Better Understanding of International GMP Regulatory Requirements

Pharmacopoeias

The rules of GMP recognize Pharmacopoeias as the official standards for Identity, Strength, Quality and Purity for Pharmaceuticals including Packaging and Labelling guideline. The purpose is to guarantee an acceptable quality of the final product by specified standards for Raw materials, Packaging materials and Dosage forms (preparations). The most predominately recognized Pharmacopoeias are the European Pharmacopoeia (Ph. Eur), US Pharmacopoeia-National Formulary (USP/NF) & the Japanese Pharmacopoeia (JP).

Within ICH the Working Group “Q4” is responsible for Pharmacopoeias and their harmonization through the three pharmacopoeia organizations (USP, JP & EP).

The three organizations conduct their harmonization efforts through a tripartite pharmacopoeia harmonization program known as the Pharmacopoeial Discussion Group (PDG). The harmonization of about 10 compendial test chapters has been considered as critical by the ICH Steering Committee, these chapters are now at various stages of harmonization. Another important task is to have the “Regulatory Acceptance of Pharmacopoeial Interchangeability”

The Expert Working Group Q4B will work on the following:

a. Facilitate the regulatory acceptance of PDG-harmonized text.

b. Clearly indicate (electronically) the regulatory interchangeability status of harmonized text for each of the regulatory regions as well as to indicate the effective date to begin use on applicable regulatory documents.

c. Ensure that from a regulatory perspective that the interchange ability is based on sound science.

d. Facilitate regulatory and industry access to the “benchmarked” harmonized text, ensuring that all are aware of exactly what text has been reviewed and given a status for interchange ability. This is deemed as essential for the regulatory acceptance of interchange ability.

e. Working with the Pharmacopoeial Discussion Group, expedite the implementation for the interchange ability.

Worldwide Regulatory Agencies

Regulatory agencies play a very important role in the pharmaceutical business by assuring the public that the products on the market are safe and effective.  Quality and Compliance Manual are to be developed to assure conformance to all major regulatory authorities.

The expectation of a quality product is the same and the requirements are similar for these agencies.  The achievement of quality is managed through different mechanisms.

Quality is determined by whether the firm complies with GMP requirements and makes scientifically justified decisions.

Pharmaceutical companies are now taking a proactive stance with the new GMP Systems approach, more effective internal auditing and increased regulatory awareness throughout the company. Quality can only be achieved when everyone works together to meet the challenge.

In the global environment, it becomes even more evident that individuals must understand the major multiple regulations and regulatory authorities that any pharmaceutical company must abide by.  There are still other regulations and regulatory authorities of smaller magnitude throughout the world that need to be considered.

On the following pages of this training unit you will see a general GMP overview of the major worldwide regulatory agencies and the regulations they enforce,

Responsibilities of Regulatory Authorities

Regulatory Authorities have a wide range of responsibilities for medicinal products. The extent may vary but in the most common responsibilities will be describe here.

New Product Review

A regulatory authority will review applications for new medicinal products including the results of laboratory, animal and human clinical testing conducted by companies. Data and GMP compliance are verified through inspections by the inspectors employed by the regulatory authority. If the regulatory authority determines the product is safe and effective the company will get an approval to sell the product.

 Acting as a “ Watchdog”

Once products are on the market, the regulatory authority monitors their manufacture and responds to reports of problems or newly identified risks. This monitoring normally includes laboratory testing of samples.

Because initial testing of products is based on a relatively small number of users, the regulatory authority will monitor reports of adverse events with products after they are marketed.  If this monitoring turns up a problem that needs to be corrected, the regulatory authority can, 1.) Ask the manufacturer to recall the product, 2.) Withdraw approval (of a drug, for example), 3.) Require labelling changes, or 4.) Send warnings to physicians or other health practitioners.

