planning and designing a pharmaceutical facility

7/30/2019 Planning and Designing a Pharmaceutical Facility

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Planning and Designing a Pharmaceutical facili ty –

A Process Designer’s View

By David Ainsworth

Planning for new manufacturing capacity in the pharmaceutical industry is notoriously difficult. Newpotential blockbuster compounds are discovered that are predicted to have a big future yet can failat the last hurdle. Older products coming ‘off patent’ may unexpectedly get a new lease of lifemeaning that existing production capacity has to be increased. Consequently many productionfacilities are built as multi-product or general purpose manufacturing units to cater for the widevariety of compounds, processing characteristics and volumes required.

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 fornew capacity introduction? This article sets out to explain some of the techniques that are beingemployed in the early stages of project development. It discusses the need for site master plans thatform the basis for future manufacturing development and addresses some of the early stageprocess development activities that influence the fundamental basis of the project. Methodsemployed in the later stages of project execution will form the basis of a second article to bepublished later this year.

This first article discusses some of the ways in which experienced external service providers canadd value to the early stages of pharmaceutical facility planning and design:

• an independent and objective viewpoint• methods and experience to analyse the process as a whole• modelling and simulation tools

• benchmarking data• methods and procedures to formulate a robust basis for the project to proceed

Site Master Planning

Despite the high-tech image of pharmaceutical facilities, many of today’s manufacturing plants areover 20 years old and have developed in an unstructured manner. Support services often will havebeen 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 haveresulted in new facilities being located in the most convenient position rather than the best locationfor the overall site development.

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

• rationalisation of existing site facilities• reduction in operating costs in support services• surveying and census of newly acquired facilities• upgrading for GMP, EHS or to incorporate new technologies

•

improvements in flows and departmental relationships



Development of the Site Master Plan

Fig 1

Projectkick-off

Survey &census

Analyse

process/business

Gapanalysis

Master planworkshop

Finalisescope &layout

Preparecost

estimate

Studycomplete

Development of the Site Master Plan

Fig 1

Projectkick-off

Survey &census

Analyse

process/business

Gapanalysis

Master planworkshop

Finalisescope &layout

Preparecost

estimate

Studycomplete

Each pharmaceutical company understands its own business better than any other organisation andin this respect the site master plan is best undertaken by the company’s own resource. However anexternal services provider can often add value by:

• bringing an independent and objective approach•

providing census techniques, questionnaires and workshops• providing industry benchmarking• offering specialist knowledge in key technology areas

• providing resources to enable the study

The resulting master plan will provide the corner stone for future development of the manufacturingsite and a framework within which each future project can fit. The illustration provided in Fig 1givesan overview of the entire process.

Process Design

Once a new candidate active compound has been identified, a pharmaceutical company sets out todevelop the manufacturing process. Almost without exception this results in the generation of abatch process though it is well understood that continuous processes are more efficient and costonly a fraction of the equivalent batch process. Speed-to-market and concerns over validation of theprocess have meant that a pharmaceutical company’s approach to process development isconservative. From a process engineer’s point of view, it seems that the end result of a hugeamount 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 simplelaboratory glassware and equipment. Recently, however, operators are questioning why they

constrain the kinetics, thermodynamics and fluid mechanics of pharmaceutical processes to thelimited confines of a stirred tank. This is where the experienced process contractor, if involved early



Fermentation

media tank

time

batch

schedule

u t i l i t y

d e m a n d

Fig 2

Simulation of Utilit y Demand versus Time

Fermentation

media tank

time

batch

schedule

u t i l i t y

d e m a n d

Fermentation

media tank

time

batch

schedule

u t i l i t y

d e m a n d

Fig 2

Simulation of Utilit y Demand versus Time

enough, can add value to the process development process. Analysed in a methodical manner, thespecific characteristics of each process become evident and alternative processing methods thenidentified.

One of the best methods available has been developed by Britest Ltd., a not-for-profit companyfounded in 1998, whose members include AstraZeneca, GlaxoSmithKline and Foster Wheeler.Britest’s objective is to deliver major competitive benefits o chemical and pharmaceutical companiesby designing the best processes and manufacturing strategy for each member, using a set of proprietary tools, known as the Britest tools. Utilising Britest methodology encourages the user todevelop a greater understanding of the process as a whole, resulting in radically different optionsbeing considered. The Britest tools are a time-effective way of starting the development process anddetermining all the potential (and unfeasible) process options.

Process Modelling and Simulation

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. Withthe computer model, numerous design alternatives can be investigated quickly and easily, enablingthe capital cost of the facility to be minimised. Demand for resources and debottlenecking can bedetermined (see Fig 2) as well as confirmation of production rates and illustration of manufacturingschedules. In addition to equipment-focued process modelling for debottlenecking and utilityanalysis the operational aspects of a facility can be modelled and analysed.

