Modelo de Temkin

And she took a ribbon out of her pocket, marked in inches, and began measuring the ground, and sticking little pegs in here and there.

‘At the end of two yards…’

The basic criterion from which any plant is designed is an understanding of the process, the equipment, material flow, and people flow through the facility. There are three documents that need to be produced at the early stage of the development of the facility. These are process flow diagrams (PFD) (Figure 4.1) and two additional documents which include engineering design criteria and information relating to plant operation and safety.

A process flow diagram is developed from direct knowledge of the project and partly from information supplied by the sales and marketing departments of the company requiring the new facility. The intent is to define the process philosophy and process design criteria to best meet the immediate and future requirements of the product. Their main purpose, as of any drawing, is to communicate information in a simple and explicit way, using unscaled drawings which describe the process. Sufficient detail must be presented on the PFD to give any experienced process engineer an adequate understanding of the process concepts, operating conditions, and equipment sizes, to permit a critical review of the process design with minimum reference to other documents, i.e. process description. Process diagrams and piping and instrumentation diagrams (P and IDs) (Figure 4.2) each have their own functions and should show only information that is relevant to their particular needs. Extraneous information such as piping, structural and mechanical notes should not be included unless essential to the proper performance of the process design. Instrument control and manual control valves which are necessary for the operation of the process are shown together with instrumentation essential to process control. Systems for providing services are not shown; however, the type of service, flow rates, temperatures, and pressures is noted at consumption rates corresponding to the material balance. Separate flow diagrams are preferred for each utility system, such as clean steam, purified water, compressed air, heating, ventilating and air conditioning (HVAC), and specialized gas systems. These are an integral part of the process. The diagrams show all items of equipment connected to the systems in continuous use and show consumption levels, capacity levels, and specifications for the requirements of the air and air flow volume. In addition the routes of disposal for the effluents are shown.

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data for any process stream. The extent of data is the minimum required for sizing the lines and the development of the P and IDs from the PFD.

In addition to the heat and material balances the working documents need to be developed from the PFDs to record the engineering operating and safety criteria of the plant design. These documents record the engineering design criteria and are maintained until the contract reaches the approved for design (AFD) stage. The second working document is the repository of all matters relating to plant operation

Figure 4.1 Product A: Requirements 650 million per annum. 1 g (1000 mg) direct compression core, film

coated tablet can use either an aqueous film coating suspension/solution or a solvent film coating suspension/solution. 600 mg active 400 mg excipient

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and safety and hence is maintained until an operating manual is issued. Both of these documents are prepared by adding the necessary information to those parts of the process flow diagrams. The purpose of the first working document (WD) is to define the maximum operating limits throughout the plant and ensure that these limits are applied consistently item by item. The WD initiates work on the process data sheets for the equipment and the P and ID (a typical P and ID (engineering line diagram-ELD) is shown in Figure 4.2).

The second working document describes the basic operating requirements which are to be incorporated into the plant design. The purpose of this document is to ensure that the interactive nature of the total plant is thought through carefully and established before downstream design work starts. This is particularly important on multi-unit plants. This document, therefore, describes the operating philosophy and indicates all the additional process lines and any associated control loops required, their functions and sizing basis.

For convenience, various flow sheets and process flow diagrams for the manufacture of various types of tablet are illustrated in the next few pages. These flow patterns give an indication of the materials and size of the equipment required at each unit operation. Also shown are material flow diagrams for a number of different building configurations. In these diagrams the basis for production purposes is a single 7 hour shift working; 5 days per week; 220 days per annum.

Figur

e 4.2

T

ypical P and ID (ELD) for part of a purified w

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Figure 4.3 Product A: Requirements 650 million per annum. Direct compressed core, film coated tablet

weighing 1.0 g

Legend

DCT: Direct compression tablet

CT: Compressed tablet

FCT: Film coated tablet

→: Process flow

IBC: Intermediate bulk container

Light grey, dark grey, black: These classifications represent various levels of clean- liness ranging from white for a sterile suite to black for unclassified.