Standards and Regulations

The regulatory authorities use regulations and product standards as the “yardsticks” that define specific requirements manufacturers must follow to assure product safety and to provide accurate information to health professionals and consumers.  This work is often performed on an international basis to encourage the use of the same or equivalent standards.

Research

Research activities within the regulatory authorities provide the scientific basis for its regulatory decisions and the tools needed to identify and assess risks.  The agency uses its research results to establish standards, evaluate new products, develop test methods and other support for product monitoring and to study emerging risks.

Enforcement – Correcting Problems

When a problem arises, regulatory authorities can take a number of actions to protect the public health.  Initially, they work with the manufacturer to correct the problem voluntarily.  If that fails, legal actions can be taken which include asking the manufacturer to recall a product, seize products, revoke the manufacturing authorization and/or ask the courts to take legal actions.

US Food and Drug Administration (FDA)

The FDA has a wide range of responsibilities for drug products, biologics, medical devices, cosmetics, foods and radiological products.  Being the largest of the world’s drug regulatory agencies, the FDA is responsible for the approval of all drug products bought and sold in the USA and imported into the U.S.

The FDA consists of administrative, scientific and regulatory staff organized under the Office of the Commissioner (appointed by Congress) and has several centers with responsibility for the various regulated products.  Technical advice and experts for ICH work are drawn from the Centre for Drug Evaluation and Research (CDER) and the Centre for Biologics Evaluation and Research (CBER).

How FDA Works

FDA’s work includes all the elements describe for a regulatory authority Products that the FDA review include:

a. New human drugs and biologics

b. Complex medical devices

c. Food and color additives

d. Infant formulas

e. Animal drugs

In 2002, the FDA itself made more than 18,500 visits to facilities that manage FDA regulated products.  The FDA also has cooperative arrangements with many state and foreign governments, who inspect their own facilities, increasing the total number of facilities that are inspected.

FDA receives more than 400,000 reports of problems a year.  If this monitoring turns up a problem that needs to be corrected, the FDA can, 1) Request the manufacturer to recall the product, 2) Withdrawal approval (of a drug, for example), 3) Require labeling changes, or 4) Send warnings to physicians or other health practitioners.

Standards and Regulations

The FDA uses regulations and product standards as the “yardsticks” that define specific requirements manufacturers must follow to assure product safety and to provide accurate information to health professionals and consumers.  The FDA works with foreign governments to encourage the safety and quality of imported products by ensuring that foreign standards are equivalent to those enforced by FDA.

Research

FDA’s research activities provide the scientific basis for its regulatory decisions and the tools needed to identify and assess risks.  The agency uses its research results to establish standards, evaluate new products, develop test methods and other support for product monitoring, and to study emerging risks.

Enforcement – Correcting Problems

When a problem arises, FDA can take a number of actions to protect the public health.

Initially, the agency works with the manufacturer to correct the problem voluntarily.  If that fails, legal actions can be taken which include asking the manufacturer to recall a product, having federal marshals seize products if a voluntary recall is not done and detaining imports at the port of entry until problems are corrected.  If warranted, the FDA can ask the courts to issue injunctions or prosecute those who deliberately violate the law.

 Current Challenges for the FDA

Today, more than ever, the FDA needs to respond to a rapidly changing world.  There are many obstacles to overcome if the FDA is to continue its high standards of consumer protection. The most important of these challenges are:

a. Keeping informed about scientific breakthroughs. FDA scientists will need to keep up with rapidly advancing technologies in all product areas.

b. Understanding more sophisticated products. These “cutting edge” technologies will translate into products with new complexities and risks.

c. Planning for new public health threats. The FDA needs to be prepared to respond rapidly to unexpected health risks, such as tougher strains of antibiotic-resistant bacteria or more dangerous food borne illnesses.

d. Predicting the impact of international commerce. Monitoring of imports and cooperation with foreign regulators will become more important as international commerce continues to grow.

e. Providing consumers with the information they need. Today’s sophisticated consumers and the wide availability of information about FDA-regulated products will challenge the FDA to ensure consumers are getting the information they need from the right sources.

f. Reducing risks to the public health. The FDA will continue to effectively manage product risks throughout their life cycle- from research and development through use/ consumption. Risk management decisions will be supported by rigorous scientific analysis that weighs, when appropriate, not only the risk-to-benefit profile of the product itself but also the risk versus the benefit associated with Agency actions.

