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transfer procedure to be extremely rigorous; following all NHS guidelines comparable to best practice in the pharmaceutical industry. Yet, despite this thorough process, media fill simulation samples were found to be contaminated with a number of different species of Bacillus (Figure 1). To identify the source of contamination, microbiological samples were obtained from different surfaces within GOSH’s controlled compounding environments and from the surfaces of items subjected to sporicidal transfer disinfection. No bacteria were recovered from the surface of large volume licensed medicinal products, confirming that risk of spore contamination was during media fill validation and not actual medicine compounding. Contamination was ultimately identified to solely originate from the TSB media bottle surfaces following storage in an uncontrolled environment. HOW DID THE CONTAMINATION OCCUR? Despite the use of sporicides, it is feasible that Bacillus spores on the TSB bottle surface and bung survived disinfection steps during transfer to the compounder. Spray and wipe steps reduce the risk of contamination as bottles are transferred to the compounder, but increased handling at each stage is also a risk. The contents of large volume TSB bottles are aseptically transferred during filling via the insertion of a sterile large bore spike pushed through the rubber septum in the cap of the bottle. This has a relatively large surface area compared to a needle used for transfer of smaller volumes. Therefore, any contaminants that have evaded disinfection, such as those under the edge of crimped bottle collars, may be disturbed and introduced into the bottle at this stage. COULD SPORE CONTAMINATION OCCUR IN ACTUAL COMPOUNDING? The recovery of Bacillus isolated on the surface of the TSB bottles and the lack of recovery from the outer surfaces of starting materials was linked to the different manufacturing controls of TSB versus licensed medicinal products. Large volume products used in aseptic compounding are licensed sterile pharmaceutical products. The bungs are sterilised prior to use, added and crimped in a Grade A environment reducing risk of spore contamination (Table 1). As contamination was only ever found during media fill simulations, rather than during actual drug compounding, this highlighted a potential risk to the sterile
REFERENCES:
Sterile / Aseptically Prepared Licensed Drugs products
Autoclaved TSB
Bungs / rubber septa sterilised via validated sterilisation before transfer to Grade A filling line
Bungs / rubber septa not processed prior to use
Bungs applied In Grade A environment
Bungs applied in uncontrolled environment (but usually Grade C)
Caps crimped in Grade A
Caps crimped in uncontrolled environment
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TSB Bottles stored in a cardboard box in an uncontrolled environment.
Table 1: Manufacturing controls of licensed drugs for compounding compared to bacteriological medium used for validation
environment rather than an immediate risk to patients. CORRECTING AND PREVENTING CONTAMINATION - CAPA Measures to minimise any risk of contamination of TSB media bottles because of the tabulated differences (Table 1) were identified: 1. Increase sporicidal dwell time to 20 minutes 2. Identify product that has been triple wrapped and irradiated, which we discuss below. The Royal Pharmaceutical Society and NHS Pharmaceutical Quality Assurance Committee has issued guidance recommending multiple layers of sterile packaging, thus reducing the need to disinfect items at each stage of transfer.9 As part of its CAPA measures GOSH sought an alternative microbiological media supplier to develop a way of ensuring the TSB units for aseptic process simulation validation were sterile, and Cherwell Laboratories were invited to collaborate with GOSH on this project. To remedy the situation, Cherwell developed a sterile, triple packaged Redipor media TSB product in line with the Royal Pharmaceutical Society recommendations. Following further studies, including stability, post-media fill and post-incubation growth promotion (fertility) testing, GOSH pharmacists found this product was easyto-use. Also, in line with CAPA it removed all risk of spore contamination of the medium prior to compounder validation, thereby eliminating false results and ultimately increasing workflow efficiency in the pharmacy unit.
1. Drug Topics. 2017. How the NECC Case Changed Compounding Pharmacy. 2. http://www.legislation.gov. uk/. 1968. Medicines Act 1968. 3. http://www.legislation.gov. uk/. 2012. The Human Medicines Regulations 2012. 4. Tara Culp-Ressler. 2012. Massachusetts Approves Tighter Regulations To Help Prevent Future Meningitis Outbreaks. 5. Congress.gov. 2014. H.R.3204 - Drug Quality and Security Act. 6. Public Health England. 2014. Bacillus cereus infections: 1 July 2014. Publication of the main findings from the PHE and MHRA investigation into the Bacillus cereus outbreak. 7. MHRA. 2015. MHRA Guidance for Specials manufacturers. 8. NHS Pharmaceutical Micro Protocols Group. 2015. Guidance for Aseptic Transfer Processes in the NHS: Addressing Sporicidal Issues. 9. Royal Pharmaceutical Society and the NHS Pharmaceutical Quality Assurance Committee. 2015. Quality assurance of aseptic preparation services (QAAPS).