CONFERENCE REPORT: TECHNICAL AND REGULATORY DEVELOPMENTS IN THE PHARMACEUTICAL INDUSTRY

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Sterile dosage forms and their GMP-compliant manufacture were once more key topic at the 19th Pharma Congress which took place in Düsseldorf/ Neuss at the end of March. In the light of the revision of Annex 1 EU Guidelines to Good Manufacturing Practice whose first draft is still expected, the contributions dealt with the current regulatory developments and with their possible consequences for the pharmaceutical production.

Jörg Zimmermann, Vetter Pharma-Fertigung, addressed the current trends concerning sterile dosage forms already in his keynote lecture. Ultimately, the global demographic developments, the increasing individualization of treatments as well as changes (cutbacks) in the national health systems have a significant impact on the treatment of patients with medicinal products. Jörg Zimmermann pointed out the resulting requirements for parenteral medicinal products. He supported keywords such as a more precise dosage patient safety or patient compliance with current technological developments concerning application systems.

True to the motto "Users report for Users" the current trends were again conveyed through a lot of case studies - among others by Ferring, GSK Vaccines, MSD, Octapharma, Vetter Pharma-Fertigung, Pfizer, Roche and Janssen.

State of the Revision of Annex 1

Again the main focus of the conference "Regulatory Trends - Revision of EU GMP Annex 1" was on the actual state of the development of Annex 1 of the EU Guidelines to Good Manufacturing Practice. Authority representatives put up fi rst information on the imminent changes for discussion. The representatives of industry, in contrast, articulated their expectations, also against the background of the deficiencies of the current EU GMP Annex 1.

The Pharmaceutical and Healthcare Sciences Society (PHSS) primarily wants to take into consideration new technologies and remove ambiguities and uncertainties. PHSS-Chairman James Drinkwater reminded the audience that there had been several small revisions of the document since its first publication in 1972, but never a comprehensive new wording. His comparison of the current EU GMP Annex 1 with WHO Annex 6 (GMP for sterile pharmaceutical products) highlighted that the much more recently published WHO document addresses a variety of issues that are missing in Annex 1 GMP Guidelines. By means of two case studies he explained PHSSs expectations especially with regard to environmental monitoring.

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Dr. Friedrich Haefele, Boehringer Ingelheim in Biberach, talked about current and future requirements concerning clean rooms and barrier systems. In his opinion essentially the following five requirements should be adopted in the revision of Annex 1:

  • Maintain ISO 14644 as the basis for the international alignment of clean room qualification;
  • Deletion of the 5?m particles criterion for the clean room classification;
  • Encourage isolator technology for aseptic processing and in general foster continuous improvement of facilities and processes;
  • Strive for global harmonisation and related with this the need for revision of other major guidelines;
  • Pave the road for Mutual Recognition Agreements (MRAs).

Arjan Langen, MSD, formulated current deficiencies and in relation with these deficiencies his expectations on the imminent revision as regards media fills:

  • "The process simulation should simulate the routine aseptical manufacturing process as comprehensively as possible and contain all critical consecutive stages of manufacture. It should also take into consideration all interventions known to take place during normal production as well as worst case situations." Concerning this detailed information on the worst case situations should be given in relation to process, personnel, interventions, hold times and process simulations lasting several days.
  • So far the requirements put the focus especially on the aseptic filling process, but references to process simulations in earlier process steps are missing.
  • Requirements concerning the 4-eyes-principle, video recordings and aspects of QA oversight should be included.
  • Rules should be indicated when a process simulation can be aborted and
  • Indications on the process simulation in closed systems should be included.

Continuous Manufacturing

Wendy Zwolenski Lambert from Novartis, representing the efpia at the conference "Continuous Manufacturing", explained her view on the future of "continuous manufacturing". The efpia, which is the European federation of national associations of researching pharmaceutical companies and brings together industry and authorities, has formed an expert group in order to prepare an ICH document. In their opinion the topic is not addressed sufficiently in the current guidelines. They say that continuous manufacturing is pushed forward by the FDA and that there are also positive signals coming from EU countries. But the industry fears that there will be other countries which will not support this development. A result of this could be that two marketing authorisations would be required (continuous and batchwise) which would be extremely impracticable and very expensive. It would also make necessary two product developments, two different equipment parks and two different product life cycles. As a first step efpia has questioned 26 of its member companies to be able to define the most important topics as concerns continuous manufacture. The result showed that the following topics are the most important: General definitions, batch definition, process validation and the content of the marketing authorisations (CTD). But data management also made it onto the list because continuous processes which usually are continually monitored by means of PAT systems create huge amounts of data. This is easily understandable, especially in times in which the topic data integrity is at the focus of the authorities and industry.