The FDA/ORA Guide to International Inspections and Travel, is intended to assist in fulfilling FDA’s overall mission of assuring that drug, medical device, biological and food products manufactured in foreign countries and intended for U.S. distribution are in compliance with the law and regulations; that non-compliance is identified and corrected; and that any unsafe or unlawful products are removed from the marketplace.

This guide provides FDA personnel with standard operation, inspection and investigation procedures to assure uniformity in the program.  It contains instructions and references to assist investigators and analysts who conduct international inspections.  It also provides information regarding authorities, objectives, responsibilities, policies and guides applicable to inspectional operations, administrative procedures, and the basic guidance necessary for FDA personnel who travel to foreign countries.  This guide is not designed to be all-inclusive, nor unduly restrictive.  The procedures and guides are designed to supplement the experience, skill and proficiency of investigators and analysts and serve as a reference.

The European Union (EU)

The European Union (EU) is the union of twenty-five European countries or Member States.  EU is a single market that will allow free movement of products throughout the EU.

These EU countries, with different histories and cultures, needed to fulfil the economic and political conditions known as the “Copenhagen criteria” to join the EU Requirements for membership are that a nation must:

a. Be a stable democracy, respecting human rights, the rule of law and the protection of minorities.

b. Have a functioning market economy.

c. Adopt the common rules, standards and policies that make up the body of EU law.

The Parliament, the Commission and the Council govern EU. The decision process in EU starts with the Commission making a proposal. Laws/decisions can be passed/taken by the parliament and sometimes the council. Within the European Union the following commission has been developed to ensure the safety, efficacy and quality of the drug products.

European Commission (EC)- Enterprise DG – Pharmaceutical and Cosmetics.

This commission initiates new proposals, whether new legislation or new authorization procedures, monitors implementation by national authorities and refers infringements to the European Court of Justice. The Commission’s Directorate General includes a unit responsible for pharmaceuticals and cosmetics.  The Commission is responsible for the

EU GMP, which is published on the website of the Commission. The GMP is continuously updated.

European Medicines Agency (EMEA)

The EU has established a joint regulatory agency in London originally named the European Agency for the Evaluation of Medicinal Products, now named the European Medicines Agency (EMEA).

The tasks of EMEA are to

a. Protect and promote public and animal health

b. Coordinate the evaluation and supervision of medicinal products throughout the European Union using the resources existing in the Member States

All member states in EU have their own regulatory agencies that provide the inspections necessary under the EU regulations.  In EU companies are required to have Manufacturing Authorizations in order to manufacture Medicinal Products.

Manufacturing Authorizations are issued by the Regulatory Agency of the Member State, who also supervises all manufacturing authorizations within their territory.  A listing can be found at the Heads of agencies website.

Mutual Recognition Agreements between EU and other countries.

In EU the Commission has the authority to negotiate Mutual Recognition Agreements with other countries. The European Community (EC) and MRA Partner Countries have established the MRAs to:

a) Reduce technical barriers to trade by facilitating market access while safeguarding consumer interests in health,

b) Grant mutual acceptance of inspection reports, certificates, authorizations, conformity marks issued by the regulated authorities of the Parties and manufacturers’ declarations of conformity certifying conformity to the requirements of the other Party,

c) Exchange information concerning procedures used to ensure that the conformity assessment bodies comply with the general principles of designation and

d) Encourage greater international harmonization

Comparison of FDA and EU Practices

Some of the differences between the FDA and the EU’s business practices are shown in enforcement actions listed below.