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



0.0

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Process Building Cost Versus Reactor Capacity

Fig 3

TOTAL REACTOR VOLUME (m3)

P R O D U C T I O N B U I L D I N G C O S T

$ m

0.0

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Fig 3



$ m

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Fig 3



$ m

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

• Plan labour (number of operators, operator position etc) and simulate operating proceduresto ensure satisfactory operations

• Demonstrate movements to optimize layouts, eliminate cross-contamination and determinenumbers 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 also reduced operating cost,resulting from increased efficiency, improved labour utilisation and reduced inventory.

Early Estimates

In order 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 needs to appreciate the likely cost of the final manufacturing facility and have agood understanding of the size of the project in order to consider the sites where it may be located.In many cases the new process may be accommodated within an existing manufacturing facility ona campaign basis with little need for plant modification.

Larger and more complex processes may involve a significant revamp to an existing facility. Manypharmaceutical companies now have significant capacity throughout their worldwide operations andthe 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 natureof existing capacity. Specific process chemistry, more toxic compounds, specific physical forms andincreasing levels of GMP will also add to the requirement. Costs of new facilities or revamps areoften preset by early discussions where a rough cost is first mentioned. Often this number is based

on little more than a guesstimate yet it can often live with the project throughout. An experiencedcontractor can provide useful early guidance if given a significant database of information. Pastproject data when analysed and reported in a consistent manner provides relatively accurateinformation from a minimal amount of information. The graph in Fig 3 illustrates one of the manytypes of correlations that are available. In this example, for a primary API batch manufacturingfacility, the overall reactor capacity is the prime factor plotted against total installed cost of thefacility.



0

0.02

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0.08

0.1

0.12

0.14

Relationship Between Process Footprint and Reactor Capacity

Increasing scale

P r o c e s s f o o t p r i n t / r e a

c t o r l i t r e

P i l o t p l a n t s

L a u n c h f a c i l i t i e s

M a n u f -

a c t u r i n g

M a n u f -

a c t u r i n g

Fig 4

0

0.02

0.04

0.06

0.08

0.1

0.12

0.14

Relationship Between Process Footprint and Reactor Capacity

Increasing scale

P r o c e s s f o o t p r i n t / r e a

c t o r l i t r e

P i l o t p l a n t s

L a u n c h f a c i l i t i e s

M a n u f -

a c t u r i n g

M a n u f -

a c t u r i n g

Fig 4

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

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

Establishing the Concept and Fixing the Scope

Pharmaceutical plant design is often heavily influenced by the user. It is unusual for a client to makeuse of repeat designs, instead requiring their own bespoke design solutions to their ownrequirements. For example, a comparison of a variety of API pharmaceutical pilot plants finds allmanner of different plant arrangements and detail for what are essentially the same processequipment configurations. In time this approach will no doubt diminish as clients become more andmore focused on minimising overall project costs and time to build.

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

For the moment however bespoke design is still an important factor in determining and fixing theuser requirement and therefore the scope of the project. Engineering contractors generally have akey role at this stage of the process development in undertaking the conceptual study. At the earlystage of a project it is essential that a common understanding of the project is appreciated by allparties. 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



VALUE OFSAVING

RELATIVE COST / RISK TO CHANGE

TIME

Recognised relationship of cost and risk of change

Process Development

COST OFCHANGE

Fig 5

CONCEPT FRONT END DETAILED DESIGN

O P T I O N S / D E V E L O P M E N T

VALUE OFSAVING

RELATIVE COST / RISK TO CHANGE

TIME

Recognised relationship of cost and risk of change

Process Development

COST OFCHANGE

Fig 5

CONCEPT FRONT END DETAILED DESIGN

O P T I O N S / D E V E L O P M E N T

workshops must then be captured in an overall plant user requirement specification (URS) and plantdesign basis documents.

The initial concept study will focus on plant arrangements and aim to provide a workable andefficient layout that satisfies the needs of the user and provides sufficient detail to enable a costestimate to be developed. All of the high level philosophy documents should be drafted and agreedat this stage to provide a firm foundation for the ensuing engineering efforts. New ideas and costsaving options should be tabled at this early stage of the project; the value of cost saving ideasconsidered during the concept study can lead to major savings. The accepted approach is to openup all avenues of discussion during the concept design stage. Once the project moves into front endengineering the opportunities to rethink will become more and more limited as the momentum of theproject picks up. As indicated in the illustration there is an early project stage where the focus of theproject is opened up; beyond concept stage this focus closes down rapidly.

Some designers are now implementing a value management approach. A key feature of thisapproach is the definition of cost-saving objectives early in the project. These objectives arediscussed with the speciality engineers and the cost achievement is analysed with the designerswhen the project cost estimate is ready. The cost objectives should then be reached by a focused

design effort and not as a result of a ‘shock’ cost-cutting exercise.

Summary

• This first article has discussed some of the ways that external service providers add value tothe early stages of pharmaceutical facility planning and design: an independent and objectiveviewpoint

• methods and experience to analyse the process as a whole• modelling and simulation tools

• benchmarking data

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

Different techniques are required in later stages to deliver the project on time and within cost. Thesetechniques will be discussed in a second article.

planning and designing a pharmaceutical facility

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