Especially in the initial phase when experiences still are made and the technologies are changing rapidly the organisation wants to react flexibly or to extend the document more easily and has therefore created a questions and answers document. It will possibly be transferred into a guidance in a later step. The paper is supposed to address continuous processes in the manufacture of active pharmaceutical ingredients and finished medicinal products as well as marketing authorisation and GMP aspects. This development shows clearly that the topic continuous manufacturing has reached the (European) pharmaceutical industry and that the interest is increasing steadily.

As Daniel O. Blackwood, Leader of Pfizer's PCM&M Programm in the USA, reported in his lecture, Pfizer also has gained some experience in the area of continuous manufacturing. He showed what a risk-based approach might look like and illustrated by means of concrete numerical examples how Pfizer has carried out such analyses. This included the results from 19 runs under different process conditions which had been defined in a DoE. Particularly impressive was the fact that all these experiments could be carried out in only two days thanks to the continuous operation. Daniel Blackwood stated "the bottleneck now is analytics" - a statement which was confirmed by other speakers.

Global Player Janssen Pharmaceutica has three platforms for continuous manufacturing at sites in Puerto Rico, Italy and Belgium. Lawrence de Belder, Senior Principal Engineer Continuous Manufacturing, explained in his case study that a HIV medicinal product is already manufactured at the facility in Puerto Rico. So far, this medicinal product had been manufactured batchwise and had been approved for this kind of production. Upon request he explained that no bioequivalence studies had to be carried out for this change in registration. He also pointed out that this will surely not be transferable to other medicinal products but that each case would have to be considered separately. According to his opinion the marketing authorisation for a product manufactured continuously might even be carried out faster than for the conventional batch production.

Whereas Pfizer wants a global standardization of the facilities as concerns development and manufacture Janssen takes a different path and tries each time to develop the ideal configuration for the different applications. Janssen has decided at the hightest level that new OSD products will only be developed in the continuous production method, says de Belder. This statement first had to be digested by the audience.

New Technologies and Trends

At the second conference day the case studies on continuous manufacturing were followed by further technological innovations and trends with respect to medicinal products. Apart from the 3D printing of medicinal products presented by Prof. Stephen Hilton of the University of London, Dr Stefan Henke, Managing Director of Lohmann Innovative Injektionssysteme (IIS) talked in his lecture about two new approaches to transport medicinal products needlefree through the human skin into the body.

On the one hand these works are pushed by the fact that only 30 out of the ca. 7.000 known drug substances can be transported passively through the skin (as used in transdermal systems). On the other hand a significant part of people is afraid of injection needles. About 50% of all children is afraid of needles. Another disadvantage of injection needles is the danger of needle-prick injuries, especially as concerns medical staff.

The first system presented is a syringe injecting a liquid jet with high pressure through the skin. Here, a reduced perception of pain can be observed because the amount of liquid can be reduced considerably as compared to conventional syringes. Currently, there are systems for 100 and 500 μl. By adapting the system it is possible to choose beforehand for each medicinal product how deep it will be injected into the skin. This can easily be simulated by means of a simulator with a skin model. In the meantime there are practical results from animal testings as well as first results from human trials with a monoclonal antibody.

The second system he presented uses micro-needles which dissolve completely in less than 10 minutes in the skin. These needles are each 600 ?m long and are applied on flexible carriers to form areas of 600 per cm². The application is completely free of pain. This system seems to be ideal for the application of vaccines. Firstly, only small amounts of active ingredients are required (this constitutes a limitation of the system) and secondly, the vaccine is only injected in the outermost skin layers where the highest density of immune cells can be found.

New construction or conversion projects

Topics at the 19th Pharma Congress were also current construction, conversion and technology projects. Dr Alexander Herrmann (Director USP Clinical Supply Center at Roche Diagnostics in Penzberg) explained the successful conversion of the Clinical Supply Center where biopharmaceutical active ingredients are manufactured, harvested and purified for clinical studies using fermenters with the sizes 1000l and 250l. In order to comply with the current state-of-the-art the USP and DSP areas (upstream and downstream) were separated. Furthermore, the capacity of fermentation was increased from 1000 l to 2000 l. This classical reconstruction project of an existing building dating back to 1986 with four floors plus basement was complicated by the fact that it was a multipurpose plant in which eucaryotic cells as well as bacteria in fermentation have to be handled. And naturally, the facility plans were not up to date, says Dr Herrmann. He explained the project phases of the extension: in order to be able to house the new USP equipment the fronts had to be opened. The nasty surprise when carrying out the FAT of the vessel was unexpected - the outer double casing did not comply with the specification. With regard to the static they also had expected something different. In the basement pillars were needed for support. But the enclosure of the high purity media worked well. It was carried out during the two shutdowns for maintenance. Important point: new loops in the distribution system were connected only after the successful qualification, prior to that the material had been rejected. The costs were slightly lower than the budget of 19,4 million. In total 38.000 working hours were registered for the project, half of them for intern work and the other half for extern work. The planning company W&M supported the works. As conclusion of his lecture Dr Hermann recommended never to take over a project too early, even if the project management says it is "almost completed". There were several changes in the management of the project which weren't very helpful should always be avoided.