FDA and EU enforcement actions compared relative to increasing seriousness:

The quality expectations for the FDA and EU, vary in that:

The FDA does not have a specific regulation requiring internal audits but certainly expects them to occur; the EU-GMP defines expectations for having an established audit program in place.

 The FDA does not mandate a Qualified Person; the EU has a legal requirement of a Qualified Person (QP) also mentioned in the Manufacturing Authorization. The FDA believes that the firm, through its Quality System, is responsible for releasing the finished product. The EU and the MHRA believe that a particular person is held legally accountable for ensuring that all quality conditions are met before releasing each batch.

Another difference is that the US enacted the Freedom of Information (FOI) Statute which allows the public to access redacted or edited records, released to the public or when no further regulatory action is contemplated, whereas the EU does not. However, regulations may differ in the different Member States.

The level of an inspector’s authority is also different. The EU inspector has a large degree of power and authority.  At any point during an inspection, an EU inspector may confiscate any material that he or she decides should be confiscated.  An inspector can also demand entry to any facility or transportation when he or she has cause to believe that there may be a problem.  An inspector can notify the regulatory head office and immediately suspend a company’s activity or order a recall, if needed.

PIC/S

PIC/S is an organization for regulatory authorities. Members have to apply for membership and pass a successful evaluation for compliance with the requirements.

PIC/S GMP is essentially equivalent to the EU-GMP. PIC/S members include health authorities in many countries among them most EU Member States, Switzerland,

Australia and Canada. Australia and Canada is described in more detail below.

Australia / Therapeutic Goods Administration (TGA)

Regulation of Therapeutic Goods in Australia

The Australian community expects that medicines and medical devices in the marketplace are safe and of high quality, to a standard at least equal to that of comparable countries.  The objective of the Therapeutic Goods Act 1989, which came into effect on 15 February 1991, is to provide a national framework for the regulation of therapeutic goods in Australia and ensure their quality, safety and efficacy.

The Australian regulatory framework is based on a risk management approach designed to ensure public health and safety, while at the same time freeing industry from any unnecessary regulatory burden.  Any product for which therapeutic claims are made must be entered in the Australian Register of Therapeutic Goods (ARTG) before the product can be supplied in Australia.  The ARTG is a computer database of information about therapeutic goods for human use approved for supply in or exported from, Australia.

The Therapeutic Goods Act, Regulations and Orders establish the requirements for inclusion of therapeutic goods in the ARTG, including advertising, labelling, product appearance and appeal guidelines.  Some provisions such as the scheduling of substances and the safe storage of therapeutic goods are included by the relevant State or Territory legislation.

Cooperative Arrangement between the FDA and the TGA

On October 11, 2000, the TGA signed a cooperative arrangement with the Food and Drug Administration (FDA), USA, regarding the exchange of information on current Good Manufacturing Practice (GMP) inspections of human pharmaceutical manufacturing facilities. Under this agreement the FDA and TGA expressed their intent to:

a. Provide copies of pharmaceutical establishment inspection reports (confidential information purged) and product sample results to one another, upon request, within certain specified time frames.

b. Notify one another when one authority plans to conduct inspections in the other authority’s territory and be receptive to permitting joint inspections for the purpose of promoting better understanding of one another’s inspectional programs and techniques.

c. Provide other GMP-related information such as recall information, adverse product trends, health hazard evaluations, and alert system information.

Both authorities agree to exchange appropriate information about manufacturers when shortage situations occur which involve medically necessary human pharmaceuticals.

The information in the inspection report allows the FDA and TGA to make their own decisions concerning the compliance of manufacturers and appropriate follow up.  Each agency may carry its own inspections in the other’s territory if it deems necessary.

The agreement applies to GMP inspections of pharmaceutical facilities where the inspections have been conducted using the current FDA GMP requirements for drugs or the current TGA GMP Code for medicinal products.

