In the GMP News from 21 February 2007, we had pointed out that EMEA intended among others to make changes to Annex 3 regarding the manufacture of radiopharmaceuticals. This has now been done, the new annex will come into force on 1 March 2009. The changes include adaptations to Part II of the EC GMP Guide (GMP for active pharmaceutical ingredients) and updates to the state of the art.
Compared to the original two-page annex, the revised version comprises eight pages including the cover sheet. The "Principle" alone with its 5 points is clearly more comprehensive than that of the older version. One of the points now states that radiopharmaceuticals used in clinical trials explicitly come under the provisions of Annex 3. In addition, the text includes the clause also mentioned in the EC GMP Guide saying that exceptions can be made from the rule if one can prove (through validation) that the result will at least be equally good. The structure of the further 10 sections follows mainly the structure of the EC GMP Guide. Chapters on reference and retention sample, on distribution and a glossary complement the other 6 chapters. One could almost call this a "brief EC GMP Guide on radiopharmaceuticals".
The introduction outlines the scope of Annex 3. Apart from radiopharmaceuticals, Positron Emetting (PET) radiopharmaceuticals are mentioned among other things. Furthermore, the document includes a GMP matrix, which gives an overview of GMP and non-GMP aspects in dependence on the production method.
Much attention is paid to the topic of quality assurance. One focus is on the GMP aspects, another one on personnel protection aspects. Both are meant to be bundled under the roof of an effective quality assurance system. The text deals explicitly with the issue of qualification and validation - and, of course, the corresponding risk analysis as a basis for it.
For the personnel, the usual training - naturally orientated specifically towards radiopharmaceuticals - is required. This requirement is also directed at personnel in research institutes. For a co-operation with research institutions, Annex 3 also requires the QA of the customer to review and approve the research activities.
Regarding the premises and the equipment, the new Annex 3 calls for a risk assessment of the environmental cleanliness levels. This chapter also refers several times to the risk of cross-contamination. Much emphasis is placed on programmes for qualification, calibration and maintenance. Monitoring is to be performed according to the respective Performance Qualification (PQ) results. Apart from that, the specific requirements on rooms and equipment regarding radioactivity are described (e. g. no absorptive surfaces; if necessary reduced pressure in the production areas). For sterile production, the text firmly requires a risk assessment with regard to pressure differences, air flow direction and air quality. For certain activities, controlled environments (grades C and A) are required.
The documentation chapter partly repeats the requirements of the same chapter in the EC GMP Guide. Interestingly, the record retention period is set at 3 years - depending on deviating national regulations.
The chapter titled production once more draws attention to the problem of cross-contamination and also to mix-ups. Special emphasis is put on the issue of validation taking account of the critical parameters and the working area. What is also mentioned is the validation of computerised systems in compliance with Annex 11. Furthermore, specific aspects of labelling in connection with radioactivity and membrane filtration are regulated.
The chapter Quality Control deals above all with those aspects of the release of radiopharmaceuticals that cannot be fully tested before their use. A separate point is dedicated to the handling of out-of-specification results. Moreover, high value is placed on a system for confirming the quality of starting materials and on the purchase of certain goods (e. g. packaging materials) from approved suppliers.
With regard to reference and retention sample, too, peculiarities of radiopharmaceuticals are addressed. The required storage period of at least 6 months can e. g. be changed on the basis of risk management. The retention of starting materials can also be shorter than the usual 2 years after release depending on their stability.
The section distribution also whitens the peculiarities of radiopharmaceuticals regarding marketing without prior testing of all aspects.
A glossary for the terms "preparation", "manufacturing", "hot-cells" and "Qualified Person" rounds off the document.
Conclusion: The new Annex 3 is much more comprehensive than the old document. It adapts the manufacture, testing and distribution of radiopharmaceuticals to the state of the art. Apart from the specific aspects resulting from radioactivity, e. g. regarding cross-contamination, the issue of risk management runs like a golden thread through the entire document. The document also places great emphasis on aspects of qualification and validation.
The revised document can be found here.
On behalf of the European Compliance Academy (ECA)