Lifecycle Management for Near-Sterile Facility Contamination Control Programs

• Shire

Introduction

Regulatory expectations for microbial control in non-sterile manufacturing remain largely undefined, which is in contrast to well-defined expectations that exist for sterile manufacturing. This deficit is particularly evident for so-called “near-sterile” processes which demand particularly low levels of bioburden, effectively blurring the line between sterile and non-sterile processes. This article aims to affirm the importance of clearly outlining the strategy, rationale, requirements and measures of contamination control programs for these complex near-sterile systems, highlighting continuous improvement using a lifecycle management approach.

Microbial control is a key component of a successful contamination control program or plan and is paramount to ensure patient safety and regulatory compliance. An effective contamination control plan is comprehensive to both product development and commercial manufacturing and defines control measures from aspects such as utilities, equipment, environment, personnel, and materials as well as measurements or metrics for monitoring effectiveness of the controls. This plan should also include the scope of measurement for microbial control and guidance for departures from the controlled state.

Contamination control encompasses all aspects of contamination such as particulate, product carryover, chemical (e.g., cleaning material residue), as well as microbial. Microbial control is imperative in the pharmaceutical manufacturing industry to ensure patient safety by assuring that (a) bioburden is essentially eliminated using validated methodologies for sterile products and (b) final product bioburden is controlled to appropriate levels based on product attributes, route of administration, and target patient population for non-sterile products.²² Pharmaceutical manufacturers are required to have appropriate written procedures to prevent objectionable microorganisms (non-sterile) or to prevent microbiological contamination (sterile) as specified in ²¹ CFR 211.113, Subpart F.³Figure 1 depicts aspects of microbial control based on the relationship to the product and highlights individual components within each concept.

 Figure 1. Microbial Control Overview

Within the context of contamination control, understanding and enhancement of microbial contamination prevention and actions will be discussed; 1) defining challenges and ambiguities of “near-sterile” (i.e., low bioburden) processes, 2) presentation of a model for establishing and maintaining a contamination control program using a lifecycle management strategy, and 3) incorporating considerations for “near-sterile” facilities as part of the contamination control lifecycle management model.

Concept of “Near-Sterile”

Regulatory expectations and guidance for aseptic pharmaceutical manufacturing are well defined ^5,9,14,23 and enforceable by regulatory agencies. Further guidance is available, such as the FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice (2004).²⁰ This guidance is intended to “help manufacturers meet the requirements in the Agency’s current good manufacturing practice (cGMP) regulations (21 CFR parts 210 and 211) when manufacturing sterile drug and biological products using aseptic processing.” To align with these regulations and guidelines, critical microbial control factors should be identified in order to ensure safety of patients using sterile finished products. These factors should be mitigated through contamination control plans for manufacturers.

Microbial control of non-sterile pharmaceutical products is reliant on the relevant pharmacopeial monographs to ensure safety to the patient. In the absence of regulatory requirements with regard to non-sterile manufacturing, the only current guidance specific to non-sterile manufacture of pharmaceutical products is the informational USP Chapter <1115> “Bioburden Control of Non-sterile Drug Substance and Products”.²² This chapter provides guidance on establishing microbial control using a risk-based approach and highlighting the importance of process knowledge versus reliance on finished product testing. This is valuable guidance for the conventional non-sterile manufacturing industry where a certain degree of microbial presence is allowable in the manufacturing environment, process, and finished products (such as topicals or oral tablets) with control over the numbers and types of microorganisms.

Manufacture of certain pharmaceutical products such as parenteral bulk drug substance may be considered more critical than other non-sterile finished products from a microbial perspective as they can be intermediates of sterile final products, although this is not well defined with regard to regulatory guidance. Even though these products could technically be manufactured as non-sterile, more stringent controls may be justified. These low bioburden processes fall into a realm where guidance is unclear and manufacturers may tend to rely on principles for aseptic processing rather than using a risk-based, process knowledge approach for contamination control. This presents a challenge during process development, environmental classification, and regulatory filing as there may be mixed or unclear expectations for alignment or departure from aseptic guidelines. The descriptive term, “near-sterile,” refers to low bioburden products for which the process is typically “clean” with occasional low bioburden recovery. Although “near-sterile” is not a technical term, it illustrates the unique situation in which many low bioburden facilities find themselves.

