How do you make all the different medicines?

(Bradley A. G. Hanna)

 

 

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.

Active drugs

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.

 

Examples

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.

Legal Requirements

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 Tests

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.

For all dose forms, tests include appearance, identification/content/concentration of the active ingredient

Other tests may include:

Liquids

Colour/flavour

pH

Tablets

Rate of disintegration/dissolution in water

Hardness

Friability (toughness)

Suppositories

Melting point

Smoothness

Hardness

Creams and Lotions

pH

Consistency

Liquid Injections

Formation of particulates

pH change

Packaging integrity

Volume

Stability

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:

Liquids

Change of active concentration

Increase in impurities

Changes of colour/flavour

Changes in pH

Evaporation from containers

Formation of sediment or crystallisation

Tablets/Capsules

Change of active concentration

Increase in impurities

Rate of disintegration/dissolution in water

Changes of colour and appearance

Suppositories

Change of active concentration

Increase in impurities

Change in appearance

Creams and Lotions

Change of active ingredient concentration

Increase in impurities

pH

Evaporation and “skinning”

Change of colour

Liquid Injections

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.


Further Information

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


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