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International GMPs

Drug Quality – GMP Implementation

The first modern code that could be considered to be Good Manufacturing Practices, as we recognize them today, were the regulations issued by the Canadian Specifications Board of the Supply and Services Department in 1957 (referred to as the QUAD regulations) used to assure that drugs supplied to the Canadian Military met quality specifications. Following the success of that regulation, GMPs started being issued by regulatory agencies at a rapid pace – the US FDA issued its first version of the GMPs in 1963, with the current version of the US GMPs essentially being drafted in 1973 and issued in 1976. The British GMPs drafted in 1968 were finalized and issued in 1973, in a rush following the Davenport incident (previously referred to).

By the early 1980s distinct GMP codes had been issued by over 25 different countries – sometimes following the basic US or British GMP in outline, but typically adding a local wrinkle to the requirements. Thus for example the British and US codes required that when an error is made in data entered in a record, correction of the error shall constitute four steps: placing a single line through the error, entry of the correct data alongside the original erroneous error, entry of the signature or the initials of the person making the change and the date that the change was made. The Australian GMPs added the requirement that in addition the reason the error had originally been made also needed to be entered in the record; the Japanese added the requirement that the strike-out be made with two lines, drawn in parallel. With the exception of the Japanese Code of GMP, the GMP codes all followed the same style, had similar texts, and made approximately similar demands of pharmaceutical manufacturers in the control of manufacture and laboratory testing.

The exception to the almost uniform world-wide style and content of the GMPs issued is Japan, whose GMP regulations were, until the latest edition in 2002 unlike that of any other country. While discussing the same issues as all other GMP codes, the Japanese style of GMPs were that they resembled detailed job descriptions describing the duties and responsibilities of various members of key management staff in the pharmaceutical company. They described the role and function of the Manufacturing Control Manager, the Quality Control Manager and the Product Security Pharmacist. Japanese Product Security Pharmacist was effectively equivalent to the European “Qualified Person”. When auditing Japense pharmaceutical companies, I have found that the concept of GMP compliance as it is understood in the West is almost totally unknown. However what the Japanese have is a passion, and yes passion is the correct word, for product quality that far surpasses anything encountered in America or Europe. Some examples:

  • entry to a tablet packaging area in a Japanese company typicall involves stripping off all street clothes down to underwear, donning freshly laundered plant uniform, and then having that uniform gone over with an adhesive roller to collect any non-viable particles that might be adhering to the outside of the uniform;
  • The typical Japanese defect rate for cracked film coated tablets is 1 tablet in a million – no Western company that I have audited in 30 years comes anywhere close to such a rigorous quality level demand;
  • The Japanese veneration and dedicated reverence to quality is illustrated in how Japanese companies react to a product complaints, where invariably the results of the compliant investigation are communicated to the person making the complaint by a personal visit to the complainant from the company’s Vice President of Quality, a recitation of the deficiencies found, and an explanation of what measures the company is implementing to prevent the occurrence happening again – a series of events that are common in Japanese culture, but to which no Western company would even dream of doing.

Most countries revise and update their GMPs about every five years to keep up with changes in the industry and changes to manufacturing and testing technology. The great exception to this is the United States FDA, which has not substantially changed its GMP regulations since issuing them in 1976. FDA’s response to this criticism is that such updating and changes are unnecessary as the first paragraph of the regulations under ‘Scope’ (section 21CFR210.1 (a)) states that “The regulations set forth in this part and in parts 211 through 226 of this chapter contain the minimum current good manufacturing practices for methods to be used in …..the manufacture, processing, packing, or holding of a drug”. So when the US GMPs are criticized for not referring to the function of “quality assurance’, or not requiring the company to perform “self-inspection”, or for not defining the term “validation”, FDA’s response is that the regulations oblige the manufacturer to keep ‘current’, and that anyway the regulations promulgated are the ‘minimum’.  [Michael: Aren’t the recently issued (draft) Aseptic Processing guidance and Part 11 requirements examples of major changes in FDA GMPs? – No they are not – but good point, keep reading]

This requirement for US manufacturers and those world-wide exporting to the United States, to keep current, gives rise to the uniform reference to the US GMP as being the “current good manufacturing practice” regulations, or cGMPs. The statement that the regulations are a ‘minimum’ means effectively that just because the authorities have not recently added something (i.e., a given requirement) into the regulations, does not necessarily mean a firm is absolved from being responsible for any unwritten” regulatory requirement. It is wise to remember this. 

