' Pharmaceutical microbiology is the part of industrial microbiology that is responsible for creating medications. All parenteral drugs, including many oral drugs, must go through rigorous microbiological testing in order to validate certain compounds by United States Pharmacopeia regulations.
Sterile pharmaceutical products Introduction
Sterility is defined as “freedom from all viable life forms.”
Certain forms of drug administration and other pharmaceutical products, such as dressings and sutures, must be sterile in order to avoid the possibility of nosocomial (hospital-induced) infection arising from their usage. This applies particularly to medicines which are administered parenterally but also to any material or instrument likely to contact broken skin or internal organs. While inoculation of human pathogenic bacteria, fungi or viruses poses the most obvious danger to the patient, it should also be realized that microorganisms usually regarded as non-pathogenic which inadvertently gain access to body cavities in sufficiently large numbers can also result in a severe, often fatal, infection. Consequently, injections, ophthalmic preparations, irrigation fluids, dialysis solutions, sutures and ligatures, implants, certain surgical dressings, as well as instruments necessary for their use or administration, must be presented for use in a sterile condition and in such a way that they remain sterile throughout the period of use. Principles of the methods employed to sterilize pharmaceutical products are autoclaving and filtration as suitable methods applicable to aqueous liquids, and dry heat for nonaqueous and dry solid preparations. The choice is determined largely by the ability of the formulation and container to withstand the physical stresses applied by moist heat treatment. The use of ionizing radiation or ethylene oxide is also appropriate in specific instances. The primary considerations relate to the ability of active ingredients to withstand the applied stress and of the container to maintain the product in a sterile condition until use. It should be realized that all products intended to be sterilized must be rendered and kept thoroughly clean and therefore of low microbial content prior to sterilization. Thus, the process itself is not overtaxed and is generally well within safety limits to guarantee sterility with minimal stress applied to the product. Because of the clinical consequences (such as granuloma in the lung) of injecting solid particles into the bloodstream, the numbers of particles present in injections and in other solutions used in body cavities must be restricted. The British Pharmacopoeia (1993) set limits for injections based on operation of a particle-detecting apparatus. The European Pharmacopoeia (1997) describes a microscope method for particulate contamination of injections and intravenous infusions, i.e. extraneous, mobile, undissolved particles, other than bubbles, unintentionally present in the solutions. The test method provides a qualitative method for identifying and detecting the characteristics of such particles together with an indication of their possible origin. It might then be possible to develop means of avoiding such contamination. Limits are given in the United States Pharmacopoeia (1995) for large-volume injections, using this method.
InjectionsDesign philosophy
Any injectable product must be designed and produced to the highest possible pharmaceutical standards. Not only must the product have the minimum possible levels of particles and pyrogenic substances, but also the formulation and packaging must maintain product integrity throughout the production processes, the shelf-life and during administration. The formulation must be such as to ensure that the product remains physically and chemically stable over the designated shelf-life. To achieve this, excipients such as buffers and antioxidants may be required to ensure chemical stability, and solubilizers, such as propylene glycol or polysorbates, may be necessary for drugs with poor aqueous solubility to maintain the drug in solution. The packaging must prevent water, excipient or drug loss during sterilization and storage and, in addition, retain microbiological integrity. Axiomatically, ingress of microorganisms must be prevented. The packaging must not contribute any significant amounts of extractable chemicals to the contents, for example vulcanizing agents from rubber or plasticizers from polyvinyl chloride (PVC) infusion containers. Most injections are formulated as aqueous solutions, with Water for Injections BP as the vehicle. The formulation of injections depends upon several factors, namely the aqueous solubility of the active ingredient, the dose to be employed, thermal stability of the solution, the route of injection and whether the product is to be prepared as a multidose one (i.e. with a dose or doses removed on different occasions) or in a singledose