Pharma Congress 2020: Exchanging ideas and experiences online

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The Pharma Congress, the largest event of its kind in the pharmaceutical industry, has a longstanding tradition: this year, it was to take place for the 22nd time - and with its parallel conference tracks, the social event and the PharmaTechnica with almost 90 exhibitors. A total of 850 participants logged on to the live online conferences and to visit the virtual exhibition PharmaTechnica from September 15-17. In the first online edition of the congress, the conferences once again focused on reports from operators who shared and discussed their experiences from current new construction and conversion projects and the use of new technologies.

Merck: New building for packaging

Mr. Oliver Kärst, Head of Pharma Engineering at Merck, reported on the new building of the Pharma Packaging Center for solid dosage forms in Darmstadt during the 22nd Pharma Technology Conference. The new packaging plant was necessary for various reasons. On the one hand, space requirements have increased enormously. At times, tablets produced in Darmstadt had to be sent to Mexico for packaging and then back to Germany. From a GMP viewpoint, the packaging plant was also no longer up to date. For example, the areas for primary and secondary packaging were not separated. A conversion of the existing building from 1930 would have been just as expensive as a new building. However, a new building also had the advantage of being able to build the packaging plant closer to the production area, eliminating internal transport routes.

Planning a new building is always a long-term matter, explains Mr. Kärst. A new building for packaging was already an issue in the 1990s. The project was finally approved in 2015 and construction was scheduled to start in 2016.

By assuming responsibility for the project, Mr. Kärst initially tried to streamline the project team. But in fact, there was still a lack of department and thus project members, and the final team consisted of 58 members. Of course, not everyone always had to attend a project meeting, added Mr. Kärst, but it was not always easy to find meeting rooms with enough chairs.

One challenge in the project was the clearing of the building site. Whoever builds a new building in Darmstadt must first demolish three old buildings, Mr. Kärst quoted an old Darmstadt "rule". The preparation of the ground also took up more time than originally planned. The reason for this was Darmstadt's location in an earthquake zone and the associated construction measures such as the erection of CMC columns. A planning error in the media supply for a mezzanine floor also led to a delay. All in all, a high-bay warehouse is quickly set up, reported Oliver Kärst, but there is a lot to do inside of it. For example, a lot of time was spent on adjusting the pressure levels.

The first packaging lines were installed in mid-2018. Handover to production took place in March 2019. A total of eight blister lines are in operation, primary and secondary packaging are consistently separated, as are the areas for hormone and non-hormone areas. In the connected automated high-bay warehouse, 3600 pallet spaces are available. Future-oriented technologies have also been implemented, such as paperless production, the use of Augmented Reality (AR) in the execution of set-up procedures and error prevention by Robotic Process Automation (RPA) for batch release process steps.

Live Online Training: Efficient Batch Record Design and Review

Recommendation

23/24 September 2021

Live Online Training: Efficient Batch Record Design and Review

The project costs also totaled 63 million euros, Mr. Kärst concluded.

Technical view on Annex 1

In his presentation, Klaus Feuerhelm, GMP inspector at the Baden- Württemberg Pharmacovigilance Control Center, addressed changes in the EU GMP Annex 1 Draft from a technical perspective. In particular, he dealt with media (compressed air), leak testing and the visual inspection of parenteralia.

First he referred to essential guidelines in connection with compressed air and sterile filtration. In addition to the legal basis he mentioned the ISPE Good Practice Guide Process Gases, the ISPE Baseline Sterile Product Manufacturing Facilities, the ISO Standard 8573-1 Compressed Air as well as VDMA Document 15390-2 Compressed Air Purity - Part 2.

As another important document he mentioned chapter 6.19 in the EU-GMP Annex 1 Draft, where I find the following points among others:

Compressed gases used in aseptic processes should be filtered sterilely. The pore size of the sterile filter corresponds to the pharmacopoeia specification (0.22 μm). Sterile filtration should be performed at the point of use. A central note of great importance is the integrity check during batch release. Instructions for checking the filter integrity can also be found in other guidelines such as the ISPE Practice Guide Process Gases. Here the following points are mentioned: before use, after use, at a predetermined interval as well as after events that are exposing the filter to elevated stress levels (e.g. sterilization). Although an integrity check before each batch release cannot be directly recognized here, the note before and after use also indicates this.

In the Annex 1 Draft you will also find central information on leakage testing of containers. Mr. Feuerhelm explicitly pointed out that there are two ways to guarantee tightness: the 100% control for containers that have been closed by melting and for the other containers a sufficient CCI concept [Container-/Closure-Integrity]. The CCI concept always consists of several measures at GMP level, which ensure that the integrity of the packaging closure system is maintained.