TGA and EU

Australia has an MRA with EU, which means that the legislation and the way TGA works with regards to pharmaceuticals has been assessed and is considered equivalent to the EU system.

Australian Code of Good Manufacturing Practice for Medicinal Products.

The Australian Code of Good Manufacturing Practice for Medicinal Products (16 August 2002), replaces the Australian Code of Good Manufacturing Practice for Therapeutic Goods – Medicinal Products (August 1990), the Australian Code of Good Manufacturing Practice for Therapeutic Goods – Medicinal Gases (July 1992) and the Investigational

Medicinal Products Code of GMP (Annex 13, EC GMP Guide, 1997).

The new Code is based entirely on the international standard entitled Guide to Good Manufacturing Practices for Medicinal Products, PE 009-2, 1 July 2004, published by the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme (PIC/S).  The modifications to that Guide and its adoption as the Australian Code of Good Manufacturing Practice, is done so with the expressed permission of the PIC/S.

It was enacted in August 2003 as the basis for the licensing of all Australian manufacturers of medicinal products.

Canadian Health Products and Food Branch Inspectorate (HPFBI)

When a product is offered for sale in Canada to treat or prevent diseases or symptoms, it is regulated as a drug under the Food and Drugs Act.  Health Canada’s Therapeutic Products Directorate (TPD) is responsible for evaluating and monitoring the safety, effectiveness and quality of pharmaceutical drugs and other therapeutic products available to Canadians.  (Note: Contraceptive drugs are included in Medical Devices.)

In January 2002 a new directive was issued, Drug GMP and Establishment Licensing, replacing the previous 1998 version.

The following show the various sections and responsibilities of the Health Products and Food Branch Inspectorate.

Therapeutic Products Directorate (TPD)

This directorate (TPD) is responsible for the regulation of pharmaceutical drugs, medical devices and other therapeutic products available to Canadians.  This includes evaluating and monitoring their safety, effectiveness and quality.

Biologics and Genetic Therapies Directorate (BGTD)

This directorate (BGTD) is responsible for the regulation of biological and radiopharmaceutical drugs, including blood and blood products, viral and bacterial vaccines, genetic therapeutic products, tissues, organs and xenografts. This includes evaluating and monitoring their safety, effectiveness and quality.

 Marketed Health Products Directorate (MHPD)

This directorate (MHPD) is responsible for coordination of consistency of post-approval surveillance and assessment of signals and safety trends concerning all marketed health products.

The MHPD works in close collaboration with other Directorates in the Health Products and Food Branch and with other involved Branches.

The FDA and the Canadian Health Products and Food Branch Inspectorate (HPFBI) share a Memorandum of Understanding (MOU) that allows each party to share inspection reports and product sample test results like those that describe the conformity of therapeutic products or of a facility that manufactures, distributes, wholesales, tests or imports these products, with applicable regulatory requirements. They also may share Information on facilities registered or authorized in each participant’s country that then market product to the other participant’s country, including facilities that only export their products.  These are only a few of the points included in the MOU, signed in 2003.

Canada, EU and TGA

Canada has an MRA with EU and Australia, which means that the legislation and the way the Canadian authority works with regards to pharmaceuticals, has been assessed and is considered equivalent to the EU & TGA systems.

Ministry of Health, Labor and Welfare, Japan (MHLW)

MHLW is responsible for the improvement of and promotion of social welfare, social security and public health.  One of its nine bureaus is the Pharmaceutical and Medical Safety Bureau, which includes the Evaluation and Licensing Division. This division is responsible for the review and licensing of all medicinal products and cosmetics. It acts as the focal point for ICH activities.

Affiliated institutions include the National Institute of Health Sciences (NIHS) and Academia, which carry out research and testing on drugs, vaccines and biologicals.

