they should be updated, withdrawn, or kept as is.
Together, ISO and IEC are responsible for approximately 85 percent of all international standards.
International Electrotechnical Commission (IEC)
Founded in 1906, in London, England, the International Electrotechnical Commission (IEC) is the leading global organization that prepares and publishes international standards for all electrical, electronic and related technologies, which serve as a basis for national standards and as references when drafting international tenders and contracts. It promotes international cooperation, covering such electrotechnologies as electronics, magnetics, electromagnetics, electroacoustics, multimedia telecommunication, energy production and distribution, as well as general disciplines such as terminology and symbols, electromagnetic compatibility, measurement and performance, dependability, design and development, safety and the environment.
IEC, in conjunction with ISO and the International Telecommunications Union (ITU), maintains a strategic partnership with the World Trade Organization (WTO). Although the WTO’s mission is to ensure that trade flows smoothly, predictably and freely, it recognizes that there are technical barriers to trade that result from the differences in national regulations and standards. As such, an Agreement on Technical Barriers to Trade (TBT) exists so that standardizing bodies in member countries comply with a “Code of good practice for the preparation, adoption and application of standards,” embodied in Annex 3 (known as the WTO Code of Good Practice).5
Where international standards exist or their completion is imminent, the Code of Good Practice says that standardizing bodies should use them, or the relevant parts of them, as a basis for standards they develop. It also aims at the harmonization of standards on as wide a basis as possible, encouraging all standardizing bodies to play as full a part as possible in the preparation of international standards by relevant international bodies, including the IEC and ISO.
International Telecommunications Union (ITU)
Yoshio Utsumi, secretary general of the ITU, describes the organization’s history : “Over [its] more than 135 years, the Union’s mandate has expanded to cover the invention of voice telephony, the development of radio communications, the launch of the first communications satellites and, most recently, the technological convergence that heralds the dawn of a new, telecommunications-based information age.”
In 1865, the first International Telegraph Convention was signed and the International Telegraph Union, as it was first called, was born. Today, the ITU, through its standardization sector, develops technical and operating standards to foster seamless interconnection of the world’s communication networks and systems. Currently, international standards development involves the new broadband global infrastructure and the convergence of Internet Protocol (IP), public-switched telephone network (PSTN), digital subscriber line (DSL), cable television (CATV), wireless local area network (WLAN) and mobile technologies. Over 70 standards have been published by the ITU in the security field alone.
Regulatory bodies throughout the EU
The European Medicines Evaluation Agency (EMEA) represents the glue joining the regulatory bodies throughout the EU. Founded in 1995, the EMEA is a decentralized body of the European Union that evaluates and supervises medicines, bringing together the scientific resources of the twenty-five EU member states in a network of forty-two national authorities. It reinforces the EU contribution to global harmonization, authorizing medicinal products and providing a recognition procedure within its membership. It is primarily involved in the centralized procedure whereby one single marketing authorization application is submitted to EMEA and a single evaluation is carried out through the Committee for Medicinal Products for Human Use (CHMP) or its veterinary counterpart (CVMP). Once a positive opinion is given and sent to the Commission, a single authorization is valid for the entire European Union.
Although it is impossible to discuss all of the organizations that exist throughout the European Union, several noteworthy regulatory agencies and their descriptions follow:
Federal Institute for Drugs and Medical Devices (BfArM)
The BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte) is an independent, higher federal authority within the Federal Ministry of Health in Germany. Working in conjunction with authorities in the EU and WHO, more than 1,100 physicians, pharmacists, biologists, technical assistants and staff work at the BfArM to prevent health risks by improving the safety of medicinal products and by risk-monitoring of medical devices and controlled substances.