form (as the term suggests, only one dose is contained in the injection). Nowadays, most injections are prepared as single-dose forms and this is mandatory for certain routes, e.g. spinal injections such as the intrathecal route and large-volume intravenous infusions. Multidose injections may require the inclusion of a suitable Sterile pharmaceutical products preservative to prevent contamination following the removal of a dose on different occasions. Single-dose injections are usually packed in glass ampoules containing 1, 2 or 5 ml of product; to ensure removal of the correct volume by syringe, it is necessary to add an appropriate overage to an ampoule. Thus, a 1-ml ampoule will actually contain 1.1 ml of product, with 2.15 ml in a 2-ml ampoule. Some types of injections must be made iso-osmotic with blood serum. This applies particularly to large-volume intravenous infusions if at all possible; hypotonic solutions cause lysis of red blood corpuscles and thus must not be used for this purpose. Conversely, hypertonic solutions can be employed: these induce shrinkage, but not lysis, of red cells which recover their shape later. Intraspinal injections must also be isotonic, and to reduce pain at the site of injection so should intramuscular and subcutaneous injections. Adjustment to isotonicity can be determined by the following methods. 1 Depression of freezing-point, which depends on the number of dissolved particles present in solution. A useful equation is given by: W=0-52~a b in which W is the percentage (w/v) of adjusting substance, a the freezing-point of unadjusted solution and b the depression of the freezing-point of water by 1 % w/v of adjusting substance. 2 Sodium chloride equivalent, which is produced by dividing the value for the depression of freezing-point produced by a solution of the substance by the corresponding value of a solution of sodium chloride of the same strength.
2.2 Intravenous infusionsThese consist of large-volume injections or drips (500 ml or more) that are infused at various rates (e.g. 50-500 ml h_1) into the venous system; they are sterilized in an autoclave.
The most commonly used infusions are isotonic sodium chloride and glucose. These are used to maintain fluid and electrolyte balance, forreplacement of extracellular body fluids (e.g. after surgery or during prolonged periods of fluid loss), as a supplementary energy source (1 litre of 5% w/v glucose = 714kJ) and as a vehicle for drugs. Such solutions are prepared using freshly distilled water as a vehicle under rigidly controlled conditions to minimize pyrogen and particle content, and filtered to remove remaining particles immediately before distribution to the final clean container. Other important examples are blood and blood products, which are collected and processed in sterile containers, and plasma substitutes, for example dextrans and degraded gelatin. Dextrans, glucose polymers consisting essentially of (1 -^6) a-links, are produced as a result of the biochemical activities of certain bacteria of the genus Leuconostoc, e.g. L. mesenteroides. A small range of intravenous infusions, e.g. those containing amino acids or chlormethiazole, are prepared in glass containers. These are sealed with a rubber closure held on by an aluminium screw cap or crimp-on ring. The rubber should be nonfragmenting, not release soluble extractives, and be sufficiently soft and pliable to seal around the giving set needle inserted immediately prior to use. Although bottles are sterilized by autoclaving, it is still possible for the infusion in glass bottles to become contaminated with microorganisms before use. For instance, during the final part of the autoclave process, bottles may be spray-cooled with water to hasten the cooling process and therefore reduce the total autoclaving time. However, due to the poor fit between bottle lip and rubber plug (a skirted insert type is used) it is possible for the spray-cooling water to spread by capillary movement between bottle thread and screw cap and even enter the bottle contents. This process is encouraged if the bottle contains a vacuum as a consequence of rubber seal failure during heating-up. It should also be remembered that autoclaving leads to considerable heat and pressure stresses on the container. Failure may result from any imperfection in the bottle or plug.
Microbes may also gain access to the contents of bottles during storage if hair-line cracks (a result of bad handling and rough treatment) are present, through which fluid may seep outwards and microorganisms inwards to contaminate the fluid. Finally, contamination may occur during use due to poor aseptic techniques when setting up the infusion, via an ineffective air inlet (allowing replacement of infused fluid with air) or when changing the giving set or bottle.Most infusions are now packed in plastic containers. The
Systemic toxicity
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