Although FDA is always talking at industry conferences about new revisions to the cGMPs being under consideration, these revisions never seem to come to fruition. FDA has however been very active in publishing guidelines for its own inspectors on how to interpret GMPs, and guidance documents for industry on how they should interpret the GMPs (for example the issuance in 2003 of guidances on Aseptic Processing Electronic Record (Part 11)  requirements. Additionally FDA maintains an extensive internet presence and its website is a mine of useful information on many aspects of GMP compliance – so much so that FDA has developed a portal to its web pages designed specifically for the use of the pharmaceutical industry, making it easier for the pharmaceutical industry to find information relating to FDA and GMPs. (see –  http://www.fda.gov/oc/industry/default.htm). 

Additionally under the provisions of the US Freedom of Information (FOI) Act the findings of all FDA GMP inspections are available for public access, and a significant industry has grown up in Washington in providing FDA inspection reports and other FDA documents to the pharmaceutical industry. This is in marked contrast to the rest of the world, where the findings of GMP inspections are never routinely revealed. In comparison in the United Kingdom for a British inspector to reveal, or leak any findings during a pharmaceutical facilities inspection is a breach of the “Official Secrets Act” (the same act that makes it against the law to reveal what Her Majesty the Queen had for breakfast this morning) and can result in the inspector spending 10 years in prison and facing a heavy fine.   As such, the US pharmaceutical industry has little excuse for not being able to keep up with FDA’s latest thinking. In fact GMP compliance in the USA is often thought of as playing a game where the goal posts keep moving, and as such close monitoring of FDA through its website, through FOI, through GMP consultants, through attendance at industry-FDA conferences, and through the trade press is compulsory for any company wanting to ensure that it stays in compliance with the cGMPs.

The World Health Organization (WHO) also deemed it useful to issue its own set of GMPs as part of a scheme for “Certification Of The Movement Of Pharmaceutical Products In International Commerce”. When first issued in 1967 the WHO GMPs were not very demanding, much like the 1963 first version of the US GMPs, and could have been met with relative ease by most developing world manufacturers. They were however one of the first attempts to provide a basic outline of the minimum steps required in establishing a pharmaceutical manufacturing facility meeting acceptable standards. In 1988 the British Commonwealth Pharmaceutical Association attempted to issue a GMP code applicable to developing nations in the Commonwealth, but this attempt floundered on the issue of whether the lesser developed nations should be required to meet the standards of the more developed nations, a constant problem when attempting to formulate international GMP codes.  In fact, there is a global disequilibrium of quality, and the relative development of a nation will dictate what level of quality (e.g., GMPs) it can afford, or sees as being relevant to its situation.

Interestingly it was the northern European nations that gave the greatest impetus to implementation of the GMPs, and to elaboration and expansion of the concepts involved with GMPs. In the late 1980s they realized that having the written document (the GMP code) was insufficient in itself; implementation of the GMPs required both the written document, and a sound policy of enforcement. If countries were to save time and effort and not need to always inspect manufacturers in other countries, then they reasoned it would be useful if one country could have faith that the national inspectorate of the other country inspected in much the same way that they did, with the same philosophy and intensity of inspection. If this could be assured, then duplicative and costly re-inspections could be eliminated.

So was born the Pharmaceutical Inspection Convention (PIC) – or more properly called “The Convention for the Mutual Recognition of Inspections in Respect of the Manufacture of Pharmaceutical Products” This country grouping was originally composed of the countries of the European Free Trade Association (EFTA). EFTA was the Western European countries that were not a part of the European Economic Community (EEC), which later evolved into the European Union. The initial members of PIC were the EFTA nations at that time: Austria, Denmark, Finland, Iceland, Liechtenstein, Norway, Portugal, Sweden, Switzerland and United Kingdom.

The original goals of PIC were:

  • Mutual Recognition Of Inspections;
  • Harmonization Of GMP Requirements;
  • Uniform Inspection Systems;
  • Training Of Inspectors;
  • Exchange Of Information; and
  • Mutual Confidence

And in achieving these goals they were extremely successful.

The great strength of the PIC isthat twice a year joint discussions are held between GMP inspectors from all the PIC member states to discuss and elaborate on specific topics within the GMPs and to derive a harmonized approach and understanding as to how the PIC inspectorates understand the technology and want to have the PIC GMPs implemented (which had been published when PIC was founded). These discussions often resulted in supplemental guidelines which proved useful to the inspectors, but also gave industry a good grounding in new science and technology, as well as insight into the inspector’s ways of thinking.

