It is well recognized that patient health can be seriously compromised by microbiological contamination of compounded medicines, particularly in the most vulnerable patients. A combination of inadequate facilities, unsanitary conditions and deficient cleanroom practices in countries lacking the necessary regulation, has led to numerous infection outbreaks from contaminated compounded medicines.
Even in well-regulated countries, some companies that fail to monitor and maintain good practice during the compounding process can still slip through the net.
For example, steroids for epidural delivery, manufactured at the New England Compounding Centre in 2012, were found to be contaminated with fungal spores leading to over 700 reported cases of meningitis and 64 deaths.
Statutory regs and disinfection measures to kill spores
To prevent such outbreaks, Good Manufacturing Practice (GMP) regulation is applied. In the UK, it has been applied for 49 years, following the introduction of the Medicines Act 1968, then the Human Medicines Regulations 2012. Compounding Pharmacies have no exemption. The ‘regulatory black hole in United States medicine compounding is now monitored and regulated by the Food and Drug Administration (FDA).
The trend towards universal standardization of compounding regulations is welcome but does not allow for complacency. Although stringent disinfection procedures were followed, Bacillus cereus contamination of intravenous total parenteral nutrition (TPN) resulted in 19 cases of septicemia and three deaths on a neonatal unit in England in 2014. Following an investigation by the Medicines and Healthcare products Regulatory Agency (MHRA), it was concluded that the contamination was introduced into the TPN supplies during manufacture, rather than via any of the raw materials.
The 2014 outbreak in England was described as an isolated incident, however, it highlighted the particular risk of contamination by resilient spores from the environment. Subsequent guidance from the MHRA included the use of sporicides in a two-stage spray and wipe the disinfection process during compounding. This guidance has been incorporated into a report by the NHS Pharmaceutical Micro Protocols Group — ‘Guidance for Aseptic Transfer Processes in the NHS: Addressing Sporicidal Issues’ — which recommends a two minute dwell time with sporicide.
Assessment of operator aseptic techniques
One of the standard procedures to maintain sterility during compounding is the assessment of operators’ ability to transfer liquids aseptically. Bacteriological medium, such as tryptic soy broth (TSB), replaces compounding medicines and the flow through the compounder is examined for microbial growth. Contamination events result in immediate cessation of compounding by the operator concerned, followed by retraining in aseptic liquid transfer. This is essential to maintain standards, providing the validation results are an accurate portrayal of competency.
Following a series of aseptic process simulation validation (compounder media fill simulation) failures from multiple operators at the UK’s Great Ormond Street Hospital (GOSH) pharmacy, it was deemed unrelated to operator competence. All operatives involved displayed excellent cleanroom techniques and practices. However, Bacillus species had been transferred to the Grade A environment in which compounding of parenteral nutrition (PN) is executed, despite strict adherence to the new NHS guidelines that address sporicidal issues. An investigation was conducted by GOSH to find the contamination source, evaluate the risk to asepsis of patient doses and identify appropriate corrective and preventative action (CAPA) measures to reduce the risk.
Identifying the cause
The study found GOSH’s media fill transfer procedure to be very rigorous from start to finish. All TSB bottles were received in cardboard cartons and held in an unclassified storeroom until required. Cardboard is known to be a potential reservoir of bacterial and fungal spores and, therefore, kept away from the pharmacy cleanroom facilities. Each bottle removed from the box was sprayed with 70% industrial methylated spirits (IMS) (2 minutes contact time), wiped, and placed in the transfer hatch to a Grade C cleanroom.
The bottles were sprayed and wiped again using a stabilized chlorine dioxide and quaternary ammonium compound sporicide. The hold time was increased to 20 minutes from the recommended 2 minutes minimum in NHS guidelines on using sporicides, which is comparable to practice in the pharmaceutical industry. The following transfer through another hatch into a Grade B cleanroom, the bottles were sprayed with 70% IMS and placed in laminar flow cabinets (LFC) or non-gassed isolators. However, despite this thorough process, media fill simulation samples were found to be contaminated.
A number of different species of Bacillus were identified by Matrix-Assisted Laser Desorption-Time of Flight (MALDI-TOF) mass spectrometry as the cause of media fill contamination. However, uninoculated test bottles of the same batch of TSB used for the validations were uncontaminated and the large bore spike, used to connect the medium to the compounder was supplied sterilized by ethylene oxide and securely packaged. This suggested environmental contamination was transferred into the bottle as the two were connected.
Finding the contamination source
To identify the source of contamination, microbiological samples were obtained from different surfaces within the Grade B environment with localized Grade A protection (LFC), from the Grade A environments and from the surfaces of items subjected to sporicidal transfer disinfection.
The sensitivity of the surface sampling, obtained using 55 mm diameter TSA-filled contact plates, was enhanced by smearing the surface of the agar over the majority of the surfaces being sampled. The TSB bottles were also sampled with contact plates. To ensure all surfaces of the bottle were sampled, the crimped collar was removed so that the part of the bung hidden by the collar could be accessed.
Bacillus species were only isolated from the surfaces of the large volume (500 ml) TSB bottles, transferred in for use in the aseptic process simulations, and from nowhere else in the Grade B room (housing three LFC). Speciation confirmed the same Bacillus species as those recovered in the media fill samples. No bacteria were recovered from other large volume bottles, containing licensed drug products, used as starting materials.
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 contamination risk during the transfer of bottles to the compounder, however, increased handling at each stage is also a risk.
The contents of the 500 ml TSB bottles are aseptically transferred during filling via the insertion of a 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 smaller volume transfers. Therefore, any contaminants evading disinfection, such as those under the edge of the collar, maybe disturbed and introduced into the bottle at this stage.
How to improve your contamination control?
Our XLTC TPN Enclosure eliminates all risks that are related to its position in the open hood as well as improving the overall usability of the machine. The Aseptic Enclosures TPN Compounding Isolator completely eliminates all risks from particulate air and touch contamination of the system, and strongly improves personnel safety by placing a barrier between the pharmacy technicians and the compounding process that is carried out by the TPN compounder. By having the machinery sitting in an isolator we are reducing the risks related to aseptic processing, eliminating the sources for touch contamination and improve the Uni-Directional First Air.
The Aseptic Enclosures XLTC TPN Compounding Isolator is a serious aseptic improvement to your parenteral nutrition preparations. It should be considered as a necessity in all future installs of such compounding equipment and made a mandatory upgrade for machines currently in operation.
To learn more about our XLTC Isolation series please contact our Pharmacy Project Team at 800.418.9289