Lean and mean

To survive in today's regulated environment, drug companies must develop cost-effective management strategies. This was the theme of a seminar organised by the ISPE - NW region.

David Selby, of Selby Hope International, is the first non-American ISPE president. Just before this meeting he had attended the ISPE Annual Meeting in New Orleans, from which the big news to emerge was that the FDA wanted cGMP to be a risk-based approach. 'If you take this at face value it is a paradigm shift; it's a different way of working; it's a different way of looking at how we should be developing our process system and managing our manufacturing,' he said.

But talking to people in the industry had made him realise there is a reluctance on the part of some major companies to adopt a risk-based approach or at least to be the first to do so. Certainly no company wants to hazard a new chemical entity (nce) being approved by adopting a risk-based approach, he said, 'and that, of course, is very understandable.'

affordable medicines

In a presentation in New Orleans, former FDA Commissioner Mark McClellan had described the FDA's new mission as 'innovation with affordability': innovation because there are not enough new drugs are coming onto the market; affordability, because although the cost of medicines in the US is only 10% of the total cost of healthcare, 'politically it is such a hot potato that clearly McClellan sees it as his mission to make new medicines available to market in an affordable fashion,' said Selby.

McClellan put a lot of emphasis on speeding up the review of new drugs , stressing that it was not acceptable to have a merry-go-round of NDAs being reviewed several times. He called for the industry and the FDA to work more closely together prior to the NDA submission, then when it is submitted the process is relatively trouble-free. 'We can think of a number of examples where NDAs have had to be resubmitted and have taken some time to get the drugs marketed,' said Selby, 'and that, of course, costs the industry dearly.'

Selby suggested that the next single biggest key to understanding where the FDA is coming from is process management. 'Very few people have got, or have had until recently, good data about process management. There's a lot of potential to be invested in process understanding.'

He said that if a company understood the processes better, and what was critical for the control of the process, then it can start to monitor those aspects that the FDA wants. 'If you monitor those critical aspects continuously, in a non-destructive manner, then we are going to get much better information about the quality of the product.

PAT costs

'Last year the FDA wanted to make it easier for companies to change and that's where the new process analytical technology (PAT) guidance came in. If we have better process understanding then it is much easier to make changes.'

An issue that industry justifiably raised was that this would cost more, so how was this going to help the affordability. What does the company get back for this change in cGMP?

Ajaz Hussein, the FDA's PAT project director, said at the meeting that if the industry is doing all of this to control the processes the FDA wouldn't expect process validation. Processing batches according to predefined criteria gives confidence the new approach should be better, so do we need process validation? The answer , according to Hussein, is that we don't.

'What we do need, though, is to be very sure that the controls we use are validated and are regularly reviewed,' Selby said. 'The emphasis shifts from the process to the critical controls. Also this should result in less product testing.'

Hussein also suggested that if the company has a good process understanding, it also has a much better understanding of what happens when it comes to making changes. He described this as 'creating your own SUPAC (scale-up post approval changes)'.

'He is saying that if a company goes down this route of better controlled processes and better understanding of processes and process capability, then it can be responsible for convincing the FDA that it doesn't need to notify proposed changes - it just tells it afterwards,' Selby told the ISPE delegates.

The crunch, however, is that the FDA now needs some indication that companies want to go down this route so that it can justify further expenditure on top of its initial outlay. It now wants the industry to follow up with submissions involving PAT technology.

leading GMP

Speaking to the seminar on the topic of benchmarking and control of GMP performance, Roger Benson, from ABB Eutech Process Solutions said that the pharmaceutical industry had led the development and implementation of Good Manufacturing Practice (GMP), but that regulatory, commercial and financial pressures are increasing the drive to improve the manufacturing performance as well.

Other sectors such as automotive, electronics and chemicals have made this journey and there was much to be learned from the experiences in these industries.

Benson said that a rigorous measurement frame enabled performance improvements to be quantified. By aligning this opportunity with the regulatory requirements of the pharmaceutical industry, with technologies such as paperless manufacturing, PAT and other quality techniques, identifying the processes for improvement should be achievable. 'The potential rewards are very significant; especially in improved quality, reduced cost of compliance, reduced manufacturing cycle times and reduced inventory,' he said.

Benson went on to describe how lean compliance could be achieved by combining compliance with the requirements of cGMP (control of practices), and world class manufacturing (control of performance). Benchmarking has been a buzz word in recent years, and is the process whereby companies continually measure and compare their performance against the best in the world, either within their industry, or without, if the comparison can be made.

He illustrated this point by comparing a 'standard' pharmaceutical plant, a 'winning' pharmaceutical plant and a 'world class' plant - in this case a food plant supplying supermarkets (see Table 1). 'You may argue that food is different from drugs, but the standards and requirements for food manufacture in terms of sterility etc. are little different from pharmaceuticals,' commented Benson. 'As you can imagine, if a single person dies from eating mass-produced food that company could be ruined, and would certainly face enormous litigation costs.'

To give an idea of the costs that could be saved, Benson highlighted the stockturn figures. He said that if the world pharmaceutical industry were to move from the current average to that of the best in the UK, the cash released would be $194bn, and if it were to meet the best world standard a further $72bn would be saved.

