GMP TRENDS: ANNEX 1, CONTINUOUS PRODUCTION AND CONTROL OF PARENTERALS
The year 2015 has been characterised by the revision of Annex 1 of the EU Guidelines to Good Manufacturing Practice on the manufacture of sterile medicinal products. This annex has been effective since 1992 and was revised and amended in the years 1996, 2003 and 2008. Because of its relevance to the current situation the review of Annex 1 was one of the main topics of the Pharma Congress 2015. Consequently, Jean-Denis Mallet, former Head of GMP Inspection at the French Afssaps addressed this current development in his keynote in detail.
Here, especially the following three developments are the key drivers: the implementation of the ICH principles, especially ICH Q 9 and Q 10 (Quality Risk Management and Pharmaceutical Quality System), the introduction and application of new technologies together with their specific requirements and the clarification of so far ambiguously worded requirements in connection with the harmonisation with US requirements.
With the joint announcement of EMA (European Medicines Agency) and PIC/S (Pharmaceutical Inspection Cooperation Scheme) in the beginning of February 2015 the schedule for further activities was presented. The pharmaceutical industry had the opportunity to formulate its ideas concerning the revised version of Annex 1 only for a short time until the end of March 2015. Key features of the new schedule include the planned publication of a first version by EMA this October. After the relevant deadline for comments for industry and the implementation of comments in the draft document the final version of Annex 1 of the EU Guidelines to Good Manufacturing Practice can be expected by the end of 2016.
Jean-Denis Mallet addressed the different developmental stages of the currently valid Annex 1 in his lecture and referred to deficiencies and uncertainties in the current document. He mentioned the focus of the current Annex 1 on small injectabilia as well as the fact that no current technologies (simulations, restricted access barrier system - RABS) are addressed concerning premises and equipment. On the basis of the current Annex 1 structure the following topics - among others - should urgently be included in the revised version of Annex 1 in his view:
Recommendation
Berlin, Germany5-8 November 2024
Contamination Control Strategies & Workshop Risk Assessment in Contamination Control
- Inclusion of eye drops and large volume parenterals
- Identification and monitoring of risks
- Goggles and requirements concerning the training of personnel
- Gaseous disinfection procedures and monitoring of premises
- Single use disposables
In his subsequent reflection on the currently published concept paper Jean-Denis Mallet specifically concentrated on the parts "Discussion" and "Recommendation". The chapter "Discussion" contains the arguments for a revision of Annex 1 such as
- further development of the ICH conceptual approach in sterile operations
- inclusion of the technological advancements
- removal of ambiguity and inaccuracies
- implementation of future Pharmacopoeial developments such as the production of water for injection (WFI) with other methods than distillation
- checking the coherence of Annex 1 with other EUPIC/ S documents and
- aligning the annex with (other) international requirements.
According to Jean-Denis Mallet no new dedicated technologies should be mentioned. But generally useful would be an expansion of the on-line 100% check instead of a final testing. He also believes that new microbiological methods and especially real-time techniques and real-time measurements are also needed.
In the chapter "Recommendations" the GMP/GDP Inspectors Working Group and the PIC/S Committee describe the reasons for and the objective of the upcoming new version. The essential points mentioned are the increasingly growing gaps between the current guidance and the regulatory and technological environment. According to this chapter the principles from ICH Q 9 and ICH Q 10 (such as risk management and CAPA) will be contained in the new version. It is also mentioned that changes in part I of the EU GMP Guidelines and revisions in other Annexes should be taken into account. Jean-Denis Mallet asked to bear in mind that not all chapters of part 1 of the EU GMP Guideline should impact the revision at the same level. Instead, priority should be given to suppliers of sterile components and to outsourced sterilization. Further, the CAPA concept should be described in the environmental monitoring strategy of cleanrooms.
In a second lecture, Roland Guinet, who also is a former inspector of the French Afssaps, addressed some special points that so far have not or at least not sufficiently been addressed by Annex 1. A working group of the French A3P prepared a corresponding statement in the last two years. Roland Guinet's lecture put the focus on the topics barrier systems and process simulation / media fill. He showed the existing shortcomings and provided proposals for the upcoming revision.
So far, the topic barrier systems has been addressed in Annex 1 only as concerns the requirements with regard to isolators. According to Roland Guinet it is important to include RABS (Restricted Access Barrier Systems) and closed vial systems. Especially in the case of environmental monitoring this could lead to improvements, meaning a reduction of sampling as compared to classical clean rooms. Appropriate proposals were made in chapter 1116 of USP 36 and taken on by the working group.
Roland Guinet put a second priority on process simulations / media fills. Here, most requirements were already harmonized with the requirements of the US FDA in the course of the last revision of Annex 1. But nevertheless there are some points that have to be formulated in a new way or more exactly. Roland Guinet demanded, for example, that the validation of aseptic processes does not only refer to the final filling. Specific reference should also be made to the phases of the intermediate, the bulk and the final bulk products. A more precise wording is also required for the design of the media fill. The wording used so far - "various interventions" - offers too much room for interpretation. All interventions during routine production should be registered and should be included in the same frequency in the media fill. Furthermore, corrective interventions as well as worst-case situations should also be included as concerns duration, number of personnel and complexity of the activities.
