Pharmaceutical Production Facilities

Design and Applications

Graham Cole

• Publisher: CRC Press
• Year: 1998
• ISBN:
  9781135743550
• Edition: 2
• Topic: Medizin
• Subtopic: Pharmakologie

Pharmaceutical Production Facilities: Design and Applications considers the concepts and constraints that have to be considered in the design of small, medium and large scale production plants. The layout, along with the flow of materials and personnel through facilities are considered with reference to ensuring compliance with current good manufac

1
Introduction

‘When I use a word’, Humpty Dumpty said, in rather a scornful tone, ‘it means just what I choose it to mean—neither more nor less’.

The pharmaceutical industry has undergone fundamental changes and restructuring since the Second World War. The substantial and rapid progress that has been made is based on research and development of new compounds with outstanding rewards for those companies that have developed ‘winners’. Products like ALDOMET, TAGAMET, and ZANTAC have rewarded those companies with sales running into thousands of millions of dollars. The costs in research and development alone (safety testing programmes, clinical trials, manufacture and marketing costs) to market one of these products is probably in the region of between 150–200 million US dollars. One result of these costs has been the mergers and restructuring that have taken place between companies: Glaxo and The Wellcome Trust; SmithKline Beckman and Beecham; Squibb and Bristol-Myers; Rhone Poulenc-Rorer; Roussel and Hoechst; Astra and Fisons; and Boots Pharmaceutical Division and BASF, to name but a few. These will continue as the top companies strive to maintain their market share and the Japanese attempt to increase their presence outside of Japan in the world market. These mergers have been designed to minimize spiralling costs in research and development, rationalize the research base by concentrating on specific therapeutic classes, and maximizing productivity in drugs manufacture.

The rewards in the pharmaceutical industry have been the result of developing unique chemotherapeutic products, and traditionally these products were manufactured by using a collection of different types of facility, a variety of construction materials, and equipment generally borrowed from other industries. For example the planetary mixer originated in the bakery. Probably the tablet machine with systems to regulate its operation is the best example of innovation in the industry. Computer integrated manufacture has taken a lot longer to develop for plants designed to produce sophisticated modern dosage forms.

However, with the impact of regulatory authorities such as the Medicines Control Agency and the US Food and Drug Administration, and the rationalization of manufacturing to supply various markets, this position is changing. There is no manual or textbook which details all the design requirements for a modern pharmaceutical plant; there is, however, a collection of documents such as The Orange Guide, The Code of Federal Regulations, and various guidelines whose impact necessitates that task forces formed within manufacturing companies require a much higher and broader level of ability and skills. Computer controlled processes are becoming the norm with plants like the Merck facilities in Europe and the USA, the Pharmachemie Plant in Holland, and many others.

There should be a comprehensive system so designed, documented, implemented and controlled and so furnished with personnel, equipment, and other resources as to provide assurance that products will be consistently of a quality appropriate to their intended use. The attainment of this quality objective requires involvement and commitment of all concerned at all stages (The Orange Guide 1983).

The pharmaceutical industry is unique in the procedures and methods of manufacture that it uses to ensure the integrity of the products it produces. These are essentially achieved by three main functions: current Good Manufacturing Practice (cGMP), Quality Assurance (QA), and Quality Control (QC). This book will be concerned with the design and operation of secondary manufacturing facilities and the involvement of these three main functional areas will be assessed in terms of the overall strategy of operating a plant of this type. The manufacturing side of the industry can be divided into two parts, and the basis that will be used here considers primary manufacture as the production of the bulk drug as a fine chemical, using a variety of routes such as organic synthetic chemistry, fermentation, or biotechnology. Secondary manufacture manipulates the drug form, using various excipients to produce a packaged dosage form.

The word ‘design’ can be interpreted to mean different things to different people. For the purpose of this book it will be defined as the preparation of drawing a plan or preliminary sketch in the process of using an invention, and it follows then that certain essential criteria must be fed into the design to ensure that it can be confirmed. It would be expected that with the volume of papers and articles currently published on the design of buildings specifically for the pharmaceutical industry, the use of sophisticated modelling of expert systems, optimization of process systems, and project engineering concepts that it would be possible to conceptually design and build a secondary manufacturing pharmaceutical facility without great difficulty. This is still true as long as the project remains simple and all parts could be visualized; potential problems could be analysed rapidly and an alternative solution found.

