The production of a certain product requires an appropriate technology, which is based on preliminary research and development. Technology in general stands for the method of a product’s manufacturing, including all the necessary work-processes and their parameters, which are required for the professional, reproducible and controlled – therefore guaranteed quality - production of the end product.
Pharmaceutical products as end products are produced by using basic raw materials (active pharmaceutical ingredients, excipients) according to a developed technology.
Fig. 3.1.
From basic materials to the end product
The physico-chemical properties of pharmaceutical substances (e.g. particle size, crystal form, habit, impurity, water content, stability and solubility) principally affect and determine the manufacturability, quality parameters and shelf life of the product.
Prudent and thorough, so-called preformulation studies are required for the detailed exploration, recognition and identification of different basic materials that paly an important role in the safe production and applicability in therapy of a preparation.
The change or alteration of any attribute of a basic substance may jeopardize the whole technological process and/or therapeutic effect, as the set of requirements of the product’s technological and biopharmaceutical testing can only be met by the technology whose parameters had been previously determined
The physico-chemical properties of raw materials (e.g. particle size, crystal form, habit, impurity, water content, stability and solubility) are fundamental in determining manufacturability, quality parameters and shelf-life of the product. Careful and thorough, so called pre-formulation studies are required to explore, recognize and determine the parameters of different substances in detail. These studies provide safe manufacturability and therapeutical applicability of the product. Any change occurring or applied to any parameter of a raw material may jeopardize the whole technological process and/or the therapeutic effect, as the requirement framework of the product’s technological and biopharmaceutical testing can only be met by the technology whose parameters had been previously determined.
Therefore, identical quality parameters of the basic substances in manufactured batches are an important condition of the reproducibility of quality parameters. Any variation may result in a review and recalibration of the whole system of operation parameters in order to maintain quality.
A product’s technology is attained through the technological process, making manufacturing of the product possible. Technological processes typically involve
stages, operations, their execution mode, procedures and the control of these through operation parameters.
Pharmaceutical technological processes generally belong to multi-step technological processes. Manufacturing processes can also be divided into process stages (e.g. preparation, composition, shape forming), during which several, different pharmaceutical technological operations are applied (e.g. measurement, sieving, granulation, compaction).
Essential steps of different technological processes are termed unit operations. From a unit operation aspect the process of pharmaceutical preparation and manufacturing can be divided into different technological operations and procedures. Pre-planned, reproducible and safe application of these is required to produce the preparation in appropriate quality and quantity every time.
Fig. 2 illustrates the system of relations in the pharmaceutical technological process, stage, operations and procedures in a generalized format. The entire process is under constant quality control: from raw materials on, through parameters of manufacturing, up to the end product.
Chapter 3: Operations and processes in pharmaceutical technology
Fig. 3.2.
System of relations in a pharmaceutical technological process
The discipline dealing with this is called the discipline of unit operations, created and its foundations laid in the early 20th century, when technological development and the increasing demand for quality necessitated it. According to the fundamental thesis of unit operations the wide range of operations involves relatively few basic operations (e.g. mixing, extracting, drying). Different operations and their implementation modes can be characterized and controlled according to the physical principles underlying each procedure.
For example the operation of mixing can be carried out manually (e.g. glass rod, pestle) or mechanically, for example by magnetic stirrer; a high-speed, high-shear force mixing device or planetary mixing method, capable of processing highly viscous media.
General technology and pharmaceutical technology, as well as the disciplines of general and applied unit operations (e.g. pharmaceutical unit operations) are closely interconnected, mutually enriching each other with experience, research results and scientific findings.
Fig. 3.3.
Connections of technology and unit operations
Unit operation can be considered as abstracted technology, as it is aimed at exploring the essence of operations, singling out typical and determinative parameters, finding correlations and setting up objective (mathematical) models, without regard to the actual individual technological solution, machinery or equipment. This describes the relationship between technology and unit operation well.
The individual operations are usually placed in a planned technological row. Their perfect harmonization and synchronization is one of the most important criteria of the quality of the end product. Therefore at the stage of developing the technology, the mutual relationship and interrelation of different operations and procedures has to be determined as well as possibility of their co-regulation. Similarly, unit operations of pharmaceutical technology usually connect in a consecutive, although concurrent, parallel applications may also occur.
Manufacturing products in different dosage forms requires various different technological units, devices, equipment, knowledge of their process- and operation unit parameters, as well as that of applicable materials, appropriate experience, skills and practice. This complex body of knowledge is also capable of advancing the technology
Chapter 3: Operations and processes in pharmaceutical technology
As the capacity of devices and equipment determines the producible volume in a given unit of time (batch size) the intended product volume must be taken into account in the planning phase. Besides the designated dosage form and the amount of substances, the physico-chemical properties of the employed materials and material systems is also an important aspect in the configuration of the technological processes.
As far as possible, the applied technology should fulfil the following requirements:
simple
transparent
easy to control
controlled by a small set of parameters
requires a low number of processes
safe (reproducibility, reliability)
cost effective (optimum use of material and energy)
generates as little as possible by-product
environment-friendly
Considering the method of execution, unit operations can be the following types:
1) batch operations, in which the steps of the operation are carried out sepa-rately, apart both temporally and spatially
2) continuous operations, in which different steps are carried out within the same apparatus and
3) mixed operations, in which some steps are carried out in batches and oth-ers continuously.
