Innovation at ISPE shows future focus

The ISPE UK Affiliate 10th annual seminar took place in Newcastle. The focus was on continuous processing and the future of EU standards. Graham Lampard reports.

Regeneration and innovation through buildings such as the Baltic Mill for Contemporary Art and The Sage have transformed the River Tyne's waterfront around Gateshead, and it was here that the International Society of Pharmaceutical Engineering (ISPE) held its annual conference.The question of innovation - in this case the design of future manufacturing facilities - was raised by the first speaker Michael Walden, from the Dewjoc Partnership. He quickly gave a positive response, especially as far as biomanufacturing with disposable technology in the development of cleanrooms was concerned.

developing themes

He said that using innovative construction methods could simplify construction sequencing, which will permit shorter construction periods while multiple construction zoning develops safe multi-level working.

However, the scope of such changes is limited, and Walden suggested that barrier technologies, single use materials, and changes to the process would offer greater innovations.

He then developed the theme using a number of case studies. One project - in conjunction with Stedim, Clean Design and Biopharm Services - was a multi-product 1000-litre perfusion-based monoclonal antibody process running for four weeks. The aim, he said, was: 'to develop a leading edge concept facility design that exploits fully the benefits of the latest innovations in single-use disposable technology', while reducing capital, labour and operating costs, along with increased flexibility and productivity. Walden outlined how each company developed different aspects of producing the cleanroom and the benefits achieved. In summary, he told the audience that the advantages fell into a number of categories:

• Single use materials mean no reusable components, hence no autoclaves, and washing is limited to the bag containers. Minimal use of the utility infrastructure also saves money.

• Segregation of solutions from each process means that solutions are held sterile in single-use disposable systems, while automated vehicles may be used for transportation of the solutions to ensure sterility.

• Improved process security, through a reduction in the extent of aseptic processing, minimises labour operations in processing areas and simplifies material and waste flows.

Overall, Walden said, the ability for fast product changeover leads to higher productivity.

'Potent drugs: new challenges require novel approaches' was the title of Dr Guenter Koerblein's lecture.

Dr Koerblein said that, despite the majority of nces developed today being deemed 'potent drugs', there are still no clear and binding international rules to define how to deal with such drugs. He pointed out that while a first attempt to assess measurement criteria has been developed out by the ISPE with its Standardised Measurement for Equipment Particulate Airborne Concentrations (SMEPAC) guidelines, it made sense to find novel approaches for the specific task of producing highly potent drugs.

defining questions

The first question was how to define 'potency'. Koerblein suggested that Occupational Exposure Limits (OELs) could be used, and he went on to explain the various definitions, from No Observable Effect Level (NOEL) to LD50s. He then discussed the arguments as to whether dilution was a solution to potency levels, but came to the conclusion that, in terms of preventing exposure, the costs were not reduced by dilution.

A second idea for reducing contamination, he said, was to change the method of drug mixing/granulation, tableting and coating. Currently, most companies have separate departments for each process step - ie parallel production - but Koerblein argued that by putting the three steps into one process - i.e. serial processing - this could reduce the likelihood of exposure because the API is moving through a contiguous process.

Again, there are pros and cons of working with each type of production. While there were difficulties with work patterns, and possibly increased 'downtimes', for machines, the benefits of reduced contamination and exposure could outweigh these problems.

Peter Damer, from Emerson Process, discussed a model-based approach to the design and validation of complex software systems in the pharmaceutical industry. Although many of the issues raised apply to software development in general, the paper more specifically addressed the requirements of automated control systems.

He highlighted a powerful case for improving software development processes. However, implementing such tools, design databases and training users how to exploit them are considerable challenges. Damer was still confident that by basing the approach on standards, many adopted in the IT industries, the vision was realisable. He said: 'In order to benefit fully from a model-based approach to IT, it is important that the models chosen are applicable from the requirement right through to operational support for the system. It is also important that the skills exist to maintain and develop the models.'