In the past most new facilities were designed as a building into which items of equipment were positioned after its completion. Manufacturing operations were considered to be a series of unit operations that could be arranged in almost any format. Dispensing, powder blending, granulation, tablet compressing, and tablet coating were generally looked upon as separate operations and could be located in almost any part of the building. There was no integration of the manufacturing system. This led to extensive development of equipment to provide self-contained operations—‘Islands of Automation’. For example table presses were produced with control and monitoring systems which reduced the operator’s role and enabled the operator to run more than one item of equipment.

However, a number of factors combined to concentrate companies’ corporate minds on the manufacturing operations (the poor but essential relation). A comparison between the amount of money spent on research blocks, offices, and marketing facilities shows where the companies believe their priorities lie. However, without comparable investment in production, designed to prevent product mixup, the recall of a product from the market can easily cost millions of dollars.

These factors can be divided into two classes, those associated with the regulatory authorities (‘what we are compelled to do we will’) and the technology push development. Fluid bed drying replaced tray drying with dramatic improvements in productivity. The replacement of starch paste using pre-gelatinized starch and cold water, simplified the development of automated granulation equipment, such as the high speed high shear mixer/granulator. Microwave drying appears to be adding a further dimension to this technique.

The advent of the oil crisis forced many companies to examine their manufacturing facility design policy to ensure a more efficient use of resources. The formation of the Common Market required rationalization of products manufacture, and 1992 provided more stimulus to the location of plants for the manufacture of single products, or groups of similar products. This has created the opportunity to design systems that are more efficient and provide the economy of scale. The use of automated handling systems, automated guided vehicles (AGVs) and automated warehouses have become the realities of life and not just ideas. The added advantage of rationalization is the allocation of valuable raw materials, stragetic planning, and the development of worldwide inventory control.

New products that are being developed by research based companies have high potency, low volume, and, together with the sustained release preparations which demand higher levels of technology in their manufacture, require smaller but more complex processes.

However, facilities are now becoming increasingly complex; what was once a labour intensive industry is becoming more capital intensive as companies build new facilities using computer controlled manufacturing processes, and large multinational companies are planning and controlling their raw materials and products on a worldwide basis.

Four main areas of design will be considered:

• process
• facility layout and design
• site selection
• the impact of environmental constraints.

The process will be examined from the reception of the raw material (chemical or packaging component) through to the warehousing of the packed product.

In the past the manufacturing facility was very localized. Management organized the flow of materials and products to a number of markets. They were concerned only with the profitability of their plant and were largely insulated from problems in other parts of the world. If they were in profit then the parent company tended to ‘leave well alone’. The infrastructure of the subsidiary was not geared to develop a worldwide strategy in terms of manufacturing philosophy and control of raw materials.

All the largest multinationals operate a central engineering group which has overall responsibility for facilities both at home and overseas, and associated with this group is a team responsible for the process and manufacturing operation.

Most of these centralized departments have attempted to impose:

• standardization of formulations
• standardization of manufacturing equipment.

This is a good theory and has had a limited amount of success. It collapses where countries have limited amounts of foreign exchange, impose import controls, generally impose limitations and conditions on the building of new facilities, introduction of new products into their market, transfer of profits outside the country, and the use of local raw materials. Compromises have to be made where there is a policy implementing a worldwide formulation for manufacture requiring the same equipment and similar environmental conditions.

The industry also suffers from the problems of small volumes (batches) using expensive ingredients and in latter years the attention of regulatory authorities like the MCA, the European Medicines Evaluation Agency (EMEA), and the FDA. The development of equipment has far outstripped the system used to integrate this equipment into continuous batch operation. Merck in the early 1970s developed an automated dedicated batch process which handled the raw material from the point at which it entered the system and ended where the dosage form was ready for packaging.

Although the material handling concept was partly the same, SmithKline & French (SKF), now SmithKline Beecham (SKB) developed along a different route. It did not have the high volume of dosages that Merck used to justify its dedicated plants (i.e. 1000 M/annum/single product). The SKF plants at Alcala in Spain and Milan in Italy used what has become known as the Lhoest Principle in an attempt to overcome the disadvantages of the dedicated plant and provide for the small number of dosages manufactured/annum and a large number of products. This added a large degree of flexibility to the operation. However, the Milan plant was manufacturing fewer than 20 products and one of these accounted for greater than 75% of the total production. In both types of plant the objective was to use totally enclosed systems for transfer of materials and product and standardization of the containers. In solid dosage manufacture dust has always been the main problem in attempting to eliminate cross-contamination especially in the transfer operation. The Pharmachemie Plant in Holland was developed on a similar mode but handles between 150 and 200 products.