Technical advice on ICH matters is obtained through MHLW’s regulatory expert groups that include members from NIHS. The Pharmaceuticals and Medical Devices Evaluation Centre (PMDEC) is an operational centre for new drug reviews affiliated in NIHS.Japan also has an MRA with EU. This MRA has a limited scope.

WHO

Many countries in particular in Asia and Africa have adopted the WHO GMP, which is available from the WHO website. Generally, the requirements are similar but less stringent than for example the EU GMP. WHO is focused on Essential medicines e.g. those that satisfy the priority health care needs of the population. They are selected with due regard to public health relevance, evidence on efficacy and safety and comparative cost-effectiveness.

Essential medicines are intended to be available within the context of functioning health systems at all times in adequate amounts, in the appropriate dosage forms, with assured quality and adequate information, and at a price the individual and the community can afford. The implementation of the concept of essential medicines is intended to be flexible and adaptable to many different situations; exactly which medicines are regarded as essential remains a national responsibility.

International Conference on Harmonization (ICH)

Harmonization of regulatory requirements was pioneered by the European Community, in the 1980s as the EC (now the European Union) moved toward the development of a single market for medicinal products.  The success achieved in Europe demonstrated that harmonization was feasible.  At the same time there were bilateral discussions between Europe, Japan and the USA on possibilities for harmonization.  It was at the WHO

Conference of Drug Regulatory Authorities (ICDRA) in Paris in 1989 that specific plans for action began to materialize.  Soon afterwards, the authorities approached the International Federation of Pharmaceutical Manufacturer’s Associations (IFPMA) to discuss a joint regulatory-industry initiative on international harmonization and ICH was conceived.

The birth of ICH took place at a meeting in April 1990, hosted by the European Federation of Pharmaceutical Industries’ Associations (EFPIA) in Brussels.

Representatives of the regulatory authorities and industry associations of Europe, Japan and the USA met primarily to plan an international conference but the meeting also discussed the wider implications and terms of reference of ICH.  The ICH Steering Committee (SC), which was established at that meeting, has since met at least twice a year with the location rotating between the three regions.

ICH Parties

ICH is comprised of six parties who are directly involved, as well as three observers and IFPMA. The six parties are the founding members of ICH and represent the regulatory bodies and research-based industry in the European Union, Japan and the USA.  These parties include the EU, EFPIA, MHLW, JPMA, FDA and PhRMA.  The observers are WHO, EFTA, and Canada, represented by Health Canada.  This important group of non- voting members acts as a link between the ICH and non-ICH countries and regions.

ICH is operated via the ICH Steering Committee, made up of the six parties plus an IFPMA representative.  Technical and scientific support from the EU for ICH activities is provided by the EMEA through the Committee for Proprietary

Medicinal Products (CPMP). The Steering Committee is supported by the ICH Secretariat, which operates from IFPMA in Geneva.

Early in the ICH Process it was agreed that there was adequate international agreement on the technical aspects of Good Manufacturing Practices (GMP) for Pharmaceutical

Products and that further harmonization action through ICH was not needed.  Recently, however, attention has focused on the need to formalize GMP requirements for the components of pharmaceutical products – both active and inactive.  In November 2000 ICH published Q7a for implementation ‘GMP for Active Pharmaceutical Ingredients’ (APIs).  In November 2005, ICH published Q8 (Pharmaceutical Development) and Q9 (Risk Management) also for implementation.

Summary

Depending on where the product is manufactured and distributed, there can be more than one set of regulatory requirements that the drug product needs to comply with. As the pharmaceutical business becomes more global and products are allowed to pass freely between countries, the approach of a worldwide standard is gathering momentum. The

FDA has several agreements with other countries (e.g. Australia and Canada) where they will accept the inspections of the U.S. instead of performing their own. In Europe the Members States of the EU accept products manufactured in other member countries.

Inspections are conducted on behalf of the EU, instead of each individual country.  EU has also several MRAs with other countries that grant mutual acceptance of inspection outcomes. Through the ICH drug standards are being harmonized.