In spite of the many advantages of continuous operations, batch operations have retained importance, being applied in the production of small batches.
Continuous operations are important primarily in large-scale manufacturing, producing large batches, as it can be a cost effective solution due to its productivity.
Unit operations can also be grouped by their characteristic features:
1) operations of material (component) transfer (e.g. water demineralization using ion exchanger resin, dissolution, drying, crystallisation, wetting, granulation, fluidisation, coating),
2) operations of separation (separation or extraction of a component:
distillation, extraction, filtering, decantation, centrifugation, drying, membrane filtering, reverse osmosis, dialysis),
3) operations of integration (merging of components: blending, dissolution, mixing, manufacture of ointments and suppositories, granulation, direct compression of tablets)
4) operations of heat transfer (caloric operations: heating, cooling, concentrating by evaporation, rectifying, drying, fluidisation),
5) mechanical operations (e.g. milling, sieving, granulation, compaction) 6) hydrodynamic operations (e.g. mixing of liquids, liquid transfer,
centrifugation, fluidisation, decantation, filtering)
Some operations may belong to more than one group of unit operations, since more than one operation may occur concurrently, as in the case of mixing: blending, dissolution, fluidising, emulsification, heat transfer, milling and homogenisation).
Operations of material transfer are often considered operations of diffusion, if these processes are controlled by the laws of diffusion.
The purpose of material transfer operations may be:
1) extraction of valuable components (e.g. extraction, distillation)
2) removal of unwanted components (e.g. removing humidity by drying) 3) introduction of components into a medium (e.g. dissolution)
4) exchange of components (e.g. water demineralisation by ion-exchanging resin)
Operations of material transfer can be:
a) equilibrium-stage operations (e.g. distillation, rectification, absorption, extraction, adsorption, drying and crystallisation),
b) non-equilibrium-stage operations (e.g. membrane filtering, reverse osmosis, dialysis and electrodialysis)
During the transport of components in operations of material transfer the constituents of the system
a) flow in the same phase, or
b) flow from one phase to another, changing the quantitative proportions, i.e.
the concentrations of the components.
Caloric operations are determined by differences in temperature. They can be explained and controlled by the laws of thermodynamics. Note that the operation of drying belonging to this group can also be classified as an operation of material transfer, diffusion (water molecules escaping through pores by diffusion and crossing the solid-gas interface).
Mechanical operations usually need mechanical force (e.g. impact, pressure, cutting) where the laws of solid mechanics are relevant. These operations are mostly used in pre-treatment, but depending on the manufacturing process they may be applied both in compositional operations and the preparation of intermediate- and end products (milling, compaction) Mechanical separating operations are also possible, such as sieving.
The characteristic parameter in hydrodynamic operations, based on the rules of hydrodynamics, is the energy of flowing liquids and gases.
In view of material- and heat transfer different kinds of operations have significant differences. There are several groups of operations according to the direction of the transfer:
1) parallel flow, 2) counterflow, 3) cross-flow,
4) vortex-flow operations.
Unit operations can be divided according to the participant phases: 1) vapour-liquid (e.g. distillation, rectification)
2) gas-liquid (e.g. absorption, desorption) 3) liquid-liquid (e.g. extraction)
4) liquid-solid (e.g. extraction, adsorption, ion-exchange) 5) solid-liquid (e.g. wetting, drying)
6) liquid-solid (e.g. dialysis, membrane filtering) 7) solid-solid (e.g. compaction) phase operations.
Chapter 3: Operations and processes in pharmaceutical technology
Unit operations of pharmaceutical technology can be divided into three main groups according to the purpose of the working process:
1) basic operations, effecting the production of the dosage form only indirectly (e.g. mixing, heat transmission, drying, fluidisation),
2) shaping operations, directly serving the production of the dosage form (e.g. preparation of solutions, suppository moulding, granulation, capsule filling, tablet compression),
3) packaging operations, playing no role in the production of the dosage form, serving the identification, dosing and protection of the product (e.g.
blistering, boxing).
It is characteristic of pharmaceutical technology that each group of products, each dosage form (e.g. solution, ointment, tablet) and different preparations of the same dosage form require specialised manufacturing technologies. Certain products thus may require both common and special technological directions.
For example, it is a general practice to introduce components of a preparation in ascending order of their weight. However, in various cases this practice is ignored.
Foul-smelling substances are usually added last to the other components, regardless of their weight.
In case of preparations containing active pharmaceutical ingredients (API) applied in small dose (e.g. hormones, atropine, quinine, ergotamine), to achieve most accurate measurement of the required active ingredient and homogeneity, dilutions may be employed, prepared in advance by applying inert excipients. Manufacturing such preparations, the homogenous distribution of the active ingredient during granulation can be achieved by dissolving the active ingredient in the granulation liquid, processing the solution in a high-shear granulator or by spraying the solution of the active ingredient on the fluidized layer.