He concluded by saying that Good Manufacturing Practice is a necessary, but not a sufficient condition for good manufacturing performance. Delivering the latter is a journey, which starts with measurement and recognition that the opportunity exists. 'It is a process of continuous improvement that will have a dramatic effect for individual pharmaceutical companies.'

unacceptable risks

Ian Williams, of CP Pharmaceuticals, looked at risk assessment in supply chain management. He said that until recently the application of formal risk assessment techniques within the pharmaceutical industry was limited, and their incorporation into formal quality processes was rare. The prescribed view, perhaps a presupposition of the regulatory inspection process, was that any level of risk is unacceptable, and a QA system should eliminate risk entirely. This, of course, is practically and philosophically an unobtainable goal.

'Risk assessment decisions are, of course, made at many stages of the business process, and few decisions are risk-free,' he said. 'However the risk element of these decisions is often unquantified and undocumented.'

He pointed out that this climate is changing, and risk assessment as a quality tool is now being introduced in a number of different arenas - most recently with the FDA's announcement that it is to use risk assessment techniques for its own activities, with the consequent expectation that regulated companies will do likewise.

Williams's paper focused on a case study at CP Pharmaceuticals on the application of risk assessment techniques to quality aspects of the supply chain. He said the study had been used to reduce delivery lead times and to establish audit priorities. 'Experience in these areas has confirmed the usefulness of the approach, and supports risk assessment in wider applications.'

project construction

Kevin Hill from AstraZeneca spoke about integrated construction and start-up for faster, cost-effective projects. He said that in recent years, advances have been made in project and construction management to make 'fast-track' projects very much the norm. 'In the early 1990s, it took around three years to build, commission and start up a new formulation facility.'

To reduce this time, approaches such as alliance working were developed, which led to a significant reduction in the time it takes to build new pharmaceutical facilities. He said that alliance working involved forming 'small, empowered teams' from suppliers as well as the contractor's workers.

However, he said that commissioning, qualification and validation remained a stubbornly lengthy post-build activity, which meant it was usually many months before the facility was finally brought into beneficial operation. Hill showed that by extending the alliance concept to incorporate the production team, the start-up phase could be dramatically reduced, in some cases halving the total project time and giving rise to substantial cost savings.

contractor questions

Hill examined the basic philosophies of alliance working, focusing in particular on the alliance between engineering and production, and highlighted the aim - which was achieved with AZ's new production facility at its Macclesfield site - as being in a position to run a facility before the facility has been built. 'There should be a seamless transition from construction to production, and completing qualification before construction is complete.'

When questioned about the role of contractors in alliance working, Hill admitted that some 'saw the light immediately', while others 'were more reticent', but that they saw the benefits of such working through cost savings etc. He emphasised how important the role of the engineering and production teams was and how it changed with time of build.

Lynn Edwards, also of ABB Eutech, spoke about the application of the Commissioning and Qualification baseline guide to streamlining validation. She said that the introduction of the baseline guide may seem cumbersome initially, but the benefits of the approach far outweighed any starting problems. 'Decisions regarding the systems/equipment to be validated are made and documented in a timely manner, details of the validation approach are clearly understood and the reporting approach is uniform as a result of everyone buying into the approach of the guide,' she said.

The guide has three key concepts: impact assessment, which assesses whether the system has direct, indirect or no impact; good engineering practice; and qualification practices. These concepts are combined with four philosophies:

• GEP is critical to the success of the approach;

• the baseline approach restricts qualification to direct impact systems only;

• if the system is direct impact, then both GEP and qualification apply;

• only GEP is necessary for indirect systems, but it is essential.

Companies often find that they are working in line with the guide to varying degrees and so the changes can be subtle rather than drastic.

Process analytical technology and science-based compliance was the subject addressed by Steve Hammond, of Pfizer. He said that Pfizer Global Manufacturing had a desire to move to 'right first time' performance. An essential part of achieving this status of almost zero defects was process understanding and control of what he called 'Critical to Quality Attributes'. PATs are an essential tool for achieving these desires, and, he believed that this same philosophy would lead to science-based compliance.

He defined PAT as 'the use of at-line or on-line sensors to effect timely measurement and control of a process'. Often this is described as real-time measurement at process critical control points (PCCPs). Many technologies have been used including UV, Mid-IR, Raman and, more recently, acoustic and imaging systems.

However, more than 70% of applications involve Near Infrared spectroscopy (NIR), because of the ease of sample interfacing, and the development of the optic systems by the telecommunication industry.

Hammond gave examples of the use of these PATs to improve the control and understanding of some important steps in the production of pharmaceutical products.

They go from the monitoring of reactions, crystallisation of APIs, through to the formulation steps of blending, granulation, and compression. Specific examples were given describing the insertion of on-line sensors into API production vessels, secondary production blenders, granulators and dryers.

The development of an on-line system that can be interfaced to a press to analyse tablet cores was also discussed.

He concluded by saying: 'I hope that the picture of tight process control and understanding, can lead to the process qualifying for the description of science-based compliance.'

2004 conference contact

The 10th ISPE seminar/exhibition and awards dinner will take place at the newly opened Hilton Newcastle Gateshead Hotel, Newcastle-upon-Tyne on the 11 November. The title of the seminar is: "Continuous Processing/European Standards for the Future." Among the speakers are Dr E Lennart of the Swedish Medicines Inspectorate, Dr Mike Cliff of Astra Zeneca and Dr Guy Wingate of GlaxoSmithKline. For further information contact: Erica N.Evans-Terlecki, 123 Heathfield Road, West Moors, Ferndown, Dorset BH22 0DE. T +44 1202 876274 F +44 1722 323222 erica.evans@cielec.com