EU, FDA and WHO Regulations Part One – Introduction, History & EU Regulatory Requirements
In recent years there has been no change to the trend of further internationalizing the production and distribution of pharmaceuticals. API’s, excipients, intermediates and finished products are shipped across the globe in highly complex supply chains.
This increasingly complex situation requires companies and their employees to be versed in the GMP requirements of more than one nation. Solely focusing on the national GMP requirements is no longer sufficient. Larger institutions such as the EMA, US FDA and WHO must be taken into account in almost every case.
In three articles over the coming months, PCS will introduce you to the history of these regulatory requirements, their requirements and structure. This first article will focus on the history of the FDA GMP, WHO GMP and EU GMP. Additionally, we will introduce you to the EU GMP structure and requirements.
To provide a short summary on some of the most important organizations/agencies worldwide (in alphabetical order, adjusted for the main audience of these newsletters):
European Union – European Commission (EC)
Organization: European Commission
Purpose: Volume 4 of “The rules governing medicinal products in the European Union” contains guidance for the interpretation of the principles and guidelines of good manufacturing practices for medicinal products for human and veterinary use laid down in Commission Directives 91/356/EEC, as amended by Directive 2003/94/EC, and 91/412/EEC respectively.
Primarily Applicable To:
United Kingdom, Ireland, Denmark, Greece, Spain, Portugal, Sweden, Finland, Austria, Romania, Bulgaria, the Netherlands, Luxembourg, Italy, Germany, France, Belgium, Slovenia, Slovakia, Poland, Malta, Lithuania, Latvia, Hungary, Estonia, Czech Republic, Cyprus, Croatia.
United States – Food and Drug Administration (FDA)
Organization: Food and Drug Administration (FDA)
Legislation: 21 Code of Federal Regulations Parts 210 and 211 (amongst others)
Purpose: The regulations in this part contain the minimum current good manufacturing practice for preparation of drug products (excluding positron emission tomography drugs) for administration to humans or animals
Primarily Applicable To:
The United States of America (USA).
World Health Organization (WHO)
Organization: World Health Organization (WHO)
Guidances: Technical Report Series (TRS) (amongst others)
Purpose: Established in 1947, the Expert Committee on Biological Standardization (ECBS) has overall responsibility for this area of work. Standards developed through the ECBS relate to the production and quality control of safe and effective products. They provide guidance for national regulatory authorities and manufacturers and serve as the standard for acceptability of vaccines for supply to countries through international agencies (terms prequalification).
Primarily Applicable To*:
Armenia, Azerbaijan, Belarus, Botswana, Burkina Faso, Burundi, Cameroon, Caribbean Community (CARICOM), Comores, Côte d’Ivoire, Democratic Republic of the Congo, Eritrea, Ethiopia, Georgia, Ghana, Kazakhstan, Kenya, Kyrgyzstan, Lao People’s Democratic Republic, Madagascar, Malawi, Mali, Mozambique, Namibia, Nigeria, Pakistan, Philippines, Senegal, Sierra Leone, South Africa, Sri Lanka, Sudan, Tanzania, Thailand, Uganda, Ukraine, Uzbekistan, Zambia, Zanzibar, Zimbabwe.
*(list contains the countries receiving the greatest share of assistance from the WHO based on: Collaborative Procedure between the World Health Organization Prequalification of Medicines Programme and National Medicines Regulatory Authorities in the Assessment and Accelerated National Registration of WHO-prequalified Pharmaceutical Products, other WHO members also require adherence to WHO regulations).
Origins of the Regulations/Guidances
The authorization of medicines by the WHO/EU/U.S. FDA builds on three key criteria; quality, safety and efficacy, to ensure that products administered to patients are of suitable quality and provide a positive benefit-risk balance. Unfortunately, the systems in place to regulate medicinal products today are based on mistakes, tragedies and slow bureaucratic decisions in the past which led to thousands of unnecessary deaths.
History of the EU GMP
2015 marked the 50th anniversary of pharmaceutical legislation in the European Union, which began with Directive 65/65 in 1965. This directive followed the Thalidomide disaster when thousands of babies were born with limb deformities as a result of their mothers taking a medicinal product (Thalidomide) during pregnancy. Throughout the world, about 10,000 cases were reported of infants with limb deformation due to thalidomide; only 50% of the 10,000 survived. Directive 65/65 lays down the principles for the modern-day EU GMP. Despite being only five pages long it establishes (amongst others) the legal framework for placing products on the EU market, stating the following;
“In order to obtain an authorization to place a proprietary medicinal product on the market as provided for in Article 3, the person responsible for placing that product on the market shall make application to the competent authority of the (EU) Member State concerned.”