Previously applied dilution can also be used in compacting dangerous and explosive substances (e.g. nitro-glycerine). Homogeneous distribution and absorption of nitro-glycerine from transdermal patches can also be ensured by application of dilution (e.g. preparing 10% dilution with lactose).
Material systems containing coloured substances, in case of tablets ’inner’ and
’outer’ phases are granulated together (unlike general practice), as inhomogeneous distribution of the coloured substance would make the surface of the tablet spotted (e.g.
in case of compacting yellow riboflavin, thiamine, nystatin, cliochinol, carotenoids ranging yellow to red depending on composition or black activated carbon).
Among several other alternatives maintaining suspension of active ingredients or excipients, preventing precipitation or re-crystallisation of suspended particles during storage, maintaining redispersibility can be included here.
Maintaining the physical, chemical and biological stability of the product, including the API and the excipients, requires specific intervention.
Adequate solutions have to be found to prevent incompatibilities, to protect APIs from the damaging effects of gastric juice (e.g. when supplementing enzymes active in the small intestine) or to protect the human body from irritative APIs (as with gastric irritative APIs).
According to the requirements of therapeutic application and based on the pharmacokinetic and biopharmaceutical parameters, the exact location of API release and the parameters of dissolution (e.g. rate, duration, repetition) have to be individually controlled in new generations of products.
Applied technology always refers to the manufacture of a particular product.
In addition to the general requirements of manufacturing and quality control, technological specification takes into consideration special technological and biopharmaceutical aspects, including the preparation’s particular therapeutic purpose, the characteristics of the substances needed in the formulation of the active ingredient and the dosage form, required unit operations and processes, technological parameters of applied equipment, the entire scope of technological parameters – essentially, the particular method of preparation or manufacture.
To establish an up-to-date framework of pharmaceutical technology, it is important to emphasize the significance of raw materials, intermediate and end products and their correlations. Certain stages may be determinative, as their purpose is to contribute to the production of a pharmaceutical preparation of appropriate quality (indirectly) or intermediate products (e.g. granulates) of appropriate quality (directly) which are required for the production of this preparation.
Pharmaceutical technology is not simply a collection of knowledge of materials, equipment, process- and operation unit parameters, technological processes and quality management systems. It also considers – from planning to implementation, from raw materials to end product - therapeutic purpose and possibilities, pharmacological attributes, dosage and the system of relations between the preparation and the living organism.
Thus, especially in the past decades, a biopharmaceutical and therapeutical approach has been an integral part of pharmaceutics and pharmaceutical technology.
This outlook allows the development of conscious, planned and biologically compatible drug delivery systems, capable of fulfilling therapeutic requirements perfectly, exploring new fields of employment, enabling, enhancing, widening and perfecting drug therapy.
Temporally and spatially controlled new generation drug delivery systems (e.g.
chronotherapeutic preparations, self-regulating systems) are conceived in this theoretical and practical framework, enabling pharmaceutical technology to adopt further technological opportunities (e.g. nanotechnology, development of biotechnological drugs) and use them in therapy in the best possible ways.
Questions
1) What is the difference between operations and procedures?
2) What are the main, general requirements for applied technology?
3) What are the main classes of pharmaceutical technological operations?
4) How can operations of material transfer be classified?
5) How can pharmaceutical technological operations be classified according to the direction of flow?
6) What are caloric operations?
7) What are mechanical operations?
8) What are hydrodynamic operations?
Chapter 3: Operations and processes in pharmaceutical technology
References
W.,H., Walker, W.,K., Lewis, W.,K., McAdams: The principles of Chemical engineer-ing McGraw-Hill, New York, 1923.
artensen J.,T.: Theory of Pharmaceutical systems,Academic Press, New York, and Lon-don, 1972.
Dévay A. and Rácz I.: Examination of parameters determining particle size of sulfa-methoxazol microcapsules prepared by a new melt-dispersion method. Die Pharmaceu-tische Industrie, 46.1.101-103.1984.
Paul Heinz List: Arzneiformenlehre, Wissenschafliche Verlagsgesellschaft mbH, Stuttgart, 1985.
Liebermann H. A., Rieger M. M., Banker G.S.: Pharmaceutical Dosage Forms, Marcel Dekker, INC 2001.
Sarfaraz K. N.: Handbook of Pharmaceutical Manufacturing Formulations, CRC Press, London, New York. 2004.
McCabe W. L., Smith J. C.: Unit Operations of Chemical Engineering, Mc Graw Hill.Companies Inc., 2005.
Dévay A., Mayer K., Pál Sz., Antal I.: Investigation on drug dissolution and particle characteristics of pellets related to manufacturing process variables of high-shear granu-lation. Journal of Biochemical and Biophysical Methods, 69. 197-205.2006
Swarbrick J.: Encyclopedia of Pharmaceutical Technology, Informa Healtcare, 2007.
Aulton M.,E.: The Design and Manufacture of Medicines, Elsevier, New York, 2007.
Recommended websites
http://www.stat.yale.edu/Courses/1997-98/101/expdes.htm http://www.nzifst.org.nz/unitoperations/