Perceptions of the expectations and guidance may vary along the spectrum of sterile to non-sterile from an industry perspective, as shown in Figure 2.

 Figure 2. Microbial Control Conditions

Challenges to “Near-Sterile” Contamination Control

Creating a robust microbial control strategy is multilayered and complex, relying on specific process and product understanding. It involves knowledge of the origin, types, and sources of microorganisms and the methods to reduce or eliminate them.¹³ Microorganisms may not behave in a predictable manner and have unique properties that make it difficult to answer seemingly simple questions such as “what level of contamination is acceptable?” Manufacturers look to regulatory guidances to help define limits and acceptance criteria, assess areas of microbial risk, and evaluate organisms of concern. However, guidance is often limited and challenges exist within each type of manufacturing facility. This may prompt near-sterile facilities to lean conservatively towards sterile guidance, which is reflective of regulator expectations of tighter standards.¹ A robust risk-based contamination control plan is especially important in the near-sterile realm because having a well-documented, thoroughly understood and appropriately mitigated strategy is necessary in the absence of regulatory guidance.

Difficulties specific to near-sterile facilities present themselves when defining what constitutes a microbial control challenge. As a spectrum for microbial control expectations exists from sterile to non-sterile products, a continuum also exists when defining contaminations or drifts from the controlled state, ranging from “distinct” to “indistinct” (refer to Figure 3).

 Figure 3. Microbial Control Challenge Continuum

Microbial issues in near-sterile facilities may appear to be more elusive due to low level bioburden allowance and may not be detected until contamination control measures fail. If there is not process familiarity of areas such as sample points (location in process and method/environment of sampling), process parameters/control (e.g. open versus closed processing), and process steps that may be conducive to microbial proliferation, subtle signs may go undetected until the issue becomes bigger (i.e. the loss of microbial control or contamination). Table 1 identifies some examples of susceptible systems, symptoms, and the associated type of microbial control challenge.

Table 1. Loss of Microbial Control Scenarios

Contamination Control – The QbD Approach

Near-sterile facilities should take into consideration the risks of a non-sterile facility and balance the expectations applied from the sterile world when developing contamination control plans, especially with regard to finished product. The common thread in all areas of pharmaceutical manufacturing is the cleanroom classification scheme for which the associated environmental controls must comply^5,10. While prevention is the primary goal of these plans, the response and readiness aspects are also key components of the program that are of equal importance. Realistically, contamination events do occur and a comprehensive contamination response, as well as a strategy for continually improving the program, will result in more effective approaches to future events. This can be achieved through application of Quality by Design (QbD) principles through risk management and lifecycle management of contamination control programs.

In recent years, the implementation of QbD during pharmaceutical development has led to quality driven by greater product and process understanding developed through risk management and an emphasis on continuous lifecycle management. Fundamental to microbial control is a deep knowledge and understanding of the process and product. This is the foundation of QbD, which is defined as “a systematic approach to development, that begins with predefined objectives and emphasizes product and process understanding and process control based on sound science and quality risk management”.⁶ While the combined concepts presented in ICH Q8, Q9, and Q10 ^6,7,8 provide the foundation for current pharmaceutical development processes, these concepts can be extended beyond this scope to other areas such as contamination control. ICH Q108 states (in reference to quality risk management), “It can provide a proactive approach to identifying, scientifically evaluating, and controlling potential risks to quality. It facilitates continual improvement of process performance throughout the product lifecycle.” With contamination control, a successful program should be built to be proactive and scientifically evaluating to aid in controlling the potential risks to quality. An oft- forgotten component of contamination control plans is the facilitation of continual improvement of process performance. In other words, contaminations often are treated as “one-time” events; once the investigation has closed and corrective and preventative actions (CAPAs) have been identified, the events are rarely revisited or the contamination control plan improved upon. Development of a comprehensive contamination control plan is a difficult task unto itself, oftentimes making the element of continuous improvement or a lifecycle management component an afterthought at best.

