Maturing of a Microbiological Contamination Control Strategy – A Next Step

By: Donald Singer, ASQ Fellow, New Beginnings Microbiology

The latest venture of pharmaceutical manufacturing into the diverse scope of issues regarding contamination control from a compliance viewpoint is described in the EU Annex 1¹ and PIC/S² documents, which have a wide scope of contaminants including foreign particulate matter, chemicals, microbiological (including endotoxins) and adventitious agents. The scope of this article will be microbiological and adventitious agent contamination.

Current microbiological contamination control strategy (CCS)^1,2 is commonly science-based from 1) preliminary understanding of the holistic perspective of people-process-facility interactions/interventions, 2) evaluation of the latter combined with risk assessments relevant to microbiological hazards, 3) “implementation of controls (e.g. design, procedural, technical and organizational), and 4) measuring the performance of controls over time as an evolution of the strategy”,³ whilst gaining continuous improvement. The strategy can originate as a new or developed (from integrating or combining existing in-house manufacturing knowledge) model. The intent and benefit from the modern quality concept, continuous improvement, is to generate a maturity in the quality robustness of a strategy, which as an outcome assures manufacturers of their key priority, patient safety.

It seems that much of a manufacturer’s time and effort, since the Annex 1 revision (2021), has been utilized to generate a ‘Good Manufacturing Practices” (GMP) document intended to express their contamination control strategy from performing evaluation and risk assessment of controls initially identified as key factors in their contamination prevention approach, either as a facility (multi-processes/products) or for each product manufactured (see Figure 1). The background for this assessment is expected by regulatory authorities to be a holistic approach, which means “practices are designed to work together to achieve proactive contamination control and are evaluated for their collective effectiveness”.⁴ This strategy thus includes ongoing monitoring and evaluation of the controls to show that they are performing as expected. This is a minimum approach to contamination prevention and should not be considered as an endpoint. Regulatory compliance should be a motivator and not restrict continuous improvement that is science-based. “Current GMP is a minimum expectation, but also the foundation for more mature quality management.”⁵

Figure 1. A current CCS

The next steps over time should be planning for a mature contamination control program which is built on continuous improvement. Being empowered and proactive, having validated well-understood processes or systems, using ongoing knowledge for development, and generation of data evaluated in a just in time manner can lead to maturity (Figure 2). When a mature program undergoes significant change, such as a new process or a re-engineered structural design, it may be appropriate to revisit an initial risk assessment and re-evaluate controls along with developing a validation strategy (Figure 3).

Figure 2. A mature CCS

From the concept of quality management maturity (QMM), “a QMM outcome is NOT a measure of product quality. It is an evaluation of an establishment’s culture, mindset, behaviors, and quality practices.”⁶ Thus, maturity of a contamination control strategy is integrating improved mindset, culture, behaviors and quality practices that substantiate and support microbiological contamination prevention. It is reasonable to align your CCS with some of the principles of quality management⁷ since it is indeed part of your quality system.

Continuous improvement is a way to strengthen a contamination control strategy, along with proactive preventive assessment and redundancy of controls, instead of using reactionary mitigations to ongoing microbiological problems or issues. Proactive planning and evaluation with ongoing oversight allow for appropriate improvements to be made in the development of a more mature strategy. Redundant controls (or layers of protection), where possible, are a strong approach to building further assurance and consistency of contamination prevention.⁸

Figure 3. Proactive response to a significant change

This continuous improvement concept is in line with moving away from legacy and subjective microbiology thinking (i.e. use of the phrase, “it depends“) to utilizing design and implementation of consistent (i.e. validated), optimized, robust systems that have built-in repeatability and ongoing process understanding, along with a consistent organizational culture with proactive behavior.⁹ Advanced technology, modern methods, automated data evaluation, experiential thinking and a management-supported proactive culture can also deliver maturity for contamination prevention. It may be valuable to integrate, where possible, the concepts of Pharma 4.0¹⁰ and Validation 4.0¹¹ of a manufacturing operation to build a mature contamination prevention system.

