David Ainsworth

Planning for new manufacturing capacity in the pharmaceutical industry is notoriously difficult. New potential blockbuster compounds are discovered that are predicted to have a big future, yet can fail at the last hurdle. Older products coming 'off patent' may unexpectedly get a new lease of life meaning that existing production capacity must be increased. Consequently, many production facilities are built as multiproduct or general purpose manufacturing units to cater for the wide variety of compounds, processing characteristics and volumes required. 

This article discusses the need for site master plans that form the basis for future manufacturing development, and addresses some of the early stage process development activities that influence the fundamental basis of the project. Methods employed in the later stages of project execution will form the basis of a second article, which will be published in the future. 

This first article discusses some of the ways in which experienced external service providers can add value to the early stages of pharmaceutical facility planning and design by providing 			

methods and experience to analyse the process as a whole

methods and procedures to formulate a robust basis for the project to proceed. 

Despite the high-tech image of pharmaceutical facilities, many of today's manufacturing plants are over 20 years old and have developed in an unstructured manner. Support services will often have been provided individually on a project-by-project basis where, with hindsight, a more holistic approach would have been more cost-effective. Time pressures on new projects may have resulted in new facilities being located in the most convenient position rather than the best location for the overall site development.  

Consequently, many companies have identified the need for a more structured planning approach to their future site developments, involving			

rationalization of existing site facilities

reduction in operating costs in support services

surveying and census of newly acquired facilities

upgrading for good manufacturing practice (GMP), environmental health and safety (EHS) or to incorporate new technologies

improvements in flows and departmental relationships.

Each pharmaceutical company understands its own business better than any other organization and in this respect the site master plan is best undertaken by the company's own resource. However, an external services provider can often add value by 			

bringing an independent and objective approach

providing census techniques, questionnaires and workshops

offering specialist knowledge in key technology areas

The resulting master plan will provide the cornerstone for future development of the manufacturing site and a framework within which, each future project can fit. The illustration provided in Figure 1 gives an overview of the entire process.

 Figure 1: Development of the site master plan.			

Once a new candidate active compound has been identified, a pharmaceutical company sets out to develop the manufacturing process. Almost without exception this results in the generation of a batch process though it is well understood that continuous processes are more efficient and cost only a fraction of the equivalent batch process. Speed-to-market and concerns over validation of the process have meant that a pharmaceutical company's approach to process development is conservative. From a process engineer's point of view, it seems that the end result of a huge amount of engineering effort simply produces a scaled-up version of the laboratory plant. 

Pharmaceutical manufacturing processes are typically developed by a team of chemists, each of whom are individually responsible for small parts of the overall process, and typically use simple laboratory glassware and equipment. Recently, however, operators are questioning why they constrain the kinetics, thermodynamics and fluid mechanics of pharmaceutical processes to the limited confines of a stirred tank. This is where the experienced process contractor, if involved early enough, can add value to the process development process. Analysed in a methodical manner, the specific characteristics of each process become evident and alternative processing methods then identified.  

One of the best methods available has been developed by Britest Ltd, a nonprofit company founded in 1998, whose members include AstraZeneca, GlaxoSmithKline and Foster Wheeler. Britest's objective is to deliver major competitive benefits to chemical and pharmaceutical companies by designing the best processes and manufacturing strategy for each member, using a set of proprietary tools, known as the Britest tools. Utilizing Britest methodology encourages the user to develop a greater understanding of the process as a whole, resulting in radically different options being considered. These tools are a time-effective way of starting the development process and determining all the potential (and unfeasible) process options.  

Once the process is available, the next stage of its development is to analyse and refine the design. This is where modelling and simulation provide invaluable aids to the decision-making process. With the computer model, numerous design alternatives can be investigated quickly and easily, enabling the capital cost of the facility to be minimized. Demand for resources and debottlenecking can be determined (Figure 2) as well as confirmation of production rates and illustration of manufacturing schedules. In addition to equipment-focussed process modelling for debottlenecking and utility analysis, the operational aspects of a facility can be modelled and analysed.

Figure 2:  Simulation of utility demand versus time.			

