FDA/GMP trends in production & technology - Part 1

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"Continuous pharmaceutical production" has been an established topic since the Pharma Congress 2012 - and was a subject of lectures yet again this year. After lectures held by FDA and EMA representatives, with Dr. Grummel there was again a speaker of the BfArM represented in the team of lecturers this year. But 2019 was the first year in which also continuous bioprocesses - upstream as well as downstream - were represented by means of case studies by Roche and Bayer.

Dr Detlef Eisenkraetzer, Director Fermentation Development from Roche in Penzberg, presented the continuous fermentation and compared it with the fed-batch technique. According to Dr Eisenkraetzer, the exclusive continuous manufacturing is not always an advantage in this case. Continuous and batch processes should be used where they provide a benefit. Aspects speaking for a continuous fermentation are a possible increase of the yield (with smaller systems) and lower investment and manufacturing costs. Seen from the process perspective the lower accumulation of metabolic by-products and the long operation periods (up to three months) speak in favour of continuous manufacturing.

Dr Eisenkraetzer said that interestingly, process deviations are also easier to handle in continuous than in batch processes. But opposed to this are higher process development costs, much more complex control strategies and possible differences in the product quality of materials from fed-batch or from continuous processes. And there remains a great uncertainty concerning the authorities' expectations with regard to process characterisation, validation and the filing of BLAs (Biologics License Application). But practical things must be taken into consideration, too. Using a continuous procedure, a much higher amount of media needs to be made available or moved within the facility. First, you have to ask your engineer whether this is compatible with the floor load capacity, Dr Eisenkraetzer added. There is still room for further developments concerning these technologies, most of which have single-use design. According to him, the systems to retain cells aren't yet available on the market in the size needed by Roche. All in all, costs must be compared for each process individually or a new comparison has to be carried out. Doing this, the most important criterion is the space-time yield which may also justify the classical or fed-batch procedure in intensified bioprocesses.

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Dr Felix Oehme, Head Biological Development at Bayer Pharmaceuticals, supplemented the part "continuous bio-tech" with his case study which examined the downstream processes when producing therapeutic proteins. Continuous downstream biotech manufacturing is even less common than continuous uptream processing. Dr Oehme stated that shorter processing times, reduced costs and the higher flexibility were the advantages or reasons for Bayer's decision for continuous downstream manufacturing. Oehme concretised that Bayer can produce 5 or 800 kg a year with the same equipment. In this way, investigational medicinal products and later authorised products can be produced without facility-tech-transfer. Dr Oehme explained in detail the continuous chromatography - the purification of a protein. In this case, five chromatography columns are interconnected parallel which makes it possible to constantly feed, elute and CIP the complete system.

According to Dr Oehme, the cooperation with the FDA was very positive. He stated that several meetings took place with the FDA's Emerging Technology Team (EMT), one of them at Bayer in Leverkusen. The FDA provided non-binding recommendations and constructive support, for instance, for the comparability study comparing the product quality in batch and continuous manufacturing. Furthermore, the continuous procedure offers much more data which are also accessible online, thereby deepening process knowledge. Thus, Bayer could demonstrate that there are no quality differences as concerns for instance by-products, content or stability of the target protein respectively the antibody.

Dr Oehme talked about maximum process times of six to eight weeks. But Bayer's new target is not the process duration but the speed. The aim is to process the content of the fermenter within two days at the most. In Leverkusen as well as in Penzberg single-usedisposables are used. At the beginning they were put together manually which took several days. Meanwhile, the supplier provides preassembled single-use systems. Dr Oehme, too, referred to the lower space requirements of continuous manufacturing as compared to the batch process. But you can profit from these lower space requirements only if you can build new (and smaller) buildings. Dr Oehme added that this advantage is practically negligible in existing buildings.

