International GMPs

GMPs: Codes, Directives, Guidelines, Points to Consider, or Regulations; and inspection severity

Good Manufacturing Practices are in effect in 104 countries, either through national codes, adherence to regional codes, or adoption of the WHO code. Whether they are stated to be regulations, as in Japan, Korea and the United States; or directives, as in the European Union, or Guides as in the United Kingdom, or Codes as in Australia, the intent of the authorities is the GMPs be strictly followed to consistently assure pharmaceutical product quality.

Japan, Korea and the United States are the only countries where the GMPs have been enshrined in law as legal regulations. In the United States non-compliance with the GMPs during manufacturing and testing, is taken by the courts as evidence that the drug is adulterated, and hence cannot be marketed. For example, the US GMPs mandate that when performing weighing operations (as well as for other specified operations such as addition of chemicals to the formulation) two people need to be present to perform the operation – one to perform and one to watch and concur that all is correct. An FDA inspector has no leeway to apply his own judgment during an inspection when faced with one person performing the operation. The regulations are the law, and the regulations mandate that two people be present throughout the operation.

In other countries, a company having a valid reason as to why there is only one person performing the activity can reasonably discuss their rationale with the GMP inspector, and the company will probably not receive a citation for non-compliance with the GMPs.

This difference between GMP regulations and GMP codes, directives and guides accounts for the reputation of the US FDA as a no nonsense inspection agency. It has often been stated that “FDA inspects for compliance; European inspectors inspect for adequate science”. Put another way, an FDA inspector will spend about 80 – 90% of the time allocated to an inspection, in an office reviewing the paperwork associated with the product’s development, manufacture and testing checking for documentary evidence of compliance, and absence of fraud. In contrast a European inspector will spend 80 – 90% of his inspection time interviewing staff and management, and walking the facility to observe the manufacturing and testing process, and assessing the soundness of the operations he is observing. 

In Europe the key document controlling GMP inspections is Commission Directive 2003/94/EC, of 8 October 2003, laying down the principles and guidelines of good manufacturing practice in respect of both medicinal products and investigational medicinal products for human use. A European directive is a proposal promulgated by the EU Commission designed to ensure freedom of movement of goods, personnel, finances, and services within the European Union. Once approved by the European Parliament, implementation of the directive requires that each member state incorporate the directive into its own national legislation within three years of original passage of the directive by the EU Commission.

Subordinate to the above directive is the “Rules Governing Medicinal Products in the European Union”, a Guide to GMP, which is then adopted by member states national legislation as legally applicable in their country.

It is apparent from the above discussion that having the written word alone is not sufficient to ensure adequate compliance with the GMP requirements. Compliance depends on the adequacy of the Code of GMP – the written word – and the rigor of the inspections that are performed by national health authorities. If these two elements are combined a table could be generated signifying which countries have in force theseverest GMPs. Such a table would likely look like this:

While the US is generally perceived by industry to be the toughest inspection agency due to its inflexibility in interpretation of the regulations, the British Commonwealth countries rank second due to their hiring practices for inspectors. US inspectors typically do not have any background in the healthcare manufacturing and food industries on joining the agency – an FDA inspector being required to inspect all types of facilities falling with FDA’s remit – but are entirely trained on the job. Inspectors in the British Commonwealth countries only inspect pharmaceutical manufacturing facilities and are not hired unless they have 5 – 10 years of management experience within the industry. Hence not only do these inspectors know what the skeleton’s look like, they have the experience to understand where the skeletons, if they exist, are most likely buried. American companies inspected by the British MHRA would place the British at the top of the above ranking; while European and Asian companies place the Americans at the top. It often occurs that an American company that has passed numerous FDA inspections will fail a British MHRA inspection. Likewise a British company, with years of compliance history to British GMPs will fail an FDA inspection. This can and often is extremely embarrassing to both the company, and the authorities, as evidenced by the failure of the British company Fisons to pass an FDA inspection in 1994 which lead to questions in the British House of Commons as to the effectiveness of the British Department of Health and Social Services (a precursor to the crrent MHRA) in doing its job.

It is interesting to note the divide between approaches to GMP inspections in Europe seems to be cultural, with countries that historically were once part of the Holy Roman Empire (HRE) having a much looser attitude to GMPs, GMP compliance and government regulations in general, than the attitude of their Northern European neighbors, who historically were outside the HRE. This is a concern that will repeat itself when considering other multi-national agreements, as explained later in this chapter when considering the potential for a US-EU Memorandum of Understanding on Mutual Recognition of GMP inspections.

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