Tài liệu Pharmaceutical Coating Technology (Part 10) pdf

10 Automation of coating processes Graham C.Cole SUMMARY Current Good Manufacturing Practice cGMP and the demands of the regulatory authorities world-wide requires greater care in the de

10 Automation of coating processes

Graham C.Cole SUMMARY

Current Good Manufacturing Practice (cGMP) and the demands of the regulatory authorities world-wide requires greater care in the design of manufacturing facilities, the selection of materials used in their construction, their layout, the equipment used in the preparation of tablets to be coated and the coating operation It is claimed that robotic systems will eventually take over all processing tasks! (Kanig & Rudic, 1986) This chapter will discuss automation concepts and suggestions based on cGMP (DHSS, 1983) in two areas:

An examination of Fig 7.1 (Chapter 7) shows the general requirement, and this chapter will describe how automation of this process can be achieved

10.1 INTRODUCTION

Since 1970 the explosion in the development of the microprocessor, the programmable controller and personal computers has provided tools to make substantial productivity improvements in manufacturing systems Many of the major pharmaceutical products in the oral solid dosage field are now produced using automated plants Merck’s ALDOMET manufacturing facility is well known and a

well-documented example (Lumsden, 1982; Fig 10.1) This process uses fluidized bed coating columns Figs 10.2 and 10.3 show schemes that uses both side-vented and conventional pans

• the design and layout of the building

• the control and transfer of materials between the various unit operations

Fig 10.1 ALDOMET manufacturing and coating process (MSD)

Fig 10.2 Feed system to automated side-vented coating pan (In Figs 10.2 and 10.3 —IBC:

Intermediate Bulk Container; AHU: Air Handling Unit; PMCS: Process Monitoring Control System; ELECT: Electricity; ph: Phase; C/A: Compressed Air; DCE: Dust Control Equipment)

The purpose here is to consider some of the ideas for automated coating systems that are incorporated into these plants, and to look at what has been achieved with products that are not produced in large volumes and, therefore, require a more

Fig 10.3 Automated feed system to standard coating pan

flexible approach The key driving forces towards providing better utilization of assets are:

It has been suggested that, in any productivity increase over the next decade, almost 60% will be provided by new and existing technology, 25% will be provided by capital and 13% by labour

management (Morley, 1984)

All of these pressures are dependent on control It is the control of the process, inventory, information flow, materials handling and the utilization of plant which is the essential part of automation

Generally, to do this efficiently requires the use of a microprocessor or computer Depending on the complexity of the operation, the number of parameters to be recorded and the degree of control required, there are a number of systems that can be used

• the rising cost of labour relative to productivity increases

• the high cost of energy and raw materials

• poor material-handling facilities

• the high cost of quality control

• inefficient use of manufacturing equipment

• short runs and a variable product mix

10.2 SYSTEMS

For the application of computer control to the coating process, some of the possible alternatives

available are highlighted here There are three main possibilities:

Each system is briefly described with points to consider when evaluating each of them and finally suggestions and conclusions on the final choice It is not an exhaustive list but more a discussion to assist in making the basic decisions

10.2.1 Data acquisition system

Fig 10.4 shows the layout of a data acquisition system These are normally small devices for low levels

of inputs only, but some have limited computing power They can also be used to provide printouts of the information gathered, similar to that described in Chapter 6 They do not provide any plant control and have only limited processing of information capacity Some can be linked to high-powered

computers which would store data or manipulate it, depending on the degree of automation required The field inputs have to be cabled back to a control location such as a control room and the system interface requires safety protection

Advantages:

Disadvantages:

Fig 10.4 Data acquisition system

1 A data acquisition system;

2 A distributed control system;

3 A centralized computer system

• Small and cheap

• No control provided

• Limited data processing

10.1.2 Distributed control system

Fig 10.5 illustrates the layout of a distributed control system In a distributed system not only are the hardware items geographically distributed, but the functions of processing, power and software are also distributed

Fig 10.5 Distributed control system

• Limited number of inputs

• No data storage

• Long lengths of field cabling required

• No local operator interface

Each hardware item performs a specific task and information is passed between the various hardware items using a dual data highway This dual highway provides good security for communications

The field devices, such as the input, output and control devices, must be protected by suitable housing and safety equipment for use in a hazardous area, particularly if flammable solvents are used in the coating process