In the following sections, concepts derived from QbD, with an emphasis on lifecycle management, will be applied to contamination control in near-sterile facilities, where the impact of more subtle microbial control issues and minimal regulatory guidance have presented a need for more defined programs.

Lifecycle Management of Contamination Control Programs

A comprehensive approach to contamination control makes the understanding and mitigation of microbial risks more robust. By taking into account the lifecycle of a product from control of input materials to the use of a product by the patient, broad use of information, knowledge, and common sense,¹⁶ the risks associated with the manufacturing process are appropriately augmented. In addition to considerations for the lifecycle of a product, one can apply the same logic to the lifecycle of a contamination control program itself. A contamination control program may be implemented as part of the Validation Master Plan (VMP)¹⁷ or even earlier, as microbiology is a concern in the development of robust formulations, such as material control, manufacturing design, formulation assessment, and packaging design.¹⁵ Once established, a contamination control plan may remain stagnant, with monitoring feedback aimed at assessment of the qualified state but not to the specific risks and mitigating factors identified as part of the contamination control plan. From a process lifecycle perspective, control and monitoring of microbial contamination is continually evolving, with learnings from contamination events, process/material changes, and even drift of microbial flora over time that should be continuously used to keep the contamination control plan up to date to ensure a high level of accuracy and relevance.

Lifecycle management, as employed in information technology, is a process for administering system software, hardware, and support over the life of a system.² From a performance management perspective, shortcomings must be detectable and able to be remediated. This concept can be applied toward a contamination control program where contamination events may signify a potential loss of microbial control which should be subsequently remediated through appropriate updates to the program.

Proposed phases (refer to Figure 4) of a contamination control program as seen through a lifecycle management lens are discussed below, highlighting the initial (Consider) and feedback stages (Cultivate) as an improved design approach for continuous improvement. Stages defined as Create, Customize, and Control align with a traditional lifecycle management scheme. The Create phase refers to the development of a contamination control strategy using a risk-based approach. This approach should be commensurate with the requirements and capabilities defined in the Consider phase (described below). A high level guidance document or standard may be an appropriate means to capture the program for the business. During the Customize phase, the plan is tailored to fit specific needs of the firm. Under the umbrella of a contamination control program, site- or process-specific microbial controls/monitoring address gaps or risks identified during the Create phase. The Control phase is the operational phase where the governance of the plan is applied to production.

 Figure 4. The “Five C’s” of Contamination Control Lifecycle Management

Consider

An effective contamination control program should be built on a solid foundation of knowledge and requirements. As employed during software validation, specifications laid out by the user are the framework for the design of a functionally proficient program that meets all defined requirements. With the patient as the ultimate “user” of pharmaceutical products, success in microbial control must rely on appropriately-designed controls based on capabilities using a risk-based approach in order to meet or exceed the requirements for the patient. According to the FDA, use of “scientific framework to find ways of mitigating risk while facilitating continuous improvement and innovation in pharmaceutical manufacturing is a key public health objective”.²¹ Contamination control plans originate from risk assessments to aid in identifying areas of microbial contamination risk. Defining clear objectives and specifications during the Consider phase sets the stage for the following program lifecycle phases, including risk assessment during the Create phase.

It is during the Consider phase that the expectations and requirements for bioburden allowance are defined and reflected as requirements for contamination control parameters. This allows for documentation of the rationale for the bioburden control scheme. For example, for a near-sterile process, the strategy for controls and monitoring to meet very low bioburden levels for a product manufactured under close to aseptic cleanroom parameters would be outlined.

Cultivate

Just as important as the creation and customization of the contamination control program is the maintenance and improvement of the program. As previously described, product knowledge and process understanding is essential in the design of a contamination control strategy from a QbD perspective. Knowledge management can be facilitated by information technology (IT) tools¹¹ to advance and improve the process.

The lifecycle management approach to contamination control programs highlighted above demonstrates how QbD can be applied to processes beyond pharmaceutical development. A key factor (and one of the objectives of ICH Q10) is embedding continuous improvement (CI) into contamination control programs to enforce an iterative, evolving process (i.e., Cultivate phase). ICH Q10 integrates CI into each phase of the process performance and product quality monitoring system throughout the product lifecycle.

