CONSEQUENCES OF ANNEX 1 REVISION FOR INDUSTRY
At this year's Pharma Congress special attention was given to the keynotes on a quality metrics case study by Aenova and on the revision of Annex 1 of the EU Guidelines to Good Manufacturing Practice (also see GMP News end of May/early June). Dr. Friedrich Haefele, Vice President Fill & Finish Biopharma, Boehringer Ingelheim, illuminated the consequences of this revision of Annex 1 for the pharmaceutical industry.
The first version dates already back to the year 1972. Dr. Haefele stated that there had already been five revisions since this time but no fundamental review. This means the time has come to revise this fundamental document on the regulation of sterile manufacture in Europe.
Dr. Haefele demonstrated the need for action on the one hand by a comparison with the FDA Aseptic Guide and on the other hand by means of his own commenting. Friedrich Haefele said that priority should be given to harmonisation. He basically believes that Annex 1 should remain limited to sterile parenteral products, and that other sterile products or active pharmaceutical ingredients should be regulated in other documents or in specific annexes. He also wants a separation between aseptically manufactured and terminally sterilised products in the new Annex 1.
He considers DIN ISO 14644-1 to be a central document that is used for the classification of clean rooms in the European Guideline but also in the US Guide. Dr. Haefele is not bothered by the fact that the limit for 5 μm particles has been deleted from the grade ISO 5 (ISO 4.8). According to him it should also be deleted from the European requirements. Deviations in the case of 0.5 and 5 μm particles are essentially the same so that it should be possible to renounce to the limit for 5 μm particles.
Dr. Haefele also proposed a simplification for the microbiological environmental monitoring. Settling plates as well as active air sampling are required in Europe at the moment. According to Dr. Haefele only the active air sampling should be compulsory whereas the use of settling plates should be optional or additional. The use of average values in the microbiological monitoring in the clean room should be forbidden. With the use of isolators with validated decontamination cycle the microbiological monitoring could be reduced to the essential pursuant to ICH Q9 Quality Risk Management.
In contrast to the FDA Aseptic Guide the European Annex 1 contains requirements concerning the crimping process as well as a differentiation between aseptic and clean processes. For the latter Dr. Haefele wants a clear definition of "Grade A Air Supply" that should be used for protection during the process according to Annex 1. Dr. Haefele stated that the industry has its opinion concerning this but that it should also be recorded in the relevant official document. By this he meant the use of air filtered according to the requirements of grade A without considering the microbiological requirements.
There are important differences between Annex 1 and the Aseptic Guide in the area of sterilisation. The US document contains no indications for a terminal product sterilisation. It is contained in the EU document. Dr. Haefele proposes to limit the requirement for a sterilisation with purest steam primarily to the terminal product sterilisation and to allow for a sterilisation with ethylene oxide or with other methods for so-called ready-to-use materials.
He sees further potential for improvement concerning the topic sterile filtration. He takes the view that the requirement for integrity testing after sterilisation immediately prior to filling can be deleted. This can be done since the data of filter validation and of the integrity testing after filling offer a sufficient level of security. To renounce to the obligatory integrity testing after sterilisation and before use reduces the complexity of the aseptic set-up and in facility construction.
A further difference concerns the quality oversight. In Europe there is no requirement that the quality assurance (physical) must take place onsite during aseptic processes. But the Aseptic Guide requires a QC oversight and here, especially the media fill is mentioned. Dr. Haefele invoked a harmonisation of the requirements, in order to strengthen the European philosophy, however. Quality assurance is a system and not an organisation. Mr. Haefele proposed a further change concerning the media fill in isolators. Here, interventions are carried out from the outside when carrying gloves. This means that they are "personneutral". The requirement that interventions during the media fill have to be carried out by the same personnel should therefore be deleted for media fills in isolators.
As concerns the topic disinfection Mr. Haefele would prefer the admission of hydrogene peroxide for the decontamination of surfaces in isolators and material airlocks and he wants to delete the mandatory rotation of disinfectants.
A further topic in Annex 1 is the monitoring of the integrity of containers containing sterile medicinal products. At the moment, Annex 1 requires a 100% integrity testing only for containers closed by fusion (glass ampoules and BFS containers). Dr. Haefele would prefer more openness and the requirement of appropriate controls for all packaging materials or pharmaceutical dosage forms.