 

Additionally the PIC/S has published highly informative guides on various aspects of GMP implementation, among which are:

  • Recommendation on Quality System Requirements for Pharmaceutical Inspectorates (PI 002-1)
  • Recommendation - Guidance on Parametric Release (PI 005-1)
  • Recommendation on Validation Master Plan, IQ, OQ, PQ, Cleaning (PI 006-1)
  • Recommendation on the Validation of Aseptic Processing (PI 007-1)
  • PIC/S Guide to Inspections of Source Plasma Establishment and Plasma Warehouses (PI 008-1)

These documents, and an extensive library of other publications reflecting the presentations given, and discussions held, at the bi-annual PIC/S deliberations, are available on the PIC/S website at http://www.picscheme.org/pubs/pubs.htm.

So successful was the PIC scheme that the European Economic Community (EEC) later to become the European Union realized fairly early after its first expansion in 1973 from its original 6 member states (Belgium, Germany, France, Italy, Luxembourg, Netherlands) to 9 member states when the PIC countries of Denmark, Ireland and the United Kingdom joined the EEC, that it would be useful for those EEC members who were not PIC members (often referred to as the “original European club”) to join the PIC, and to adopt the PIC GMP Guideline as the official EU GMP guideline.

Due to legal technicalities, in order for these “original European club” countries to join the PIC, the PIC was forced to change its format from being a formal inter-governmental convention between member countries into an association of member national health authorities changing the PIC into the Pharmaceutical Inspection Cooperation Scheme (PIC/S) – but this was a legal technicality and it did not slow down the PIC in the scope of the work it was coordinating. The EU is now about to become a grouping of 25 countries, covering a population of approximately 450 million people, with the stated goal of achieving the free movement of trade, including pharmaceuticals, between them. As such, a PIC format of all national inspectors performing their inspectors to a single recognized and harmonized standard makes eminent sense from the perspective of eliminating bureaucratic waste.

Recognizing these obvious advantages in inspection efficiency Canada and the United States have both begun discussions with the European Union on enacting a scheme termed the “Mutual Recognition Agreement (MRA)” that would allow the inspections by one country to be acceptable in the other. Thus FDA inspectors would no longer need to travel to inspect in Finland, but could rely on the inspection report of a Finnish GMP inspector. In a study to determine the standards of GMP inspections throughout Europe, FDA determined that most countries had acceptable GMP inspection systems, but that those of Southern Europe (historically parts of the Holy Roman Empire – previously discussed) were below standard and would not be acceptable to FDA under an MRA. The EU responded that the EU was one trading block, and that FDA either accepted everyone (inspection reports from all 15 member states), or accepted nothing. The FDA chose the latter and despite much effort between FDA and the EMEA (the European Medicines Evaluation Agency) the Mutual Recognition of GMP Inspections discussions floundered. Interestingly the Canadian Health Product and Food Inspection Branch (HPFBI) had no such qualms and an MRA is in place since February 2003 between the Canadian and European Union.

Despite the US FDA publicly stating that they are the “gold standard in GMP development and enforcement” (as stated by Ms. Stephanie Grey, then head of FDA’s Office of Compliance,  at a national PDA conference in 1998, and by other senior FDA staffers at other industry meetings in the USA and internationally), in fact it is the PIC that has expanded the scope and concepts of GMP the most world-wide. 

The PIC has now significantly expanded beyond being a club of Western European nations, with several Eastern European nations having joined (Czech Republic, Hungary, Latvia, Romania, Slovak Republic), along with  Australia, Canada, Malaysia, and Singapore, thus making PIC/S a truly international grouping of nations. Additionally the US FDA and WHO maintain observer status within PIC.

The regionalization of GMPs has had such obvious advantages that other regional groupings have tried to emulate it, but with only marginal degrees of success. Written GMP guides exist but coordination of inspections to a uniform standard are fairly haphazard. Regional groupings with GMP codes are ASEAN (Association of South East Asian Nations), a grouping now consisting of Brunei Darussalam, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, and Vietnam; and Mercosur, a South American grouping of Argentina, Brazil, Paraguay and Uruguay. It is anticipated that the much hoped for Free Trade Area of the Americas (FTAA) between the North American Free Trade Area (NAFTA), Central and South America might give impetus to a harmonization of GMPs within the Americas, probably dominated by the Canadian and United States philosophy of GMP.

 
   
   

 

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