Within Germany, in addition to the BfArM, the Pharmacopoeia is a collection of quality requirements which is continually updated and which consists of the German, the European, and Homeopathic Pharmacopoeia. Together they work towards the international harmonization of quality requirements. 6
International Laboratory Accreditation Cooperation (ILAC)
ILAC is an international cooperation of laboratory and inspection accreditation bodies that focuses on:
• The development and harmonization of laboratory and inspection accreditation practices
• Laboratory and inspection accreditation to industry, governments, regulators and consumers
• Assistance and support for developing accreditation systems
• Global recognition of laboratories and inspectional facilities, thus facilitating acceptance of test, inspection and calibration data accompanying goods across national borders
On March 1, 2005, the IEC and ILAC signed a memorandum of understanding to improve efficiency and reduce assessment costs for testing labs. According to IEC Conformity Assessment Board Chairman Don Gray, “This agreement helps to ensure that the standard is applied in the same way by both the IEC and ILAC, which makes life easier for the testing laboratories.”
Medicines and Healthcare Products Regulatory Agency (MHRA)
The MHRA is a British executive agency that replaced the former Medical Devices Agency (MDA) and Medicines Control Agency (MCA). The objectives of the organization are to influence international regulation, to support industry and scientific innovation, and to minimize the cost of regulation. MHRA monitors how medicines and devices are advertised and how they come to the notice of the general public. The organization also functions as an advisor to other regulatory bodies. The British equivalent of the FDA, the MHRA concentrates on ensuring that the right processes are in place.
Recently in the news as the agency that brought the gears of Chiron to a halt in the manufacture of Fluvirin® vaccine, MHRA is charged with the safety, quality and efficacy of medicines sold or supplied in the UK. In addition, it monitors and ensures compliance with statutory obligations relating to medicines and devices through inspection and taking enforcement action when necessary, as in the Chiron case. The agency operates a quality surveillance system to sample and test medicines and address quality defects, monitoring the safety and quality of imported, unlicensed medicines. It also investigates Internet sales and potential medicine counterfeiting. The MHRA does not have executive powers.
Medical Products Agency (MPA)
The Medical Products Agency (MPA) is the Swedish national authority responsible for regulation and surveillance of the development, manufacturing and sale of drugs and medical products. Acting as a regulatory authority, it collaborates with other EU drug regulatory authorities. MPA monitors clinical trials and is responsible for inspection and quality control in manufacturing. Dedicated to the goal of ensuring safe and effective medicines on the European front, the MPA is an active participant in clinical effectiveness, safety, biotechnology, quality and side-effect monitoring.
It is the opinion of the MPA that the existing European system enables new medicines to reach the market faster, benefiting both patients and manufacturers. In addition, because of the collaborative nature of the European Union members, product quality is maintained while duplication of efforts is minimized. 7
Parenteral Drug Association (PDA)
Founded by drug manufacturers in 1946 and headquartered in Bethesda, Maryland, the PDA disseminates technical information within the pharmaceutical industry. The PDA Quality and Regulatory Affairs Department monitors international and U.S. communities for new guidance that affects PDA members. PDA volunteers worldwide promote the exchange of rapidly evolving information on the latest technology and regulations for high-quality pharmaceutical production. 8
The organization has more than 10,500 individual members worldwide, exchanging information via conferences, meetings and open forums that attract manufacturers, suppliers, users, and academic and regulatory officials.
PDA’s Quality and Regulatory Affairs Department interacts with the FDA, EMEA, WHO, ICH and other global regulatory bodies. It publishes such guidelines as the “Draft Guidance for Industry on Formal Dispute Resolution: Scientific and Technical Issues Related to Pharmaceutical Current Good Manufacturing Practice,” and “PDA GMP in the 21st Century: Risk and Quality Glossary.”
Pharmaceutical Inspection Cooperation Scheme (PIC/S)
The Pharmaceutical Inspection Cooperation Scheme (PIC/S) is a cooperative arrangement between the quality systems of worldwide pharmaceutical inspectorates and health authorities that are leading international development, implementation and maintenance of harmonized cGMP standards. Membership provides networking, training of inspectors and exchange of information. PIC/S is an organization of international inspectors that publishes documents that, although not obligatory, reflect common understanding. Its goal is to support a more common application of GMP inspections worldwide and common inspection approaches, as well as to share information.