Finally, he reaffirmed the use of modern barrier techniques for the aseptic manufacture as state-of-the-art and repeated his wish for a harmonisation of the requirements for sterile and aseptically produced medicinal products. MRA, mutual recognition agreements, could reduce the number of regulatory inspections at the companies.
The revision of Annex 1 from a regulatory point of view
The revision of Annex 1 from a regulatory point of view was presented by Dr. Arno Terhechte from the Bezirksregierung (district government) Münster and Dr. Beate Reutter, Landesamt für soziale Dienste (regional authority for social services) of the Land of Schleswig Holstein.
Originally, it was the German Expert Group 3 (Sterile and Aseptically Produced Medicinal Products) who initiated the revision of Annex 1 by issuing a concept statement to EMA's IWG (Inspectors Working Group) in 2012. In the process of recasting a request was made to PIC/S for support. A joint EMA-PIC/S working group presented a first draft for a concept paper in September 2014. This concept paper was published with a very short deadline for comments in February 2015. It is now apparent, however, that the original timetable for revising the document cannot be kept. Nevertheless, a proposal for a new structuring of the document was published in February 2016. As concerns the content many of the points of the current Annex 1 have been maintained but the document's structuring was replaced completely. Proposal for the new structure of Annex 1:
- 1. Scope
- 2. Principles
- 3. General
- 4. PQS (Pharmaceutical Quality System)
- 5. Personnel
- 6. Premises
- 7. Equipment
- 8. Utilities
- 9. Production and Specific Technologies
- 10. Non Viable and Viable Environmental Monitoring
- 11. Quality Control
- 12. Glossary
Essentially new are the chapters 1, 2, 4 and 8. As German member of the working group Dr. Reutter explained the main ideas of the new chapters and the objectives of the new wording.
Chapter 1 describes the applicability of Annex 1 to all sterile medicinal products. Additionally it is planned to include elements of risk management to a greater extent. Some of the Annex 1 guidance shall also apply to microbiological issues of non sterile medicinal products.
Chapter 2 highlight the greater adaptation of Annex 1 to the existing requirements of the EU Good Manufacturing Practice Guideline. This chapter contains a cross-reference to chapter 3 (Premises and Equipment) and to chapter 5 (Production) of the EU GMP Guideline Part I. It also points out that the manufacturing methods should regularly be reviewed in the light of scientific and technical progress.
Chapter 4 on the pharmaceutical quality system puts the focus once more on the reinforced use of risk management, root cause analysis and product impact assessments.
Chapter 8 "Utilities" shall describe media such as compressed air and steam and is supposed to comment on the topic WFI by reverse osmosis and on the topic biofilms. Alternatively, it is considered whether these topics should be moved to a separate section of the GMP Guidelines. The decision still has to be taken.
As German representative in the working group on the revision of Annex 1 Dr. Reutter is responsible for the topic barrier systems. She describes the changes to be expected in this context in a second lecture.
One of the main reasons for the revision is that until now the focus was put exclusively on isolator technology. In the meantime industry uses more and more RABS (Restricted Access Barrier Systems). The corresponding requirements on these systems shall be included in the revised version of Annex 1. The following topics will be addressed: definition of open and closed RABS, distinction between RABS and isolator, definition of adequate environmental conditions, dealing with glove ports, dealing with glove systems and transfer devices. Further points that now have to be addressed are the different isolator technologies - positive pressure and negative pressure - as well as the adequate background environment for isolators. Usually a Grade B background environment is expected for RABS while a risk based definition of the environment is expected for isolators. Depending on the design of the isolator - open or closed / positive pressure or negative pressure - as well as on the design of the process and of the decontamination an environment Grade B, C or D can be suitable.
Minimizing the contamination risk by significantly reducing the interventions into the Grade A environment will generally lead to the authorities expecting the use of barrier systems more and more and in the medium term requiring it. Here is the last statement of Dr. Reutter on this topic: "Inspectors prefer well designed aseptic processes with best protection against microbial or particulate contamination caused by interventions."
Authors:
Dr Robert Eicher
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy around pharma technology.
As Operations Director Dr Andreas Mangel organises and conducts courses and conferences for the ECA Academy in the areas sterile production and computer validation.