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Manufacture of WFI

Concerning pharmaceutical water Klaus Feuerhelm, GMP inspector from the Leitstelle Arzneimittelüberwachung (control centre of surveillance of medicinal products) in Baden- Wuerttemberg, presented the new possibilities to produce WFI with other procedures than distillation. Main parts of his lecture were references and information in the European Pharmacopeia (Ph. Eur.) and in EMA's questions and answers document (draft version).

The new monograph of the European Pharmacopeia doesn't contain concrete specifications as concerns the facility design. GMP aspects are not addressed. For this reason he takes the view that they should be regulated in other documents. Reference is made repeatedly to the revision of Annex 1 of the EU GMP Guidelines in this regard. But the draft of the new Annex 1 which is not official yet gives only little hope.

The first important information referred to the change carried out in the monograph as compared to the draft version. The monograph states in respect to the method of manufacture: "by a purification process that is equivalent to destillation." This means that the method of manufacture is no longer focused on reverse osmosis. Reverse osmosis is described as possible alternative. But finally it remains the decision of the operator to introduce also other methods. This does not hinder the state of the art in science and technology. But the GMP inspector also stated that this more liberal phrasing also entails some risks. He then discussed EMA's questions and answers document for which the deadline for comments expired in November 2016 and which has now been published in its final version. It is structured into two parts:

  • Part I Production of WFI by non-distillation methods - reverse osmosis
  • Part II Biofilms and control strategies

Klaus Feuerhelm stated in his presentation of some questions and their comments that the document tries to explain GMP aspects. According to him there are some statements which aren't easily comprehensible such as: "Systems should be in place to test membranes routinely for any potential integrity breaches that could lead to a significant contamination event."

Integrity testing for RO membranes is not possible yet. In this respect the requirement doesn't make sense. Mr Feuerhelm emphasized again and again that the main content of the document is about the formation and removal of biofilms. The reference to biofilms is a central topic in the complete EMA document. Sanitization of the systems will play a central role during inspections in addition to the monitoring. The questions and answers paper also contains several references and requirements concerning sanitization. If the sanitization concept is insufficient this will have consequences for the operation of the system. The following reference in the Q&A document was highlighted: "The distribution and storage systems should be designed as to permit routine steam sanitisation along with routine chemical sanitization and in accordance with other good design practice to minimize areas of reduced flow."

Accordingly, the material of the distribution and storage systems should allow for a steam sanitization as well as for a chemical sanitization. This means that a steam sanitization will usually be expected for distribution and storage systems. But elsewhere reference is made to ozone. Apparently ozone is to be used also in routine operation. This can only mean that the storage tank is continuously treated with ozone. In several parts of the document rapid microbiological testing is mentioned as control strategy in respect to the formation of biofilms. But the document does not explain in detail which rapid tests are meant and at which position they should be carried out using which frequencies. There remain a lot of unanswered or insufficiently answered questions for the GMP inspector. They include the following ones:

  • How are AP and HPW systems handled which will be used for the manufacture on WFI in future?
  • How many TOC measuring points and measuring points for the conductivity are required?
  • Clear and detailed requirements for the routine monitoring are missing.
  • Can we count on a uniform way of working of the GMP inspections within Germany or in the EU?

In the last part of his lecture Mr Feuerhelm addressed the main points with regard to inspections during the period 2016/2017. These included especially sanitization concepts, the prevention of biofilms, calibration and the handling of data and data integrity.

Especially the topic data integrity will play an important role in future GMP inspections concerning water systems. Mr. Feuerhelm mentioned the following examples:

  • Which data or raw data with GMP relevance will be generated?
  • How is data documented?
  • Has it been defined which reports must be documented?
  • Can the acknowledgement of a report be assigned unambiguously to persons or groups of users?
  • Is the history of reports stored?
  • Which data is stored or archived for how long?

 

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.

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