Computer type functions are distributed throughout the process area using smaller microprocessor devices It can support local operator control devices located in the plant area providing these are

adequately protected

This system can provide process control for continuous variables such as atomizing air pressure and tablet-bed temperature and batch or sequence control It can be linked to other devices such as an

existing in-house computer

Advantages:

Disadvantages:

10.2.3 Centralized control system

Fig 10.6 shows the layout of a centralized computer control system This is very similar to the

distributed control system It can perform all the same functions, but they are centralized within a

computer system The computer would normally be the process control manufacturer’s standard

Advantages:

Disadvantages:

• Batch, sequence operations and continuous control is available

• Data logging and data storage are available

• Calculations on the stored data can be performed

• Logs and reports can be generated

• Local operator interfaces can be provided

• Batch and sequence control can store and use many different recipes and values, and the system can be used to optimize process control

• System is easily expandable and very flexible

• Short field cable lengths

• High security of control as all functions are distributed

• System more suitable for plants with greater than 500 loops

• High cost due to its large capacity

• Local plant equipment must be protected in safe enclosures

• Same as distributed system

• System size tends to be intermediate between the systems illustrated in Figs 10.4 and 10.5

• Long lengths of field cabling required

• System operation dependent on one device (the computer) thus a redundancy of a back-up

computer may be required to increase reliability

Fig 10.6 Centralized computer system

Ideally the type of system required for a coating plant should have the following capability:

• Data logging and process control of various parameters, temperature; spray rates

• Batch control is required with various recipes and sequences

• Optimization of batch control parameters

• Flexibility to change the process, size of batches, product, etc

• Local operator interface in hazardous area

• Interface to field devices suitably protected against hazardous area (intrinsically safe circuits, etc.)

• Operator control/display within the control room via VDU/keyboard/printer devices

• Calculations and optimization of sampled and/or measured variables for analysis

Either the centralized or the distributed control system would be suitable for a film-coating facility, depending on the number of coating pans which, in turn, is related to the number of variables to be measured or recorded

A number of additional options are also possible:

In general, however, the centralized system is preferable to the distributed system for the following reasons:

A typical centralized control room is shown in Fig 10.7

Most process control and data logging manufacturers use their own computers and their software structure may not be comparable with the in-house computer software However, the necessary interface can be provided, but this is always difficult and should be avoided if possible

10.3 INSTRUMENTATION

Examples of the instruments necessary for automation were examined in Chapter 6 Here the

instrumentation will not only control the process but will assist in moving materials from one unit operation to the next A further example is shown in Fig 10.8

10.4 FACILITY DESIGN AND EQUIPMENT REQUIREMENTS

There are many different types of tablets that can be coated, ranging from a cosmetically coated tablet to those that use the osmotic pump principle to release the drug Examples were illustrated in Fig 7.3 (Chapter 7)

In the development and implementation of any automated tablet-coating process there are a number

of objectives that must be addressed:

• Printouts and logs required

• System size relatively small (150 loops approximately)

• A dual processor computer to provide back-up security for control and data storage

• Links to an in-house computer can be accommodated if a separate system is used This data can

be passed to the in-house system for processing or display if required

• Inventory control could be added

• In a potentially hazardous plant, it may be worth considering a separate emergency shutdown system for increased safety

• It is smaller and cheaper

• System input/output interface is simpler while the distributed system requires special housings

• It allows the possibility to use an existing computer

1 What types of product are to be handled?

(a) Are they highly potent?

Fig 10.7 Centralized control room

Current Good Manufacturing Practice suggests there are two overriding considerations that take precedence These are:

A five-year forecast of requirements will be needed as there may be new coated-tablet products coming through from Research and Development and some older products may be declining in volume These factors should be assessed in the design

(b) Can they cause allergic reactions in the operators?

(c) Are they mutagenic?