ICH Q8(R2) provides guidance for developing a control strategy to ensure consistent product quality, as well as creating an adaptable program to respond to sources of variability based on product and process understanding. More specifically, ICH Q8(R2) states that, “Product and process understanding, in combination with quality risk management, will support the control of the process such that the variability can be compensated for in an adaptable manner to deliver consistent product quality.” In order to become adaptable in light of greater product and process understanding, enablers of the microbial control strategy must be integrated and evaluated as part of the Cultivate phase. ICH Q10 defines enablers as “a tool or process which provides the means to achieve an objective” and broadly identifies knowledge management and quality risk management as enabler categories. Enablers include the quality system, facility and equipment system, production system, raw materials system, and laboratory controls system; if these are not robust, the microbial control strategy is not successful.¹² To further build upon this, if continuous improvement is not built into programs, it becomes a weak enabler where a successful program is not sustainable. Effective management of cases of non-conformance is also required to enable the Cultivation of the contamination control program.

To create a strong enabler of the continuous improvement phase of the microbial control strategy, the system should be built as automatic and real-time as possible. ICH Q10 recommends use of the change management system to ensure that CI occurs in a timely and efficient manner. Change management is a useful tool if the appropriate risk assessments or root cause analysis is employed and the changes occur are specific and effective, as it holds parties accountable to take action by certain timelines. A shortcoming of change management is when risks are inadequately assessed and corrective actions are set in place that do not address the root cause or identified risk.¹² Junker, B. et al.¹¹ provides additional examples of control mechanisms to enforce active evaluation of “the state of QbD,” moving towards a proactive culture, rather than a reactive culture. Instances of control mechanisms include use of technical governance, metrics, sponsorship, incentives, and consequences.

An example of the use of the aforementioned control strategies as an automated and real-time process is presented by Toler, S.¹⁸ In this example, a real time risk assessment (RTRA) procedure was developed to integrate microbiologists with on-the-floor manufacturing operations to provide observations during production, influencing better contamination control. Susceptible steps are identified through use of risk assessment tools with a cross functional team, which define the scope of the RTRA. Immediate actions are taken based on observations of high risk activities, allowing mitigation of risks at the time of occurrence. The benefits of applying this type of program are:

• Application of a formal documentation system with standardized response and communication.
• Use of a standardized assessment where the data generated builds upon identified worst case risks to prioritize mitigation.
• Real time identification of process and product improvements and swift response to a changing landscape.
• Cross functional participation and communication, including support by senior management.
• Generation of reports at frequent intervals to summarize current RTRA conditions, creating automation of program evaluation.
• Lifecycle management and continuous improvement embedded into the contamination control program.¹⁸

This example of “on-the-floor” cultivation illustrates the benefits of a real-time feedback loop used to continuously improve and mitigate risks. This aligns with the FDA initiative of Process Analytical Technology (PAT), which is designed to improve efficiencies by using an integrated systems approach based on science and engineering principles for assessing and mitigating risks related to poor product and process quality.¹⁹

Key concepts of QbD such as risk management knowledge management, PAT, and CI provide the framework for a contamination control strategy using a lifecycle management approach. As these concepts are applied more frequently in day to day function in the pharmaceutical industry, a new standard for improved and customized microbial control will better equip manufacturers of near-sterile products to balance expectations and requirements.

Summary

From a near-sterile perspective, the spectrum of microbial control challenge is broad due to the allowance of a certain amount of bioburden balanced with processing conditions which may be close to sterile expectations. In order to ensure the highest degree of relevancy and efficacy, contamination control must be a living, integral aspect of routine operations, while continuously being updated and improved. Lifecycle management of a successful contamination control program requires Quality by Design and Continuous Improvement elements. An effective program is built on the foundation of extensive product and process knowledge, risk management, active communication, and real-time program management with regard to response and advancement based on deficiencies exemplified by contamination events.

A paradigm of self-sufficiency may require a change in mindset/ culture and the application of innovative solutions for automating this feedback loop. This concept of cultivation is important for each individual facility/process due to the variable and adaptive nature of the microbial world. In addition to setting defined requirements and considerations for a contamination control program, lessons learned from contamination events are just as important in shielding patients by reinforcing product quality and safety.

References

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