Contamination control is relevant and a priority for both sterile and non-sterile manufacturing. Realizing that all inputs to manufacturing at some early point are non-sterile, the importance of understanding and evaluating microbiological quality is significant, along with determining what controls are best chosen to build assurance and reducing or removing variability of outcomes and subjectivity of evaluation.

Pharmaceutical manufacturing with chemical origin actives provides a basic framework strategy with key critical control areas of: supply chain, formulation, any scale-up modifications, the finish-fill operation and sterilization.

Biopharmaceutical manufacturing adds complexity to the critical control area scope because of the biological origin of active ingredients (e.g. mammalian cells) and they are produced upstream under conditions that promote cellular and microbial growth.¹² The biopharmaceutical actives are also commonly restrictive downstream in sterilization methods, often leading to one option, bacterial retentive filtration, which must be well understood, validated and controlled.

Similarly to biopharmaceutical manufacturing, cell and gene therapy processing have additional complexity, that of a final ‘product’ which cannot be sterilized (at this point in time) by common methods including filtration. Early processing steps of viral vectors can be ‘sterile-filtered’ but once combined with human cells lead to a non-sterilizable therapy. The level of controls for processing these therapies cannot be overstated.

The following are thoughts on what a next-generation mature contamination control program looks like in some of the relevant categories of microbiological control.

In sterile or aseptic manufacturing, microbiological control is developed by experience and good design. Best practice ‘engineering design’ approaches to generating clean air, reduction in human intervention, and the use of sterilized materials and sterilizable equipment have all been developed for industry’s need for continuous improvement. Yet, barrier protection coinciding with human intervention¹³ still seems to be commonplace, which slows or prevents developing a mature contamination control strategy. This also continues to carry variability of control, by allowing the known and inherent variability of microbial monitoring to be an indicator of the potential opportunity of contamination, instead of using a robust design that assures protection of the process and product. Automation is key to some improvements, whether by use of robots or by innovative engineered activities that replace human intervention.¹⁴ Also, use of digital systems would be expected as part of automation; yet, digital data evaluation (or even (AI) artificial intelligence) for environmental monitoring data may be useful to enhance ability to evaluate large data entries for possible improved speed to identify a contamination event but does not add value to actual contamination control of a manufacturing process.

Both clean air and reduction in human intervention can be easily achieved with closed systems (i.e. isolators) equipped with robotics. The need for cleanrooms, which are purposely built to allow human activities, can be replaced by these closed systems, thus reducing risk from human intervention and gaining consistency and efficiency with automation. The removal of gloves and glove ports will also reduce procedural or ad hoc human intervention, reducing microbiological risk.¹⁵ Using robots that can be decontaminated in the chamber and have flexibility to perform any operation that a human used to perform, leads to good aseptic robot design,¹⁶ incorporating a ‘whole fleet concept design’ approach. Appropriate design and materials (e.g. for decontamination) along with automated actions of the robots should reduce concern of ‘first air’ intervention, which is more relevant to human activities.

Processing materials such as vials, syringes, filling needles, stoppers, etc. can be acquired pre-sterilized in ‘ready-to-use’ formats for material transfer (see Figure 4), increasing assurance of sterilization and maintenance of aseptic practices. In-line processing of the filling and stoppering environment can integrate such modalities as electron beam or ionizing radiation and vaporized hydrogen peroxide with accompanying validation approaches, to develop aseptic surfaces that do not require further monitoring for microbial contamination.¹⁷

Microbial monitoring of sterile closed system surfaces is unnecessary. Also, microbial monitoring of air in a fully closed, decontaminated isolator environment, which has been validated, rarely provides value, yet compliance expectations questionably still exist.¹⁸ Use of technology such as biofluorescent monitoring coinciding with non-viable particulate monitoring is a more relevant approach to continuous monitoring expectations, if only to support the validation and ongoing preventive approach.

Infrastructure for any aseptic manufacturing must be well maintained and monitored to ensure support for all functions of the manufacturing process (Figure 5). As indicated by the HACCP (Hazard Analysis of Critical Control Points) model,¹⁹ if the infrastructure fails at all, it can negatively impact the contamination control systems.

