3. Processes and Technologies 3.1 Introduction 3.2. Active Pharmaceutical Ingredient (API) manufacture (Primary Manufacture) 3.2.1 Biological Processes 3.2.2. Organic chemical synthesis 3.2.3. Extraction from a Biological source 3.3 Formulated product (FP) manufacture (Secondary Manufacture). 3.3.1. Compounding 3.3.2. Granulation 3.3.3. Drying 3.3.4. Milling 3.3.5. Blending 3.3.6. Tabletting 3.3.7. Tablet Coating 3.3.8. Capsules 3.3.9. Non-Oral Formulations 3.3.10. Packaging 3.3.11. Cleaning and maintenance activities 3.4 Sterile production 3.4.1 Clean Rooms 3.4.2. Sterilisation Hazards 3.4.3. Production Hazards 3.5 Research and Development:
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3. Processes and Technologies
3.1 Introduction
3.2. Active Pharmaceutical Ingredient (API) manufacture (Primary Manufacture)
3.4 Sterile production3.4.1 Clean Rooms3.4.2. Sterilisation Hazards3.4.3. Production Hazards
3.5 Research and Development:
3. Processes and Technologies
3.1 Introduction
The processes which are employed during the manufacture of Pharmaceutical
products can be broadly classified under the environments in which they are carried
out, namely:
Active Pharmaceutical Ingredient (API) manufacture (Primary Manufacture) –
Large scale manufacture of raw materials produced in high concentrations
Formulated product (FP) manufacture (Secondary Manufacture). – Large
scale manufacture and packaging of products which contain the required dose
of Active Pharmaceutical Ingredient.
Research and Development (R&D) – This is characterised by small scale
laboratory type activities which are varied and involve a large number of
materials.
Some of the processes which are undertaken are common to all of the stages of
manufacture; however other processes are integral to particular stages. Figure 3.1
below broadly summarises the type of processes undertaken within the different
environments.
Figure 3.1.1 Manufacturing process in the pharmaceutical industrySource Adrian Hirst – Adapted from ILO Encyclopaedia of Occupational Health and Safety
3.2. Active Pharmaceutical Ingredient (API) manufacture (Primary Manufacture)
The manufacture of Active Pharmaceutical Ingredients (APIs) typically involves the
manufacturer of medium sized quantities of material such as tens to hundreds of
kilograms of solid material and thousands of litres of liquids. The basic production of bulk API products can employ three different types of process:
Biological Processes - These predominantly involve fermentation where
microorganisms are cultured in a substrate to produce useful substances e.g.
Antibiotics, steroids and vitamins. However other biological processes are
used such as the production of vaccines and genetically modified organisms.
Organic chemical synthesis – The use of chemical reactions to manufacture
specific molecules.
Extraction from a Biological source – The use of a solvent or other
extractive mechanism to release substances from plants or other natural
materials. e.g. digoxin, and opiates.
3.2.1. Biological ProcessesFermentation is the most commonly used biological process. This involves the use of
specifically selected micro-organisms and microbiological technologies to produce a
chemical product. The process is typically undertaken on a batch basis and involves
three stages:
Inoculum and seed preparation - Inoculum preparation involves preparing a
culture of the specific micro-organism being used. Typically spores of the micro-
organism are activated with water and selected nutrients in warm conditions. The
micro-organisms may be grown on agar plates, test tubes or flasks.
Fermentation - The cultured cells are transferred to a small vessel (seed tank) for
further growth. After suitable growth has been achieved the cells are transferred to a
larger fermentation tank. The tank is supplied with nutrients and heat and is normally
agitated and or aerated. After the biochemical reactions are complete, the
fermentation broth is filtered to remove the micro-organisms.
Product recovery - Depending upon the drug being manufactured the API may be
present in the filtrate or within the cells which have been filtered out. The recovery of
the material may involve various steps such as solvent extraction, precipitation ion
exchange and absorption. A variety of solvents can be used to extract and
synthesize materials, in recent years there has been an increase focus on the
environmental fate of waste from the use of solvents. Table 3.2.1 gives a list of some
commonly used solvents, and there environmental preference. A schematic diagram
of a fermentation process is given in figure 3.2.1.
Figure 3.2.1 Diagram of a fermentation process
Source: Adrian Hirst – Adapted from ILO Encyclopaedia of Occupational Health and Safety
Solvent Used in Chemical Synthesis
Used in Fermention
Used in Extraction from
a biological source
Environmental Preference
AlcoholsEthanol Yes Yes Yes PreferredButanol Yes Yes Yes PreferredPropanol Yes No Yes PreferredMethanol Yes Yes Yes PreferredPropylene Glycol Yes No No UsableKetonesAcetone Yes Yes Yes PreferredMethyl Ethyl Keteone
Yes Yes Yes Preferred
Methy Isobutyl Ketone
Yes Yes Yes Preferred
Halogenated SolventsDichloromethane Yes No Yes Undesirable
Dichloroethane Yes No Yes UndesirableChloroform Yes Yes Yes UndesirableCarbon Tetrachloride
How the API is formulated into the finished pharmaceutical product is critical for both
the manufacturing route and the patient.