Michael Warmuth, from Abbott Laboratories, said at Interphex 2004: 'The paradigm shift that the industry must make in order to move forward will be to gradually change from batch processes to continuous ones.' With that in mind, Mike Cliff from AstraZeneca (AZ) spoke on 'Future oral solid dosage manufacturing technology - continuous granulation.' He said that AZ has a continuous granulation process dating back to 1986, but that there are still 'issues' over continuous granulation within the industry: on the whole, the focus of continuous granulation is on high capacity; there are real and perceived GMP issues over the technology; the technology is not widely adopted and, unfortunately, new technology is not being developed.

Yet the method fits in with the FDA's PAT initiative, and Cliff thought that: 'many of the established benefits of the technology are now seen as solutions to current issues facing the industry.' These include:

• Providing better containment when handling potent compounds and APIs.

• Providing better process control.

• The possibility of Just In Time manufacturing; decreased stocks and increased reliability.

Cliff said that technology is being developed by suppliers and pharmaceutical manufacturers with more applications of the technology being considered; the focus being on small, even 'micro' scale units.

financial drivers

These systems include semi-continuous and continuous granulating machines from Reitz, GEA, Leistritz, Bohle and Glatt. In conclusion, Cliff said: 'The environment for continuous processing is improving, with regulatory, safety, health and environment (SHE) and financial drivers supportive of the idea.'

The one problem he foresaw was that, although equipment suppliers and some pharmaceutical manufacturers are investing in continuous processing technology, and much of the technology exits, a suitable drying technique still needs to be developed. He did, however, say that AZ is investing in the development of continuous processes.

'European standards for the design of HVAC systems to suit the pharmaceutical industry' was the topic for Nick Jardine from Clean Design. He presented some of the considerations which may be necessary in the design of HVAC installations for the pharmaceutical industry in order to meet the requirements of the European standards (see table 1).

One area of concern, Jardine said, was how the design criteria set out in the latest standards are far inferior to those of 25 years previous (see table 2). 'That's progress for you,' he quipped. Jardine then discussed the various cleanroom design criteria; monitoring requirements and HVAC systems for bulk pharmaceuticals; oral solid dosage forms and sterile manufacturing.

Dr Guy Wingate, chair of the GAMP Council, spoke on: 'GAMP in the evolving regulatory environment.' He said that, using FDA findings over the previous five years, it was clear there was a significant increase in '483 letters - used by investigators to record their observations of non-compliance with cGMPs - concerning deviations involving computers. This occurred in all aspects of production, from the laboratory through to the production floor.

An interesting fact was that while 10% of the '483s were related to spreadsheets and databases, this increased to 25% when the FDA issued warning letters; suggesting that companies were unaware that computer related problems were not only site-specific, like the current '483 letters, but company-wide.

On the subject of warning letters he said that they are typically issued to a site in response to the discovery of significant issues or through repeated non-compliance of previous '483 items.

However, as shown above, a global commitment is expected when multi-site computer systems are seen as deficient, with large scale remediation, as associated with networked IT applications, required to be put in place.

GAMP guidelines

Wingate said that a new FDA warning letter was in the offing. This warning letter is to be issued to an organisation in response to common issues being identified from single inspections of multiple sites; global commitment is sought for related types of deficient computer system used across company, the implication being for large scale remediation associated with site specific system types (e.g. CDS; SCADA; local GMP database applications).

Other regulatory issues included a new GAMP guidance for electronic records, which is expected this year.1-3 Wingate discussed how GAMP had developed these records and gave examples of record controls that satisfied the guidance. He also gave the audience a few words to consider about a risk-based approach to manufacturing.

As with all ISPE conferences, there was something for everyone. The presentations were full of the information needed to survive in today's highly regulated industry.

ISPE Conference 2005

"Pharma, Pharma Wherefore Art Thou Pharma": What is the future of UK Pharmaceutical Manufacturing? The 2005 ISPE seminar/exhibition takes place on 17th November in Stratford-Upon-Avon. For more information: T +44 1202 876274 F +44 1202 323222 erica.evans@cielec.com