A medicine dose form is the combination of various ingredients including the active drug, packaged in suitable containers with descriptive labelling and outer packaging text. Depending on many factors, medicines are provided as oral liquids, tablets, capsules, lozenges, creams and ointments, suppositories and injections. All injections are required to be sterile and other preparations are required to have minimal bioburden (microbial) levels.
The manufacture of medicine dose form is various, complex and multi staged.
An active drug, contained in the dose form, can be prepared by a variety of means.
Historically active drugs were derived from plants. Such extraction procedures continue to this day and vary from simple water and alcoholic procedures through to using the extraction as a first step, followed by further synthesis and purification.
These days extracts can be chemically isolated and characterised but it often proves cheaper and more reliable to synthesis the active by chemical means. Synthesis paths of newer drugs are likely to be optimised in the early period of the drug development program. The new generation of drugs includes proteins, where cells are grown in fermentation tanks, extracted and then purified.
In all the above cases active drugs must be characterised and purified within limits, acceptable to Regulatory Authorities.
Medicine Manufacture
A schematic for the manufacture of medicines is:
Excipients are materials added to the active ingredient to enable the final dose form to be made.
Dose types and (some) ingredients are:
Liquids - (eg cough mixtures)
Ingredients - Active ingredient, water, flavour, colour, buffers.
Customarily, pre-weighed ingredients are added to water in a mixing tank and stirred until fully dissolved. The solution is then filtered.
Tablets
Ingredients Active ingredient, starch for binding, lactose, talc, magnesium stearate.
Tablets are made by mixing powders, often wetting them and redrying to form a granule. The granule is then fed into a tabletting machine, which compresses tablets using a punch and die mechanism. The tabletting process is very similar to a coin minting machine.
Suppositories
Active ingredient, waxes.
The waxes are melted and active ingredient added, all with constant stirring. The solution is then allowed to solidify. A direct analogy is lipstick manufacture - a wax combination without active ingredient but with colourings.
Ointments
Active ingredient, oils and waxes.
The oils and waxes are mixed and active ingredient added, all with constant stirring
Creams and Lotions
Active ingredient water, oils, emulsifiers, perfumes.
Creams and lotions are emulsions. Emulsions are an intimate mixture of very fine particles of either oils or water, surrounded by a continuous phase of the other. The stability of the emulsion is maintained by means of surfactants. Usually the active ingredient is dissolved in water, with oils and surfactants heated and added, all with constant high speed stirring and homogenising.
The manufacturing processes and testing for medicines are among the most regulated of all. In Australia human drug manufacture is licensed by the Therapeutic Goods Administration and Veterinary Drugs by National Regulatory Authority. The legal requirements of manufacture are set out in a Code of Good Manufacturing Practice, issued by the Australian Therapeutic Goods administration. Manufacturers are licensed by TGA to manufacture in accordance with the Code.
Quality Assurance systems and test regimens must be in place to ensure that medicines are made reliably and reproducibly, ie that the contents of the container match the label claim. Quality Control evaluation is performed on materials prior to blending to confirm identification, purity and impurities for medicine ingredients and packaging components are as per specifications. The level of active ingredients and other physical and chemical parameters are tested at the completion of the dose form manufacture. As appropriate, microbiological testing is also performed.
Other tests may include:
Colour/flavour
pH
Rate of disintegration/dissolution in water
Hardness
Friability (toughness)
Melting point
Smoothness
Hardness
pH
Consistency
Formation of particulates
pH change
Packaging integrity
Volume
Major criteria of medicine R & D and ongoing production are to ensure that a medicine is stable during the shelf life period. By (temperature) accelerated and real time storage, the shelf life of the medicine is established.
A stability evaluation program is an ongoing requirement for commercial medicines.
Parameters evaluated for stability evaluation include:
Change of active concentration
Increase in impurities
Changes of colour/flavour
Changes in pH
Evaporation from containers
Formation of sediment or crystallisation
Change of active concentration
Increase in impurities
Rate of disintegration/dissolution in water
Changes of colour and appearance
Change of active concentration
Increase in impurities
Change in appearance
Change of active ingredient concentration
Increase in impurities
pH
Evaporation and skinning
Change of colour
Change of active ingredient concentration
Increase in impurities
Formation of particulates
pH change
Packaging integrity to maintain sterility
Analytical instrumental techniques used include high performance liquid chromatography (HPLC), infra red and ultraviolet spectroscopy, coulometric water measurement, pH meters gas liquid chromatography.
A variety of non-instrumental techniques and wet chemistry methods are used also.
Book Reference: Lachman et al The Theory and Practice of Industrial Pharmacy.
Websites TGA
US Food and Drug Administration (FDA) http://www.fda.gov/default.htm
European Medicines Evaluation Agency
International Council for Harmonisation http://www.pharmweb.net/pwmirror/pw9/ifpma/ich1.html