The conference addressing the increasing digitisation in the pharmaceutical industry was a novelty at the Pharma Congress 2019. The company Novartis was represented with a case study demonstrating the implementation of a Manufacturing Execution System (MES System). Dr Thomas Schwarz (Head Strategic Planning) and Zinaid Dzinovic (Programm Manger MES) showed in their lecture the change from batch documentation on paper to electronic documentation at the site Stein (sterile products). Four stages of development can be distinguished: 1. The pre-digital plant, with documentation only on paper; 2. so called digital silos with digital stand-alone solutions, 3. the connected plant with connected digital systems and semi-automatic analyses, 4. the predictive plant with connected systems along the complete value-added chain and the full-fledged 5. adaptive plant. Zinaid Dzinovic added that the pharmaceutical industry is in stage three right now. This is the connected plant. Here, the MES has a central role and has become indispensable. At Novartis the rollout of the MES is planned in three phases. It started in 2016, and Novartis is in phase 2 now. Phase 3 is planned for 2020 and stands for the upgrade of the production of solid pharmaceutical formulations in Stein. It was an important question to which extent the paper documents used so far have to be made available or should be made available in the digital MES. Support documents for instance or their raw data can also be kept in other systems; in the MES only the result or the information "complies/does not comply" is kept. At Novartis, the answer was based on the following three criteria: is the document mentioned in the registration dossier, does it have a direct influence on the product quality or the patient safety and which importance does the document have for the manufacturing process? Process harmonisation should be more important than digitisation. It is not possible to digitally depict every paper process 1:1 and it is easier to digitise these processes after they have been adapted, confirmed Zinaid Dzinovic. One main advantage of a paperless documentation of the manufacturing process is the batch record review. This is the review of batch data by means of the quality organisation in the context of the release which can now also be carried out digitally. The benefits of the MES are not associated to processes such as filling a vessel or stirring its content, but to the review process and for instance to the omission of double signatures (review by exception). In any case, a change in the mindset of production and QA is necessary and a certain IT affinity of the personnel makes it easier. Training courses concerning the system and the interfaces are of essential importance, added Dr Schwarz. According to him, contract manufacturers can also be "digitised" by developing and using a common interface. When asked about IT failures, Zinaid Dzinovic could give the following reassuring answer: that all systems are designed redundantly and that it is always possible to switch to paper. The support by the IT department is important and these colleagues should not be outsourced in faraway countries, added the two Novartis speakers.

Roche in Penzberg is also "digitising", or rather their processes are increasingly automated and generate numerous data. Jessica Prasser, expert for biostatistics at Roche in Penzberg, talked about how to use these data in a meaningful way. The central part is the validated data base IBIS (Integrated Biotech Information System) which merges data from different systems, links those data and makes them usable. Data from production (e.g. MES), quality control (e.g. LIMS), quality assurance (e.g. Trackwise), logistics and utilities (such as environmental monitoring or SAP) as well as from development are introduced. Since the system and many interfaces are validated, valid data for records, trendings, etc. can be generated which can be used for the follow-up of deviations, for example. Being a regulatory requirement, the process monitoring required by ICH Q10 also requires valid data. Previously, such data were issued, processed and further used as excel sheets, making a validation difficult. Process monitoring systems (PMS) serve not only for complying with the requirements by the authorities, but also improve process understanding. Discovering trends allows a timely intervention and process improvements. Here, statistics play an important role. Normal process capability observations (CpKs) are not possible since biological processes such as the ones carried out by Roche are not normally distributed. Furthermore, biological processes present unavoidable systematic variations (such as the ageing of material for chromatography columns or batch-related raw material qualities). According to Jessica Prasser, they first had to learn which statistic or which type of control card to use in order to get useful process limits. The way to the definition of process control limits led from the I-MR chart over Levey-Jennings to the Nelson Rule 2 and finally to the Nelson Rule 6. In the case of a violation of rules or limits, designated staff members are informed by E-mail so that they take measures. This also corresponds to the approach review by exception (see above).

The Conference "Pharmatechnik" (Pharmaceutical Engineering) took place for the 21st time and, as always, put the focus on construction and investment projects that could be carried out in the last years and which were presented by the pharmaceutical users/owners. Apart from Merck, Roche, Allergopharma, CSL Behring and GE Healthcare, the programme contained two lectures on case studies from Fresenius (US) and Oncotec about the integration of isolators.