A useful resource for consideration with sterile product manufacturing improvement is a list of prerequisites for aseptic process simulation (Figure 6) as described in the PDA Technical Report 22.²⁰ Note that there are some similarities on the two lists. A broad scope is critical to assure successful and robust validation, which is paramount for contamination control.

Figure 4. Materials transfer risk

Figure 5. List of examples of HACCP prerequisite areas

Figure 6. Examples of aseptic process simulation prerequisites

Revisiting Innovative Approaches

The aseptic manufacturing field has seen innovative approaches to aseptic/sterile environments that have become commonplace in other industries, such as:

• Isolators and robots (microprocessing industry) - Fully automated manufacturing and cleaning systems in isolators with HEPA (high efficiency particulate air) and ULPA (ultra-low particulate air) filters
• Aseptic packaging (food industry) - Utilization of product (e.g. fruit juice) subjected to a high temperature short time treatment then filled in hydrogen peroxide-sterilized packaging

But, the latter approaches are not fully implemented across the pharmaceutical field.

Also, some other innovative and robust aseptic technologies designed for pharmaceutical manufacturing that have not become commonplace in injectable manufacturing are:

• Closed vial filling²¹ - Fully closed vials with product filled through elastomer stopper and immediately sealed, preventing exposure to external air (some vaccines use)
• Form Fill Seal technology²² - Plastic parison packaging formed with high heat under HEPA filtration, subsequently filled and then sealed by heat (some eye products use)
• Fully closed systems for product handling - Sterile packaged single use systems (SUS) including filter connector, tubing, and filling needle can eliminate some interventions and cleaning validation

These are all missed opportunities for continuous improvement to gain robust contamination prevention towards a more mature strategy.

A common and misused approach to new technologies in the pharmaceutical industry is to over-evaluate technology by looking for faults rather than benefits, e.g. use of Failure Mode and Effects Analysis (FMEA). Indeed, it is useful to understand what weaknesses can be expected in use of a new technology. Expectation for ‘perfection’ can be an unnecessary barrier. Such an example as ‘pre-mortem’ evaluation²³ rather than post-mortem evaluation can develop a better understanding of potential problems before they happen and how to mitigate them. But defining faults should not prevent the evaluation of its strengths, which can often outweigh the weaknesses. Implementation of advanced or innovative technologies has been slowed not by compliance expectations, but often by over-evaluation and over-emphasis of identified weaknesses.

Maturity can only be achieved by balanced weighing of strengths, benefits and weaknesses from an assessment and then smart implementation with pragmatic validation and knowledge building.

Maturity is developed from a balance of intended outcomes with improvements in design, operator aseptic behavior (where operator intervention has been minimized), and use of automation (where appropriate and effective), such as automated transfers, automated decontamination, sterilization, and automated fill-finish operations. The intended outcomes could include:

• Reduced origins of microbial contaminants
• Elimination of human intervention
• Reduced opportunity of contamination to formulation, process, environment

An example to benchmark where you are today and where continuous improvement can progress contamination control is shown in Table 1. The ‘initial approach’ list would be assuring that the strategy meets Annex 1 expectations, and as stated earlier…is a minimal approach. Design improvements include sterilization as a first intent ‘treatment’, installation of closed systems for containment, and automation. Designing and building robustness into the process and concomitant procedures can be derived with validation and oversight of validated processes over time. This, of course, is intended to replace the high variability (and presence) of human interactions and add more consistency into contamination prevention. A beneficial effect of proactive behavior and culture is acceptance of nothing less than having strong assurance that preventive controls are working effectively and consistently.

Acknowledgements:

I would very much like to thank my trusted colleagues, James Agalloco and Noël Long, for their perspectives, vast expertise and mindful review of this critical topic.

References

1. European Commission, 2022. The Rules Governing Medicinal Products in the European Union Volume 4 Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use: Annex 1 , Brussels: European Commission.
2. Pharmaceutical Inspection Co-operation Scheme (PIC/S), 2023. “Guide to Good Manufacturing Practice for Medicinal Products - Annex 1: Manufacture of Sterile Medicinal Products
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