Microbiological stability: what recommendations?

Pr I. Krämer Department of Pharmacy, University Medical Center, Johannes Gutenberg-University, Langenbeckstraße 1, 55131 Mainz, Germany

Microbiological stability of ready-to-administer (RTA) parenteral products means that sterility of the source products is retained during the aseptic preparation process and throughout the period of storage and use of the products. Viable microorganisms and/or endotoxins administered parenterally via contaminated preparations, may lead to nosocomial infections, SIRS/sepsis and increased mortality of patients. Deterrent examples of infections caused by contaminated ready-to-administer preparations emphasize the necessity of Good Preparation Practice (GPP) and intensive precautions to keep the products sterile.
The risk of primary microbial contamination is directly related to extrinsic factors (e.g. preparation process, clean room environment, staff qualification) and intrinsic factors of the preparations (e.g. nutrient content, pH, redox potential, water activity). Specific factors influencing microbiological instability are the complexity of the preparation, the growth potential of the preparation and the interval between preparation and administration. Manual handling, multiple additions of multiple components, mixing of large volumes and growth promoting qualities of the mixed components increase the risk of microbial contamination of the preparations. Closed system procedures in well-controlled environments and growth inhibiting properties decrease the risk of microbiological contamination and instability. Secondary contamination occurs during the period of storage, transport and usage of the preparations.

Microbiological quality and safety of the pharmacy preparations is to be insured by in-process controls (e.g. environmental monitoring), sterility tests and validation of the aseptic preparation process (e.g. media fills, viability tests of microorganisms). The validity of sterility tests of extemporaneously or in series/batch wise prepared RTA parenterals is constricted by the singularity of each preparation and time restraints. Definition of a batch, sampling plans and test methods are hardly to be transferred from the relevant monographs of the European Pharmacopoeia. In the case of patient individual preparations dummy solutions can be prepared simultaneously and tested for sterility. In the case of batch wise preparation a representative number of preparations can be sampled for sterility testing. According to the pharmacopoeia membrane filtration and direct transfer to an appropriate media are to be used as microbiological test methods. Suitability of the method has to be proven and incubation periods of 14 days are to be considered. Therefore alternative rapid microbiological methods like automated detection of CO2 in blood culture bottles are often used. This non-destructive method can be also used for microbiological stability tests. Corresponding to the antimicrobial effective tests of the pharmacopoeia, viability and growth of microorganisms in RTU preparations are investigated by adding a controlled inoculum of test organisms to a sample of a specified parenteral preparation. Results of these studies can be hardly transferred to similar parenteral preparations and cannot be used to define the in-use stability of preparations. However, the combined results of antimicrobial effectiveness tests, sterility tests, media fills, and environmental monitoring programs are useful for the validation of the preparation process in the individual pharmacy department and to define the expiration date of an individual preparation.

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