(i) total containment of the product within a closed system;

(ii) providing a barrier between the product and the operator, i.e total protection

2 Are these products beta-lactams, e.g penicillin? If this is the case, then a separate manufacturing facility must be designed

3 What quantities and mix of products are required? There may be relatively small quantities of a number of products required rather than large quantities of individual products In one case, flexibility of the operation is the main objective requiring a multiplexity of services, whereas a single dedicated production line can save on materials handling, personnel, and special

conditions (protection from light and oxygen)

Fig 10.8 Schematic of an instrumented and computer-controlled coating pan

of a facility, the refurbishment of an existing operation or in selection of new equipment for

development and production purposes

10.5 PROCESS CONCEPT

To design the facility requires an understanding of the overall tablet-coating process The building and building services provide the envelope around the process and the process operation must be performed

in areas designed to conform to cGMP It will also need a validation programme

For any tablet-coating operation there are four essential requirements:

A flow diagram should be developed, as shown in Fig 11.2 (Chapter 11) All or some of these operations take place whether in a laboratory or on a production scale For efficient and accurate

operations the following stages must be assessed:

1 a supply of tablet cores;

2 a supply of coating materials;

3 the process equipment;

4 a building to house the equipment, raw materials and finished product

10.5.1 Warehousing

In all companies, the size of the inventory is critical to the efficient operation of any plant More and more companies are employing Just-in-Time (JIT) concepts to minimize stock levels and ensure that First In First Out (FIFO) principles apply A typical flow diagram is shown in Fig 10.9 In addition, storage space must be available for raw materials and finished stock The simplest way of handling all these requirements is by installing a computer-controlled materials management system This records incoming goods, allocates location, and notifies internal departments of the arrival of these goods The status of the material can be controlled using the computer and with limited personnel access the Quality Control Department can provide means of quarantining the materials until they are passed for

production use or sale

10.5.2 Dispensary

A schematic example is shown in Fig 10.10 The size and equipment required will depend on the scale

of the operation and the nature of the materials being dispensed

All balances will be selected on the basis of their sensitivity and range of weights required For

example:

In some cases a floor balance may be installed for larger quantities up to 200 kg It should be

remembered that the cost of balances increases with their sensitivity These balances will need to be located in cubicles in the dispensary, so that there is no danger of cross-contamination and different products can be weighed out simultaneously An area should be provided for the short-term storage requirements of materials used in large quantities and an adjacent area should be provided for materials used in small quantities, i.e colours and surfactants

Each cubicle should be equipped with laminar air flow to ensure maximum protection for the

operator, minimize dust contamination of the surrounding area and cross-contamination

Each dispensary should be equipped with suitable dust masks, air supplied suits, safety showers and eye wash stations, to ensure the maximum safe handling of the materials Carefully designed HVAC (heating, ventilating and air conditioning) and dust extraction systems are major requirements

10.5.3 Process

The next stage in the material-handling procedure is to transfer the batch of raw

1 storage of raw materials—warehousing

2 raw material dispensing

3 process operations

4 packaging

Balance 1 0.010 kg (sensitivity 0.01 mg)

Balance 2 10.0 kg (sensitivity 500 mg)

Balance 3 50.0 kg (sensitivity 1.0 g)

Fig 10.9 Flow diagram for storage of materials

Fig 10.10 Schematic diagram for an automated pharmaceutical dispensary

materials to the production area for preparation of the powder mix ready for tablet core manufacture and raw materials for the preparation of the coating

The layout of the process area will depend on the material-handling concept If pneumatic transfer is used for an automatic transfer operation, then the IBC can be linked to the blender/granulator/dryer/mill and the blender to the tablet machine or an intermediate bulk container (IBC; see Fig 10.11)

Figs 10.2 and 10.3 show an automated feed and receiving system for tablet-coating equipment Units are linked to a process monitoring and control system (PMCS) For an automated system, coated tablets can be stored in an IBC until released to packaging; the IBC can be positioned above the packaging unit and the coated tablets are then gravity fed into the blister packer or securitainer filling unit

The objective in all these operations should be to minimize manual transfer and reduce exposure and contact of the product to the operator and the environment

10.5.4 Layout and design of facility

A typical layout is shown in Fig 10.12 Process areas require high-quality finishes to maintain cGMP standards Traditionally pharmaceutical secondary manufacturing facilities have been designed on the basis of single rooms or cubicles for each stage of the manufacturing process Transfer of materials has been accomplished using a large drum or mobile trolley Today the industry is investing in more

automatic transfer systems for material handling in an attempt to reduce costs and improve yields This results in a more integrated manufacturing unit Computer integrated manufacturing (CIM) is becoming more widely used in the