Christian Mrotzek, Senior Director Engineering & Technology at Fresenius Kabi in the US presented the modernisation of three production sites. Before 2008, Fresenius Kabi had not produced in the USA. Meanwhile, they have three sites there: Grand Island (NY), Melrose Park (Illinois) and Wilson (North Carolina). Over the last six years, 500 million dollars were invested in the expansion and modernisation there. 350 million dollars were spent for the expansion of Melrose Park. This is the largest single investment in the history of Fresenius Kabi.

At the site Grand Island (State New York), there were several construction sites. Here, the investment concerned three aseptic filling lines and four lyophilisators. The challenge was to put ten year old lyophilisators, which had never been used before, into operation. Furthermore, one building had been used for the production of penicillin. The old equipment had to be removed and scrapped completely. And the building had to be cleaned of all rests of the product. An impressive way was chosen in this case: the complete building was "wrapped" and sanitised with chlorine dioxide.

The greatest challenge proved to be the expansion at the site Melrose Park, a multi-product fill and finish facility where inter alia highly potent products are produced. In this case, a building as big as seven soccer fields was modernised and updated. In addition, a new building was affixed to an already existing one in which the production had to be carried on during the building activities. Technical and cleanroom areas were separated consistently. In one room, five integrated isolator lines are mounted for the filling process. The loading of the lyophilisator is carried out automatically. The aim is that the operator can see and supervise the complete process, from the washing of the vials over the depyrogenation to the filling, and capping. Kick-off was in 2016 and the first production is planned for 2020. The product transfers are planned to start in 2021.

It posed more problems to incorporate the best practice approaches from Germany into the projects. According to Christian Mrotzek, the answer was often "that's how we do it in the US". He also attached great importance to the cooperation in the team. He explained that it does not work to lead a team, which is supposed to work successfully in the USA, from Germany. Now, all 60 persons are stationed together in one building rented for this purpose, which works out well. Christian Mrotzek finished his lecture with the conclusion that having engineering inhouse is a strategy which has led to success.

The lecture on technical innovations at Oncotoc was held jointly by Dr Matthias Beck (Manager New Business Development at Oncotec) and Uwe Harenberg (Managing Director at GESA). Oncotec is specialised in the filling of highly active products and hence, all filling lines at the site in Dessau are in isolators. A relatively new establishment is the fill and finish of highly active ADCs (Antibody Drug Conjugates). Here, single-use equipment is also utilised which is relatively new at Oncotec. The project presented is composed of different parts. In an existing building there are four filling lines. The building adjacent to this one houses the visual inspection. Now, a connection between the two buildings was constructed in order to improve inter alia the product flow. In the building with the visual inspection, a new large scale vial filling line was integrated for example for ADCs. Here, robotic technology is used additionally (in the isolator). A gripper can handle all vial sizes without making it necessary to change the format. The zero-loss-concept in this area is worth mentioning. By means of sensors communicating with the robot, it is possible during the stoppering as well as during the capping process to return units with missing stopper or cap and to automatically repeat the closing operation so that no unity has to be rejected as "bad". Here, the isolator is in class D and the mouseholes are protected with a local class C plug-in. In the isolator there is only a pressure level (in class A of course) with additional laminar flow units as supplementary protection. It was possible to prove compliance with EU and FDA requirements by means of validation and extensive smoke studies.

Klaus Feuerhelm, GMP inspector from a local GMP authority in Baden-Württemberg/Germany, talked about GMP requirements concerning compressed air systems and about typical inspection topics in this area.

Compressed air has a broad range of applications in the pharmaceutical industry. Until now, compressed air or compressed air systems were only seldom subject to inspections by the authorities. Klaus Feuerhelm explained that the topic was only rarely taken into consideration in legal frameworks. The topic was specifically addressed for the first time in Annex 15 of the EU GMP Guidelines which entered into force on 1. October, 2015. The reason for this certainly was that compressed air may have direct or indirect contact with the product, but is seldom a component of a medicinal product. Nevertheless, there is always more or less of a risk of the (medicinal) product being contaminated, added Klaus Feuerhelm.