The Thalidomide, which shocked and alarmed public health authorities and the general public in the EU, made it evident that to safeguard public health, no medicinal product must ever again be allowed to be marketed (in the EU) without prior authorization.
History of the U.S. FDA GMP
The FDA GMP’s have a very different origin. In 1906, Upton Sinclair published a book; “The Jungle”; detailing the filthy conditions of the meatpacking industry. This prompted congress to publish the “Pure Food and Drug Act of 1906”.
Although this was a step in the right direction, only corrective measures were included (taking manufacturers to court after an offence was found) but lacked proactive measures. It wasn’t until 1937 that the law drastically changed. A manufacturer of a drug used to treat streptococcal infections in liquid form (S.E. Massengill Co.) performed a flavor, appearance and fragrance test on its product and found it to be satisfactory. Over 600 shipments were sent out. The medicine is predominantly consumed by children who soon started dying painful deaths with symptoms including abdominal pain, kidney failure and urine stoppage. More than 100 people, most of them children, lost their life.
The cause, using diethylene glycol (DEG) as a dissolvent. Despite the discovery of DEG’s toxicity in 1937, Harold Watkins, the company’s chief pharmacist and chemist, was not aware of this. Some authors suggest the minimum toxic dose is estimated at 0.14 mg/kg of body weight and the lethal dose is between 1.0 and 1.63 g/kg of body weight. It was found that the solvent used to formulate the elixir was 60 gallons (227 liters) of DEG.
Congress then passed the Federal Good, Drug and Cosmetic Act. This act required manufacturers to provide evidence showing a drug is safe before being allowed to market it. The FDA was granted powers to inspect factories and cosmetics and therapeutic devices were now also subject to regulatory review.
In the years leading up to the Thalidomide incident, alarming findings were made by senators on advertising claims and the science behind drug efficacy claims. Again, no action was taken until it was almost too late.
The U.S. barely escaped the fate of the EU. The company which wanted to import Thalidomide to the U.S. filed for approval six times but did not include all the information required to make an informed decision. The scientist in charge of the application; Ms. Frances Oldham Kelsey was troubled by this lack of information. In her meetings with the company she felt that “they were at no time being wholly frank with me, and that this attitude has obtained in all our conferences, etc. regarding this drug”, despite complaints to superiors by the company, Kelsey stood her ground, prompting the FDA to reject the application for marketing and distribution six times.
This near miss led Congress to pass the Drug Amendments of 1962, introducing; additional controls over novel, prescription and investigational drugs. Effectiveness had to be shown before approval and adverse reactions now had to be reported to the FDA. Lastly, ads in medical journals needed to show risks and benefits rather than just the benefits of the medicinal product.
The Drug Amendments Act of 1962 formalized the FDA Good Manufacturing Practices.
Origins of the WHO GMP
The first WHO draft text on GMP was published in 1968. In 1969, when the World Health Assembly recommended the first version of the WHO Certification Scheme on the quality of pharmaceutical products moving in the global market, it accepted the WHO GMP as an integral part of the Scheme. The Expert Committee on Biological Standardization (ECBS) was founded in 1991 and establishes the general approach to the quality control of biological medicines.
More than one hundred countries have incorporated the WHO GMP into their national laws on medicinal products, and many others have adopted its provisions in defining their own national GMP requirements. The WHO GMP is used as a basis for the WHO Certification Scheme and prequalification of vaccines for procurement by United Nations agencies such as UNICEF.
EU GMP Requirements – Structure & Legal Basis
The EU GMP has directives, guidelines and annexes. The FDA has its Code of Federal Regulations and the WHO publishes rather bulky documents called the Technical Report Series, but which code/guideline or regulation applies to what and when?
The EU GMP is dictated by the European Commission.
The European Commission is the executive branch of the European Union.
The EU GMP Directives contain the principles for medicinal drug manufacture. The directives can be considered “the law”. A directive shall be binding, as to the result to be achieved, upon each Member State to which it is addressed, but shall leave to the national authorities the choice of form and methods, this allows for minor differences in interpretation between member states.
The guidelines can be seen as an extension of these directives (the law). Guidelines are self-executing and do not require any implementing measures.