It can have a major impact on “patient compliance”, ie. whether the patient takes the
medication reliably as prescribed. Some routes of administration and some types of
formulation are more acceptable to patients, but they have to be compatible with the
metabolism and absorption of the drug. For example, patients generally prefer oral
doses to injections, but if the API breaks down in the stomach, oral administration
may not be effective. The key considerations are usually known as
pharmacokinetics (concerning the processes of uptake, distribution, and
elimination of drugs).
pharmacodynamics (concerning e.g. the physiological effects of drugs)
Formulation also determines the efficiency with which the drug is absorbed by the
patient. Improving the formulation can therefore reduce the amount of API that is
needed, which can in turn reduce the risk of occupational exposure as less API will
be handled in the workplace.
The pharmaceutical delivery route selection, whether it be oral in the form of solid,
semi-solid, or liquid, or non-oral, is determined by a number of physiochemical
characteristics of the API, target dose and target patients.
Formulated (or Finished) Product Manufacture involves the incorporation of the
Active Pharmaceutical ingredient with other materials to produce a product with the
required dose which can then be administered to the patient. The other,
pharmacologically inactive, materials are called excipients. They may include
binders, fillers, flavouring and bulking agents, preservatives and antioxidants. These
ingredients may be dried, milled, blended, granulated and compressed in order to
produce the required characteristics of the product.
Processes for formulation are driven by the product form. Typical products are:
Oral Formulations Tablets. A tablet is usually a compressed preparation that typically contains:
‒ 5-10% of the drug (active substance);
‒ 80% of fillers, disintegrants, lubricants, glidants, and binders; and
‒ 10% of compounds which ensure easy disintegration, disaggregation, and
dissolution of the tablet in the stomach or the intestine.
In addition to traditional formulations, many drugs are now available in
‒ fast-dissolving versions, for quick therapeutic action
‒ modified-release versions, for slow release over an extended period.
Capsules. A capsule is a gelatinous envelope enclosing the active substance.
Capsules can be designed to remain intact for some hours after ingestion in order
to delay absorption. They may also contain a mixture of slow- and fast-release
particles to produce rapid and sustained absorption in the same dose.
Targeted forms for specific patient populations (eg. chewable, effervescent)
Technology Enabling Dosage Forms (e.g. Melt extrusion, Spray drying…)
Other Formulations
Gas propellant Inhalers, dry powder inhalers Vials (or phials), prefilled syringes, ampoules Eye drops and nasal sprays Liquids such as cough mixtures and medicines for children and the elderly
who cannot swallow solid dose forms Creams, ointments
Figure 3.3.1 gives an outline of the various processes which may be required.
Figure 3.3.1 Pharmaceutical manufacturing of dosage-form products Source: Adrian Hirst adapted from ILO Enclcylopedia of Occupational Safety and Health
FP manufacture typically involves larger volumes with tens of kilograms of solid
material and processes are conducted at relatively high speed. The most common
form of Formulated Product is that of a tablet.
3.3.1. Compounding
Compounding involves the mixing of different ingredients in order to produce a bulk
material from which individual doses can subsequently be manufactured.
Compounding may involve the mixing of solids and liquids to produce solutions,
suspensions, syrups, ointments or pastes.
3.3.2. Granulation Dry and wet solids are processed to form granules of a desired size and morphology.
The process essentially causes individual constituents within the compounded
product to stick together. The design of granulation equipment varies but the
equipment essentially involves the physical mixing of powders together with liquids
and possibly heat and dry air or steam. Granulators are typically fully enclosed.
Wet granulation is a process of using a liquid binder to lightly agglomerate the
powder mixture. The amount of liquid has to be properly controlled, as over-wetting
will cause the granules to be too hard and under-wetting will cause them to be too
soft and friable. ; figure 3.3.2 shows a schematic diagram of a typical wet granulator.
Dry granulation processes create granules by light compaction of the powder blend
under low pressures. The compacts so-formed are broken up gently to produce
granules (agglomerates). This process is often used when the product to be
granulated is sensitive to moisture and heat. Dry granulation can be conducted on a
tablet press using slugging tooling or on a roll press called a roller compactor
Figure 3.3.2. Schematic diagram of a typical wet granulatorSource: Adrian Hirst
3.3.3. Drying Solids which are wet with either water or solvents need to be dried at various stages
of the manufacturing process. Dyers can be of different designs but generally involve
the use of mild heating, vacuum and forced airflow to evaporate water/solvent.
Tray dryers require the sold material to be spread out a thin layer on a metal
tray. A series of trays is then placed within a chamber where heat and or
vacuum are introduced.
Fluid Bed dryers agitate the wet solids with hot air inside an enclosure. The
agitation of the powder together with the heat allows the solids to be dried
quickly without significant handling.
Spray dryers dry material by spraying a fine mist into a hot-air chamber, the
material then falls to the bottom as dry powder.
Freeze Dryers dry a frozen product in a vacuum. The vacuum allows the ice to turn
directly into vapour without first passing through the water stage.
Rotary dryers involve rotating the material inside a drum or tumbler into which
hot air is fed.
Picture of a fluid bed dryerSource: pharma-machines.com
Freeze Dryer Source: GEA
Tray Dryer Source: Chitra machines
Figures 3.3.3 Photographs of different dryers
3.3.4. Milling Dry solids are often milled to change their particle size and morphology such as
when trying to produce free-flowing powders. Mills have different designs but
essentially involve applying energy to materials to break them up. This energy might
be applied by an impellor, hammers, rotating balls or rollers.
3.3.5. Blending Dry solids are blended to produce homogeneous mixtures. Blending normally
involves tumbling powders within an enclosed container although the use of
specialist mixers fitted with blades appropriate for powders can also be used. Figure
3.3.4 shows a V blender facility where different materials are transferred in by