Microbiological contaminants pyrogens

Microbiological aspects of pharmaceuticals are of importance not only to sterile products but to all products, in that gross contamination should be avoided irrespective of how the product is used or administered. Although bacteria, moulds and yeasts constitute the major sources of contamination, pyrogens are also included under this heading. 

The pharmacopoeias deal with ingredient water of two types. Purified Water and Water for Injection. The principal difference in biological quality between the two types of water is that Water for Injection is specified to be pyrogen-free (less than 0.25 Eu of bacterial endotoxin per mL). Only water of Water for Injection quality may be used to dissolve, dilute, or compound parenteral products, because endotoxins may pass through 0.22 pm sterilizing filters. Control of bacterial endotoxins is achieved in the first instance through control of microbiological contamination. 

The manufacture of sterile products is subject to special requirements in order to minimise risks of microbiological contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance bears a particularly great importance, and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects must not be placed on any terminal process or finished product test. 

Because these manufacturing processes are susceptible to particulate, pyrogenic and microbiological contamination, the skill, training and attitudes of the personnel involved are critical. Operators should be skilled, disciplined and responsive to supervision. Supervisors should be diligent and dedicated. Managers should communicate goals and provide facilities and systems that preclude or minimise the risk of error. 

The microbiological contamination of products (bioburden) is minimal prior to sterilization. There is a working limit on contamination immediately before sterilization that is related to the efficiency of the method to be used and the risk of pyrogens. All solutions, in particular large-volume parenterals, are passed through a bacteria retentive filter, if possible immediately before the filling process. Where aqueous solutions are held in sealed vessels, any pressure-release outlets are protected, e.g., by hydrophobic microbial air filters. 

In the manufacture and filling of terminally sterilised parenteral veterinary medicines, particular attention should be given to the need to minimise microbiological contamination of the product before sterilisation. Pyrogen contamination (endotoxin level) should be controlled to the same limits as for human medicines. 

Microbiological contamination of raw materials can lead to a finished product that does not meet the requirements for microbiological purity and in addition a high endotoxin level can be found leading to a pyrogenic response after intravenous injection. 

Freedom from pyrogenic contamination and endotoxins Freedom from particulate matter Physical, chemical, and microbiological stability... 

These guidelines do not replace any of the sections in Parts One and Two but stress specific points for the manufacture of sterile preparations to minimize the risks of microbiological, particulate, and pyrogen contamination. 

The starting materials and primary packaging materials must be contaminated as little as possible by microorganisms or pyrogens. If necessary, the specifications must contain standards for their microbiological purity. 

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