The computer model adds value at all stages of the design process from early conceptual design through to the ultimate operation of the facility. There are a number of different modelling methods available to the engineer. Both static and dynamic simulation packages are available such as Witness and Super Pro Designer. Effort put in at this early stage of the process development will be handsomely rewarded over the lifetime of the facility. 

Operability modelling and simulation, which include capacity modelling, enables the designer to			

plan labour (number of operators, operator position, etc.) and simulate operating procedures to ensure satisfactory operations

demonstrate movements to optimize layouts, eliminate cross-contamination and determine numbers of intermediate containers required

optimize dispensing points, use of intermediate containers and buffer storage

optimize utilities and services. The benefits of operability modelling include reduced capital cost and reduced operating cost, resulting from increased efficiency, improved use of labour and reduced inventory. 

To develop the new project concept it is important to have an early realistic appreciation of the magnitude of the required facility in terms of scale and cost.  

Senior management must appreciate the likely cost of the final manufacturing facility and have a good understanding of the size of the project to consider the sites where it may be located. In many cases the new process may be accommodated within an existing manufacturing facility on a campaign basis with little need for plant modification.  

Larger and more complex processes may involve a significant revamp to an existing facility. Many pharmaceutical companies now have significant capacity throughout their worldwide operations and the requirement for new greenfield project capacity is now less than it has been in recent years. However, there will always be a number of new facilities required if only to replace the ageing nature of existing capacity. 

Specific process chemistry, more toxic compounds, specific physical forms and increasing levels of GMP will also add to the requirement. Costs of new facilities or revamps are often preset by early discussions where a rough cost is first mentioned. Often this number is based on little more than a guess or estimate, yet it can often live with the project throughout. An experienced contractor can provide useful early guidance if given a significant database of information. Past project data, when analysed and reported in a consistent manner, provides relatively accurate information from a minimal amount of information. The graph in Figure 3 illustrates one of the many types of correlations that are available. In this example, for a primary active pharmaceutical ingredient (API) batch manufacturing facility, the overall reactor capacity is the prime factor plotted against the total installed cost of the facility.

Figure 3:  Process building cost versus reactor capacity.			

The scale or the size of a new facility is also an area that can be estimated at an early stage from minimal information. The size of a manufacturing facility is something that has generally required a reasonable amount of design work to be executed before reasonable information has become available. However, the experienced designer can provide very early guidance on the scale of a new facility if it has analysed and correlated a number of previous designs. The analysis requires the definition of different areas of the facility, which must be clearly understood to make use of the relationships generated. In the example illustrated in Figure 4 the relationship between floor area and reactor capacity for differing manufacturing scale can be seen. With a minimum of process knowledge a good estimate can be made of the new plant area requirements.

Figure 4:  Relationship between process footprint and reactor capacity.			

Given an early appreciation of cost and size of facility the planning and design process may continue to the early stages of conceptual design. 

Pharmaceutical plant design is often heavily influenced by the user. It is unusual for a client to make use of repeat designs, instead requiring bespoke design solutions. For example, a comparison of a variety of API pharmaceutical pilot plants finds all manner of different plant arrangements and detail for what are essentially the same process equipment configurations. In time, this approach will no doubt diminish as clients become increasingly focussed on minimizing overall project costs and time to build.  

As with other industries a greater degree of standard or repeat engineering designs will prevail as manufacturers face stiffer competition in the marketplace. 

For the moment, however, bespoke design is still an important factor in determining and fixing the user requirement and, therefore, the scope of the project. Engineering contractors generally have a key role at this stage of the process development in undertaking the conceptual study. At the early stage of a project it is essential that a common understanding of the project is appreciated by all parties. A series of questionnaires and workshops is useful in ensuring that all aspects of the project are fully covered and that all parties fully understand the project scope. The outputs from these workshops must then be captured in an overall plant user requirement specification (URS) and plant design basis documents.  

Articles

Planning manufacturing capacity in the pharmaceutical industry is not for the faint-hearted. How can process designers help their clients to overcome some of the problems they face when planning to introduce new capacity? This article sets out to explain some of the techniques that are being employed in the early stages of project development.