In the last point Roland Guinet addressed the handling of contaminated units. Normally, a zero contamination is expected. Depending on the amount of media fills which are divided in groups up to 5000 units, between 5000 and 10000 units and more than 10000 units the measures to be taken are indicated in the case of one or two contaminated units. But the statements themselves are relatively imprecise. For the group up to 5000 units no single contaminated unit is permitted. If there is one, the media fill has failed. But what are the expectations in such a case? An investigation, a revalidation? Here, clear indications are missing as well as for the other two groups of media fills mentioned.
On the whole, this is an exciting development, that was further taken up in different lectures of the congress and that will be the cause for many discussions in the years to come.
In the second key note contribution Dr. Harald Stahl, Senior Pharmaceutical Technologist at GEA, addressed the global developments of the pharmaceutical production and especially the production of solid forms. His very interesting contribution first illuminated the sales figures of the top 20 pharmaceutical companies with prescription drugs and their estimates concerning the growth until 2020. Interestingly, the highest increases in sales are expected for companies with biotech products (large molecules). This is also true for vaccines. According to Dr. Stahl the times are over for small-molecule blockbusters. As concerns generic drug products there exists a massively increasing cost pressure in more and more countries. Health insurance funds conclude framework contracts with manufacturers while physicians are only allowed to prescribe the active pharmaceutical ingredient for a constantly increasing number of products.
In the OTC business where patients or customers can be addressed directly through advertisements of the pharmaceutical companies it is still possible to earn money. It is not without reason that Bayer has taken over the OTC business from Merck for $14.2 billion. With good commercials analgesics can be sold for a much higher price, for instance.
In the global distribution of the markets the USA is still on place one followed by Japan. This might change soon. It is expected that China will pass Japan by 2017 and will be on place two of the list behind the USA. Hence, it does not come as a surprise that equipment suppliers as well as pharmaceutical companies have an increasing interest in the Chinese market and build up dependencies there. But countries such as Brazil, Russia and India also show a significant growth.
But notwithstanding increasing sales the pharmaceutical industry still puts too much focus on obsolete production technology. Concerning this, Dr. Stahl cited Dr. Janet Woodcock, Director of CDER, FDA. According to her the production technology is outdated, and this will not change only by means of a refinement of procedures or documents. She prefers a rethinking from a batch to a continuous production, the sooner the better. Her interest naturally is a better product quality because of a better product knowledge. According to Dr. Stahl it is vital especially for the price-driven manufacture of solid dosage forms to convert to continuous production. This conversion process has already started - as demonstrated by case studies of the companies GSK, Astra Zeneca, Roche, Janssen Phama, Vertex and Pfizer. According to GSK it is expected that production costs can be reduced by 50%. But the scale-up from development to production will also be faster and hence cheaper. Time is the only scale-up parameter in the complete continuous production.
The company Vertex received its authorisation by the FDA for a product manufactured on a continuous system in March. The company Pfizer goes even further. Apart form the continuous procedure the production is supposed to become mobile, too. With the help of a joint-venture specifically set up for this purpose the production equipment for the continuous production will be assembled and qualified at site A to be transported to site B where it will be reassembled ready for production.
Control of Parenterals
The ECA conference "Control of Parenterals" concentrated on the visual control of sterile pharmaceutical dosage forms as well as on methods of leak testing (container-/ closure-integrity testing).
Recommendation
Berlin, Germany5-7 November 2024
Contamination Control Strategies
In the part on leak testing Dr. Martin Becker, Head of Technical Operations at hameln pharmaceuticals, addressed specifically the testing of ampoules for which a 100 % leakage check is required in contrast to other primary containers such as ready-to-use syringes. A 100 % test can be carried out for ready-to-use syringes or vials but sampling testing is also accepted. But it has to be considered that according to an FDA statistic from the year 2014 22% of the recalls were caused by possible lacks of sterility. The main cause are leakages such as fissures in the primary packaging. Dr. Becker compared the different leak testing methods as concerns their suitability and their limits. He considers that the visual control clearly is a method to control the container integrity. Even if this method is not very sensible and only "holes" bigger than 25 μm can be seen he nevertheless considers it to be the single method to distinguish scratches from fissures. And with a visual control it is possible to detect leakages that have quasi been closed again by escaped and dried product. Furthermore, the visual control is a process that has to be carried out in any case for parenterals. The method of choice at hameln pharmaceuticals (and at many other fillers of ampoules) is the high-voltage-leak-detection. As Dr. Becker explained, the testing machines usually run at the same speed as the test machines for the visual inspection so that it is easy to adjust the speed of both systems. In order to be prepared for the problem of a possible decomposition of the product, stability should be tested as early as during development to prove that the high voltage treatment has no influence. But it should be known that the high voltage treatment causes the production of ozone - in the interior of the ampoule as well as at the exterior. Therefore, in the case of sensible products, the oxygen in the headspace should be replaced for example with nitrogen prior to closing the ampoules. According to Dr. Becker the falsereject rate is at 1-2 % during the corresponding operation. It is important that the operator carries gloves because otherwise the false-positive results will increase. Apart from the visual control the high-voltage-leak-detection is the only method that can detect leakages that have been closed again by dried product. The economic efficiency of the system was also addressed. According to Dr. Becker the costs increase with bigger ampoules and smaller batches. With big batches less time is lost for the set up and for cleaning.
Author:
Dr Robert Eicher & Dr Andreas Mangel
CONCEPT HEIDELBERG