What is important to recognize is that the pharmaceutical industry has some special requirements that need to be interpreted correctly. To do this requires an understanding of the jargon. Some examples are:

• (cGMP) current Good Manufacturing Practices
• Validation
• FDA (Food & Drug Administration)
• IDIP (Intensified Drug Inspection Programme)

which fall so lightly from those professionals employed in the industry.

This book is an attempt to harness some of these ideas together with concepts such as Validation to help provide a route for both scientists and engineers through these minefields.

My thanks are due to my wife for her indulgence in providing the secretarial expertise and my colleagues both past and present to whom I owe a debt of gratitude.

We should also not forget Lewis Carroll whose lines in Alice’s Adventures in Wonderland and Through the Looking-Glass and What Alice Found There are still as appropriate today as they were in 1865 when first published.

‘Let the jury consider their verdict’ the King said, for about the twentieth time that day.

‘No. No’ said the Queen, ‘Sentence first—verdict afterwards’.

2
Project Design and Management

‘I should see the garden far better’, said Alice to herself, ‘if I could get to the top of that hill: and here’s a path that leads straight to it—at least, no, it doesn’t do that—’

Design includes all the aspects of process engineering, building, plant design, environmental services and validation of any new facility, modification or refurbishment; and there are typically a number of attributes and sequential stages of a project that have to be studied.

• Feasibility
• Process engineering
  • Personnel flow
  • Process utilities
• Material flow
  • Layout
• Construction and validation.

During the feasibility study, the attributes that are critical to the success of the project and its operation mean that it has to be viable in terms of being practicable. It must be able to be operated satisfactorily in terms of producing a consistent product within the defined specifications and produce the required quantities and range of products. Its reliability must be such that it can be operated during its expected life cycle within the defined operating conditions and costs.

All projects must be constrained within strict financial limits based on the return on investment (ROI), and an expenditure ceiling must be applied on the operating costs of the plant. If any of these are allowed to slip then the company can be disadvantaged when selling in a competitive market place.

An important aspect of the project to consider at this stage is under what regulations will the plant or new facility have to operate. In particular does the MCA, EMEA, or FDA have a role to play in the design? Does the plant require validation (well thought out, well structured, well documented common sense)? Validation has tended to concentrate on secondary manufacturing systems, but it is now being increasingly extended to primary manufacturing facilities.

Feasibility

The life cycle of any project follows a regular pattern, and what is feasible and what is not must be closely examined. All instigators of projects and those who become assigned to the project team tend to look at what is available in the market place and what technically is available, and this generally produces a concept that far exceeds the financial resources of the company.

There are many commercial pressures to proceed to contract at the earliest possible date, but the utmost care is needed at this point. Up front decisions have a major impact on the long term viability of a project, and the design stage should be fully worked out before placing contracts.

In comparison, the detailed design is unlikely to affect the overall project viability, but will contribute to the ease or difficulty in commissioning, validating, operating, and maintaining the plant.

A production plant has many separate parts, and it is impossible to set about putting those parts together without a comprehensive project definition or brief. Most corporations will grant approval for a project on outline information, and so the project manager must develop the brief with his project team.

Market Requirements

What is the product definition?

How many units are required per shift/day/week/year?

What are the range of product sizes/contents/material?

What are the foreseen future market trends?

A spreadsheet needs to be generated to define these essentials.

Regulatory Requirements

Which regulatory authorities will approve the product and inspect the operations?

What are the anticipated standards required for the design, validation, and documentation of the process and its operative environment?

Financial Constraints

What is return on investment (ROI) expectation?

What are the capital constraints/limits?

What is the foreseen market price for the product/profit margins/maximum acceptable cost of production (COP)?

Timing

When is the product expected on the market and at what volume?

Define a realistic time frame for the project (neither pessimistic nor optimistic) and rigidly plan and control the project against this schedule.

Conceptual Location

Each project is likely to have had at least a conceptual location when submitted for management approval (i.e. ...