For example, Commission Directive 2003/94/EC states the following:
It is not a coincidence that the guidelines of Volume IV of the EudraLex (for human and veterinary use) are structured as follows:
|Chapter 1||Pharmaceutical Quality Systems|
|Chapter 3||Premise & Equipment|
|Chapter 6||Quality Control|
|Chapter 7||Outsourced Activities|
|Chapter 8||Complaints and Product Recall|
In addition to these chapters, there are annexes which may be applicable to certain product groups or situations such as Annex 1 for sterile products.
Differences With WHO and FDA
The difference between the EU GMP and the WHO GMP are mostly concerned with the level of detail. Where the WHO GMP provides more guidance on the implementation of its requirements through extensive annexes to it’s Technical Reports. These include (for example) cleanroom design considerations, cleaning validation implementation and how to train staff in the pharmaceutical industry.
The laws relating to GMP are fundamentally similar between the EU GMP and the US FDA GMP. It is the detailed guidelines and their implementation where the discrepancies become obvious. An obvious example is the Qualified Person (EU GMP Annex 16) which cannot be found in the US GMP. Other, more subtle, differences will be discussed in part 2 of this series.
EU GMP Applicability
The EU GMP applies to twenty-eight member states; the United Kingdom, Ireland, Denmark, Greece, Spain, Portugal, Sweden, Finland, Austria, Romania, Bulgaria, the Netherlands, Luxembourg, Italy, Germany, France, Belgium, Slovenia, Slovakia, Poland, Malta, Lithuania, Latvia, Hungary, Estonia, Czech Republic, Cyprus, Croatia. A number of countries are currently applying for candidacy; Albania, Bosnia and Herzegovina, Montenegro, North Macedonia, Serbia and Turkey.
When you are not located in the European Union and want to import your products to the European Union you must find a buyer (importer) in the European Union or establish your own legal entity in the EU. Your buyer / importer will audit you against the EU GMP regulatory requirements. If you do not comply, they will not buy your product as their own license is at stake.
If you are looking to introduce new products to the European Union you may require a Marketing Authorization (MA) which can be filed with the European Medicines Agency (EMA). There are three options; decentralized procedures, centralized procedures and a national procedure. If you require assistance in the application for such procedures, establishing an import organization or finding an importer, PCS can assist you with navigating the regulatory requirements and pitfalls.
EU GMP Inspections
Inspections under the EU GMP/GDP are performed by NCA (national competent authorities) who are largely responsible for the authorization of medicines that do not pass through the centralized procedure. The inspections by NCA’s are (in most cases) shorter than inspections by the FDA and WHO.
Each EU member state has its own NCA.
In some cases, such as the Netherlands, there are two NCA’s; the Inspectie voor de Gezondheidszorg en Jeugd (IGJ) is responsible for assessing the quality and safety of medicines already approved or under review by the CBG, while the College ter Beoordeling van Geneesmiddelen (CBG) is responsible for the assessment of new applications.
The National Competent Authorities also supply thousands of European experts who serve as members of the Agency’s scientific committees, working parties or in assessment teams supporting their members.
In most cases the GMP/GDP inspections conducted by European NCA’s have a ‘innocent until proven otherwise’ approach. Inspectors are usually open to dialogue and are allowed to accept different interpretations of the regulations if proven to be equally effective or better whilst not being detrimental to patient safety or product quality.
Even though unannounced inspections exist within the EU, inspections are usually announced in advance. This ensures key personnel is on site when the inspectors arrive. If your company is expecting to receive a EU/WHO/FDA inspection, PCS can help you prepare for the inspection through consultancy, training and GMP/GDP upgrade trajectories
The three main organizations responsible for the modern-day GMP’s implemented in nearly every country worldwide are the European Union, the U.S. Food and Drug Administration and the World Health Organization. Although their applicability and scope differ greatly, they share a common goal of improving the availability, quality and efficacy worldwide.
The history of the EU GMP and U.S. GMP is based on tragedies which have transformed the legislation on medicines and food dramatically since the early 20th century. The WHO GMP was founded later to fill the gap in biologics and to assist nations lacking the resources to approve and inspect medicinal products in a proper way.
There are distinct differences between the different pharmaceutical regulatory requirements of the EU, FDA and WHO. Partly because of their history, scope and applicability but also because the approach of the inspectorates responsible for upholding the GMP/GDP requirements may differ significantly. The EU GMP is based on directives and guidelines which are well structured and include annexes for additional guidance, they apply to all EU member states and for importers from outside the EU. The main differences with the FDA and WHO requirements will be discussed in the next two parts.