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This information can be illustrated to provide additional data on batch sizes and equipment requirements (see Figure 4.3).

Batch size will depend upon the process.

For convenience, 500 kg will be used as a sub-batch, and 6 sub-batches will be consolidated in one day’s production, to give one batch of 3000 kg (3 tonnes) for analytical control purposes.

Storage capacity will depend upon the inventory control philosophy. Here, one week (5 days) of raw materials is used as the design basis.

Therefore, sufficient capacity to store 9000 kg of active and 6000 kg of excipient material in drums or bulk containers is required. Identification of individual batches

Figure 4.4 Product B: Requirements 300 million per annum. 200 mg FCT prepared using wet

granulation, can use either an aqueous film coating or a solvent film coating. 2 mg active, 198 mg excipients

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is essential. Bulk containers (IBCs) should be considered for the storage of the active material and the main excipients, and design of the IBC would be based on the size of the batch and the material characteristics. These IBCs could be used directly in the process or the material transferred into a bulk storage silo adjacent to the dispensary.

Alternatively, data required for a compressed film-coated tablet using wet granulation methods is shown in Figure 4.4. Figure 4.4 can be improved to give a

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spatial appreciation of how each unit operating links together and the areas that are required. This is shown in Figure 4.5.

In the following flow diagrams the following legend is used: black, dark grey, and light grey. White would be used to signify a sterile area but in the examples shown, it is not applicable. Black signifies the basic requirement which might be used for a GMP warehouse. Dark grey would be an increase in standard which might apply to a packaging area and light grey may be used in a solid dosage manufacture area to

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Figure 4.6 High rise tower using gravity to aid material flow

indicate an improvement in the finishes and quality of air that the HVAC is designed to provide.

In Figures 4.6 to 4.9 two diagrams are shown: the diagram is a schematic section through the building indicating process flow and the bottom diagram is a schematic footprint indicating the types of finishes that have to be considered for the various environmental requirements. These figures represent differing options for the flow of materials through various building arrangements.

The transfer of the product from coating to packaging can use a pneumatic transfer system, a conveyor, or an AGV/IBC bulk container for feeding the packaging line.

Option A (Figure 4.6)

This building has four upper floors and a ground floor designed to maximize the use of gravity in feeding powders and product starting in the dispensary and finishing in the packaging area.

Option B (Figure 4.7)

This is designed to maximize the use of pneumatic/vacuum transfer systems and is intended to be a totally enclosed dedicated system. There would be an

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option within the design to change the transfer system from each unit of equipment for each product to operate the plant on the campaign basis.

Figure 4.7 Three floor system using automated guided vehicles to aid material flow

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Option C (Figure 4.8)

This is the ‘Lhoest’ concept; the pneumatic transfer systems have been replaced by an AGV/IBC mechanical handling system.

Option D (Figure 4.9)

This is similar to option A with the exception that the process route has been so designed to minimize the product and people flow and use one warehouse for incoming raw materials and outgoing finished product.

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Figure 4.11 Tablet compressing

Figures 4.10 to 4.13 represent some examples of PFDs for tablet compressing, capsule filling and coating cubicles using an IBC as the vehicle for material transfer. The flow diagrams (Figures 4.1 and 4.4) shown for product A and product B illustrate a direct compression process and a wet granulation process, and are intended only to highlight some possible options. Figure 4.3 shows the mass flow of material and product through a facility. These have been developed by using company data and making a number of assumptions. These are:

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• The tablets can be compressed, coated, and packaged in a normal manufacturing environment controlled at 20°C±2°C and 50% RH±10% RH.

• The tablets are round and bi-convex (i.e. no shapes). They may be intagliated with a product number, symbol, logo, or break bar.

• Sugar coating is not required.

Figure 4.12 Film coating

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Additional documents that are very useful at the early stage of any project are room data sheets (Figure 4.15, pp. 44–45), equipment lists and equipment data sheets (Figure 4.14, p. 43).

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Pharmaceutical Process