Microbiologists Contribute to a Quality Culture

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Equipment and Processing Report

Equipment and Processing Report, Equipment and Processing Report-06-17-2015, Issue 8

Presenters at IVT's Microbiology Week discussed best practices and recent guidance publications for microbial control in sterile and non-sterile pharmaceutical processes.


Creating a quality culture is a worthwhile goal for any pharmaceutical company and is supported by FDA, which wants companies to aim for "right first time". Microbiologists can play a role by helping to prevent microbial contamination incidents, rather than just investigating them after they occur. By getting involved, the microbiologist can shift the focus from compliance to quality, noted Karen Ginsbury, founder and CEO of PCI Pharmaceutical Consulting Israel and chair of IVT's Microbiology Week, in the conference's opening remarks on June 2, 2015. The cost of non-compliance is high, added Ginsbury, pointing to some recent problems related to contamination and environmental monitoring practices called out in warning letters this year. Facility design, cleaning strategies, and using investigation findings to fix problems at the source, however, can prevent microbial growth and create quality in both sterile and non-sterile manufacturing.

Monitoring and then analyzing the resulting data can reveal problems in the making. "You may not have exceeded action levels, but if you find a discrepancy when you compare data in different production areas and compare these to historical data, you can take action anyway, such as running an extra cleaning cycle," urged Ginsbury. In the case of a contamination event, "You should 'reconstruct the crime scene' to find out what went wrong. A single root cause is seldom found, because there are often multiple contributing causes. You should fix these and then monitor further," she added.

Monitoring and preventing contamination in a non-sterile (i.e., controlled, non-classified) process, in which limited but controlled bioburden is allowed, is actually more difficult than in a sterile or aseptic process, in which no bioburden is allowed, because aseptic processes have more stringent controls, said Chris Knutsen, associate director of analytical and bioanalytical development at Bristol-Myers Squibb, in a presentation at the conference. Crucial areas for microbial control in non-sterile manufacturing include incoming materials (e.g., APIs and excipients), personnel, and water. "Standing water is a common source of contamination in non-sterile manufacturing," said Knutsen. "Water organisms grow easily and can form a biofilm that is difficult to clean. A common problem, for example, is hoses that are stored with water trapped in them."

New guidance documents
Operators of non-sterile processes now have more specific directions to follow, since in 2014, USP published an informational chapter, USP <1115> "Bioburden Control of Non-sterile Drug Substances and Products," which details risk assessments and environmental monitoring for non-sterile processes. Prior to this publication, operators of non-sterile processes sometimes used USP <1116> "Microbiological Evaluation of Clean Rooms and Other Controlled Environments," which is an informational chapter for aseptic processes.


In February 2015, the European Medicines Agency published a concept paper describing a revision of Annex I of the EU GMPs, which will include updates for sterile processing and adaptation to International Conference on Harmonization Q9 and Q10 documents. The revision will also specifically address non-sterile processes, noted Ginsbury.

A Parenteral Drug Association (PDA) publication, planned for publication in 2015, is a technical report on cleaning and disinfection, said Jim Polarine, technical service manager at Steris, who serves on the task force for this report. In a conference presentation, he described components of validating disinfectants for a cleanroom. Vendors will test efficacy of disinfection against ATCC standard reference organisms, but ideally, users should test in-house environmental isolates. First, the cleanroom should be monitored for six to twelve months and organisms should be identified. From these data, isolates can be chosen for in-vitro testing. Knowing what flora are normally present in a facility is crucial. If something changes-a new floor, for example-the disinfection program should be revalidated, said Polarine.

Polarine also discussed best practices for disinfection, which include ensuring appropriate contact time and testing the effect of water quality on the disinfectant. It is possible to have too much of a good thing, however. Over-use of sporicides can break down flooring or wall materials, and these damaged surfaces create places for microbes to grow, noted Polarine. Some sporicides can cause corrosion; when this occurs, the corroded part should be replaced or monitored for microbial growth.

More discussions on these and other topics will be discussed at IVT's Validation Week in Philadelphia, Oct. 27–29, 2015.