According to the organization, its mission is to “lead the international development, implementation and maintenance of harmonized Good Manufacturing Practice (GMP) standards and quality systems of inspectorates in the field of medicinal products.”9 The agency develops and promotes harmonized GMP standards and guidance documents; fosters training for competent inspectors; assesses and reassesses inspectorates; and facilitates cooperation and networking for competent authorities and international organizations.
PIC/S combines both the Pharmaceutical Inspection Convention (PIC) and the Pharmaceutical Inspection Co-operation Scheme (PIC Scheme) which operate together. PIC was originally founded in 1970 by the European Free Trade Association as the “Convention for the Mutual Recognition of Inspections in Respect of the Manufacture of Pharmaceutical Products,” representing Austria, Denmark, Finland, Iceland, Liechtenstein, Norway, Portugal, Sweden, Switzerland and the United Kingdom. It soon expanded to include Hungary, Ireland, Romania, Germany, Italy, Belgium, France and Australia. It was eventually discovered, however, that an incompatibility between the Convention and European law prevented new countries from joining as members. As a result, the PIC Scheme was formed on November 2, 1995, and the two are jointly referred to as PIC/S.
The major difference between the two efforts is that PIC represents a formal treaty that has legal status and involves the mutual recognition between countries of inspections, while PIC/S is an informal relationship between health authorities for the exchange of information and has no legal status. Twenty-seven authorities participate in PIC/S (convention and scheme). Before a regulatory authority qualifies as a member of the PIC/S, an assessment establishes that the authority possesses the ability to apply an inspection system that will match the requirements of PIC/S.
World Health Organization (WHO)
WHO is the United Nations’ specialized agency for health, created in 1948. WHO establishes guidelines for the manufacture of sterile preparations to minimize microbiological, particulate and pyrogen contamination risks. The organization establishes air quality cleanliness characteristics, guidelines regarding exposed surface composition, equipment characteristics, warning systems, processing, sterilization, labeling, personnel clothing, and quality control in manufacturing.
In “Drugs and Money, Prices, Affordability and Cost Containment,” published on behalf of WHO in 2002, the report states that the “...enforcement of regulations will however need to be strengthened. At the same time it is clear that the harmonization with EU criteria may create a series of problems around the availability of medicines, as some manufacturers may find it difficult to fully comply with GMP in time, and as it may prove difficult to complete the full review of old registration dossiers before the day of accession. This will lead to a welcome cleaning up of the eastern European drug scene, but at the same time may also lead to the disappearance of many cheap generic products from the market.”10
The report continues to identify ongoing challenges for central and eastern Europe and newly independent states: “Drug regulation is rapidly brought into line with EU regulations, as negotiations for the enlargement of the Union proceed; however it will at the same time be necessary to prove better systems for the enforcement of regulations and policies than those currently existing, and it is vital to ensure that this harmonization will not lead to decreased access of needed drugs.” III
1. European Medicines Evaluation Agency (EMEA) Web site: http://www.emea.eu.int
2. International Federation of Pharmaceutical Manufacturer’s Associations (IFPMA) Web site: http://www.ifpma.org
3. International Conference on Harmonization (ICH) Web site: http://www.ich.org
4. International Standards Organization (ISO) Web site: http://www.iso.org
5. International Electrotechnical Institute Web site: http://www.iec.ch
6. Federal Institute for Drugs and Medical Devices (BfArM) Web Site: http://www.bfarm.de/en
7. Medical Products Agency (MPA) Web site: http://www.mpa.se/
8. Parenteral Drug Association (PDA) Web site: http://www.pda.org
9. Pharmaceutical Inspection Cooperation Scheme (PIC/S) Web site: http://www.picscheme.org
10. World Health Organization (WHO), “Drugs and Money, Prices, Affordability and Cost Containment,” edited by M.N.G Dukes, F.M. Haaijer-Ruskamp, C.P. de Joncheere and A.H. Rietveld. IOS Press, 2002.