Annex 15 of the EU GMP Guidelines contains some unspecific information on compressed air in section 8 "Qualification of Utilities". It is specifically required that compressed air systems are qualified according to Annex 15 of the EU GMP Guidelines (DQ, IQ, OQ, PQ). But there is no direct reference to compressed air in the currently still valid Annex 1 of the EU GMP Guidelines. In the current draft of Annex 1, compressed gases are a general topic, though. It contains, for example, the following indication:

7.19 Compressed gases must be filtered through a sterilizing filter (with a nominal pore size of a maximum of 0.22 μm) at the point of use. Where used for aseptic manufacturing, confirmation of the integrity of the final sterilization gas filter should be considered as part of the batch release process.

Annex 1 is uncompromising: "must be filtered". Where compressed gases are used for aseptic manufacturing, integrity testing of the sterile filter has to be carried out. The result is then part of the batch documentation.

Klaus Feuerhelm also addressed the specification of compressed air. According to his experiences, one in two companies cannot provide a specification for compressed air in the case of an inspection. Klaus Feuerhelm stated that the parameters to be specified should be identified in the context of a risk analysis. Depending on the application there may possibly be more than one specification. Only the process owner may define the specification on the basis of his knowledge on the area of application. Contact with the product and the form of application of the medicinal product play a major role for the specification. Important parameters of the specification are water content (pressure dew point), oil content, particles and microorganisms. ISO 8573-1: 2010 Compressed air - Part 1: Contaminants and purity classes is helpful for the preparation of a specification. The different classes of the standard may be combined, for instance particles class 1, water class 3, oil cl

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Some detailed information on compressed air can be found in the EFG 3 Aide Memoire "Überwachung von Sterilherstellern" (Surveillance of sterile Manufacturers). Here, the specification is addressed specifically: Apart from the type of manufactured product, the design of the facility and the quality of the raw air also have to be taken into consideration in the risk assessment.

Limits for bacterial count/particles are expected. Klaus Feuerhelm added that it is not clear why the microbiology also is addressed.

The technical standards of the series ISO 8573 are a useful basis for the preparation of the specification and for carrying out the measurements. In connection with the assessment of hydrocarbons, attention should be paid to the fact that they are a mixture of oil aerosols, oil gas and other hydrocarbons. Accordingly, the definition of oil as mixture of hydrocarbons with ? 6 C-atoms (ISO 8573-1:2010) is useful.

According to Klaus Feuerhelm, gaps in the routine monitoring are criticised during inspections again and again. In principle, it must be differentiated between parameters to be determined continuously and those to be determined discontinuously. Parameters to be determined continuously are pressure, temperature, flow, flow velocity, humidity of compressed air (pressure dew point) and oil content. Parameters to be determined discontinuously are mainly particles and microbiology. By means of the pressure dew point, it is possible, for example, to determine how great the risk of water condensation is. In connection with the oil content, Klaus Feuerhelm talked about the use of oil-free and oil-lubricated compressors. To this effect the EFG 3 Aide Mémoire contains the following note:

"In this respect, it is pointed out that systems with compressors and chilldryers containing oil are regarded as being only partly suitable for the use in the manufacture of medicinal products. It is required to carry out an extensive risk assessment. Alternatively, compressor systems without oil and adsorption dryers with integrated control of humidity (dew point) are used for instance."

In this respect, it should be noted that some consider that compressors containing oil do not pose a greater risk. But if the compressors are oil-free, the subsequent cleaning efforts are much smaller, added Klaus Feuerhelm.

He mentioned the following further typical inspection findings concerning compressed air: missing logbook of the generation or of the distribution system, missing functional design specification concerning the qualification, no filter integrity test after removal of the terminal filters in the compressed air system, missing assessment of the quality of the raw air and missing requirements concerning cleaning or sterilisation of the piping behind the sterile filter.

But according to Klaus Feuerhelm, there was a clear trend towards a visible improvement of inspection results in 2019, especially concerning the qualification activities.


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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