Compared to the currently valid version of the EU-GMP Annex 1, the visual inspection requirements in the Annex 1 Draft have been changed. New in particular is the demand for the classification of defects and the evaluation of the risk of defects for humans. The evaluation of the patient risk is difficult. There are currently hardly any concrete scientific statements on patient risk, added Klaus Feuerhelm.

A collection of the defects arising in the process should be presented in a defect library. This defect library will then also be used for staff training. The staff performing the inspection should undergo a qualification for visual inspection at least once a year. The qualification of the employees is described. The qualification should be performed using appropriate samples from the manufacturer's defect library records and taking into account worst case scenarios (e.g., inspection time, line speed when the product is transferred to the operator by a conveyor system, container size or fatigue at the end of the shift) and should include visual inspection.

At the end of his presentation, Mr. Feuerhelm gave some more information about AQL in manual control. From a regulatory point of view, AQL testing is not yet mandatory in Europe, but is state of the art. Most companies that perform visual inspections are now practicing this in most cases. In the USP Informational Chapter <1790> you can find detailed information about the AQL. The number of critical defects should be zero in the AQL-test. This is also required in the USP <1790>. If an AQL limit value is exceeded, the entire batch should be 100% re-tested, explained Klaus Feuerhelm. For the release decision two criteria must be evaluated: the trend analysis of the 100% batch inspection and the result of the manual AQL inspection. 

WFI und WFI-Cold Production

In a second presentation Klaus Feuerhelm talked about current GMP requirements for pharmaceutical water including WFI and WFI cold production. In particular, he addressed changes due to the EU GMP Annex 1 Draft, filters in water systems and the WHO Guide on the production of WFI by non-distillative methods, which is also still in draft status.

Regarding the innovations in the Annex 1 Draft, Mr. Feuerhelm mentioned the references to dead legs and references to pipes with gradients. The formulation "Where filters are included in the system..." is unfortunate according to Mr. Feuerhelm. Here, one could assume that filters could also be installed in the warehouse and distribution system, which is unacceptable from a GMP point of view. Filters could only be installed in the processing area itself and, possibly, at the point of use. From his point of view, however, filters at the point of use are controversial and there should be sufficient justification if this is to be implemented.

Also included in the draft was the requirement for a turbulent flow. This requirement can be found in practically all current guidelines for pharmaceutical water, added Klaus Feuerhelm. Areas without turbulent flow are considered susceptible to biofim formation. Summing up, he pointed out that essential aspects for WFI systems such as dead legs, biofilm formation, importance of sanitization, filters in water systems or turbulent flow are finally addressed. But he also critically noted that certain points, such as rouging, are still being ignored. The newly published ISPE Baseline Water and Steam Systems devoted over 15 pages to the topic of rouging. In the opinion of Mr. Feuerhelm, the topic is still far from being sufficiently discussed.

In the second part of his lecture Mr. Feuerhelm discussed the meanwhile permitted cold production of WFI according to EU-GMP Annex 1 Draft. The method has not yet become established in Baden-Württemberg. Only one drug manufacturer is said to use it. Klaus Feuerhelm addressed the question of whether reverse osmosis is absolutely necessary and, if it is used, whether double reverse osmosis is appropriate.

At first glance, reverse osmosis does not appear to be absolutely necessary and a different system design would be conceivable. The pharmacopoeia monograph with the statement speaks for this in particular:
"produced by a purification process that is equivalent to distillation"

This sentence is not isolated in the pharmacopoeia, added Klaus Feuerhelm. Because in the following, further possibilities are enumerated and this allows the assumption that the reverse osmosis is also necessary. This is formulated even more clearly in Annex 1 Draft:

Where the WFI is produced by methods other than distillation, further techniques such as nanofiltration and ultra-filtration as well as electrodeionization (EDI) should be considered in conjunction with reverse osmosis (RO) membranes.

Live Online Training: Product Transfer - Organisation of a GMP-compliant Site Change

Recommendation

28/29 September 2021

Live Online Training: Product Transfer - Organisation of a GMP-compliant Site Change

According to Mr. Feuerhelm a reverse osmosis would be necessary in any case.

However, a one-step reverse osmosis seems to be sufficient. The formulation "by reverse osmosis, which may be single-pass or doublepass" is clear. But there seem to be situations, where a double reverse osmosis can make sense. Mr. Feuerhelm quotes the ISPE handbook "Production of water for injection without distillation". Here it says: "Depending on the nature of the raw water, it has to be checked whether a reverse osmosis process has to be carried out in one or two steps. A two-stage reverse osmosis increases the process safety".

Finally, Mr. Feuerhelm briefly dealt with the draft of the WHO document "PRODUCTION OF WATER FOR INJECTION BY MEANS OTHER THAN DISTILLATION". In his opinion there are no essential references or innovations to be found here.

 

Author
Dr Robert Eicher
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy around pharma technology.

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