How will the implementation of the revised EU GMP Annex 1 and the requirement for a Contamination Control Strategy impact pharmaceutical microbiology practices and resources in the coming years?
Melisa Byrd, Microbiology Supervisor, and Renee Johnston, General Manager, Element: There are several implications to pharmaceutical microbiology due to the Annex 1 revision. Because the Annex 1 revision outlines Contamination Control Strategy (CCS) requirements, many manufacturers may find their programs to be coming up short. For example, there is an expectation to trend both microbial and non-viable particle monitoring, with more stringent limits being established by the CCS. In areas of high risk, such as in Grade A environments, non-viable and viable monitoring should be continuous throughout critical processes, using systems with alarms and timely responses.
Another major update includes an expanded section on sterile filtration and Pre-Use, Post-Sterilization Integrity Testing (PUPSIT). In short, it will be required that bioburden samples be taken immediately prior to sterile filtration. This may pose technical challenges for small batch volumes, products that clog, etc. Although exceptions to this requirement may be met through a tedious CCS, supply chain and process controls are a major challenge in that justification.
Altogether, the updates, which are many, will be a challenge for many manufacturers to implement.
Allen L. Burgenson, Global Subject Matter Expert, Associate Director, Lonza Walkersville, Inc.: Contamination control during the manufacturing process is critical to product quality attributes such as sterility, endotoxin content, or other degradation processes.
Anne Weeks, Senior Field Marketing Manager, MilliporeSigma: I expect that the implementation of EU GMP Annex 1 will continue to have an expanded and lasting impact on how pharmaceutical production is implemented. The document opens pathways to adopting new and meaningful technologies to help make more informed decisions, while also placing a large impact on the important role that microbiology and robust contamination control have. I predict that we will continue to see more leaps in technological advancements for environmental monitoring and cleanroom design overall.
Eric Clement Arakel, Manager, Global Product Management, Reagent and Consumable Solutions, Sartorius: The extensive feedback from the two consultation phases, the detailed final document, its expanded scope, and the increase in sheer size indicate that the revision of the EU-GMP Annex 1 was long overdue. The new guidance is clearer, promoting a proactive/precautionary rather than reactive approach, benefiting both manufacturers and patients. The CCS represents a major paradigm shift, requiring the identification of contamination risks, preventive strategies, and monitoring systems to ensure compliance.
Since the CCS requires several elements to be considered, this will necessitate a period of reassessment for existing strategies and monitoring methods, potentially needing revalidation or the evaluation of alternatives, unless these measures are already in place.
For instance, viable/microbial monitoring has been a significant discussion point. Continuous viable air monitoring is now required in Grade A and recommended in Grade B, environments. However, the guidance leaves the door open as to whether this should be done through active air sampling or settle plates. Despite clear specifications on maximum action limits for viable particles, there is ambiguity regarding the minimum air volume that must be sampled during critical processing and at rest, causing confusion among users and solution providers. However, these ambiguities will be resolved over time by comparing the capabilities of monitoring solutions and engaging with auditors and regulatory authorities regarding the CCS and their expectations.
What are the most promising new technologies or methodologies (e.g. rapid microbial methods, MALDI-TOF, biomarkers) that could significantly advance pharmaceutical microbiology testing and monitoring capabilities?
Byrd and Johnston: The field of pharmaceutical microbiology is rapidly evolving with the advent of new technologies. Several promising advancements stand out for their significant potential:
Rapid Microbial Methods (RMMs): RMMs are a promising technology for several reasons. These technologies provide, in some cases, immediate results. Often, they are destructive to a sample but are used like a watchdog – with immediate results a manufacturer or lab can pause operations and address issues as they arise. This has huge implications for batch safety and positive implications for investigations. Rapid technologies that are non-destructive, such as methods using respiration detection, may have longer turnaround times but the capability for microbial identification of contaminants.
Matrix-Assisted Laser Desorption/Ionization-Time of Flight (MALDI TOF) Mass Spectrometry: MALDI-TOF is revolutionizing microbial identification by providing rapid and cost-effective identification of bacteria and fungi. It works by analyzing the unique protein fingerprint of microorganisms, enabling precise identification within minutes. These technologies and methodologies significantly advance pharmaceutical microbiology by improving the speed and efficiency of microbial testing. Their integration into routine practice will enhance product safety, quality, and regulatory compliance. Although this technology is promising, it has shortcomings in accuracy, whereas other methods, such as those that use gene sequencing, are more reliable.
Weeks: While there may not be as many exciting or game-changing new technologies in the microbiology testing world, I do think that some established technologies are getting due attention and regulatory support. Some USP chapters that are currently in draft form could support the adoption of RMMs for some products that experience bottlenecks in release but also are robust enough to minimize false positives, and to account for slow-growing microorganisms that may be in some in-process samples.
Another exciting area is the transformation of how we handle and analyze all the data we capture. We are increasingly able to leverage big data and implement AI and generative learning models to help us interpret our microbiological data and be more agile in our decision-making.
Arakel: Rapid microbial methods (RMMs) have been discussed since the late 1990s, including respiratory/metabolic activity assays, solid phase cytometry, ATP bioluminescence, nucleic acid-based tests, Raman spectroscopy, and isothermal calorimetry. However, adoption has been limited due to factors such as cost-benefit analysis (especially when a complementary analytical method takes longer), method sensitivity and specificity, detection limits, and validation hurdles for method equivalency to compendial methods. Viable but non-culturable (VBNC) cells present additional challenges for sensitive methods.
The COVID-19 pandemic and vaccine demand highlighted the need for RMMs. Novel therapies, such as cell therapies with limited shelf lives, also necessitate rapid microbial testing. The vein-to-vein time for these therapies is decreasing from three to five weeks to six to seven days. CAR-T therapies, now being considered for first-line regimen in B-cell lymphoma patients rather than the customary six rounds of chemotherapy, and involving lymphodepletion, urgently require rapid microbial release methods. The USP chapters on RMMs for short-shelf life products that are under development are highly anticipated.
For rapid sterility testing of cell therapies, most RMMs claim time-to-result in three to seven days, while PCR-based molecular methods can detect minimal contamination in complex matrices with varying cell densities within hours. Ultimately, the product’s shelf life, the method cost-benefit, and the logistical approach for CAR-T manufacturing (centralized vs. decentralized/point-of-care) will likely determine the adopted method.
With increasing automation, digitization, and the use of AI/machine learning in microbiology, what skills will be most critical for the next generation of pharmaceutical microbiologists?
Byrd and Johnston: With an increase in automation, digitization, and the use of machine learning (ML) in microbiology, many of the same skills that are critical now will remain critical for the next generation of microbiologists. Specifically, investigational skills will remain an essential tool for microbiologists. While data collection and trending may become more streamlined, data analysis will remain instrumental to investigations. Although ML may be able to guide investigations, Root Cause Analysis and investigation strategies will remain key to a successful microbiology program.
It will remain important for microbiologists to have operational skills. Microbiologists must understand the power of automated processes while remaining cognizant of their shortcomings. AI/ML could prove to be useful in identifying pain points in the microbiology processes and could be used as a tool to aid in quality control, workflow management, and equipment maintenance. Embracing a plethora of strategies for quality assurance will always be a desirable skill for microbiologists.
Burgenson: Despite the use of all of these technologies, nothing beats knowledge and mastery of the subject. There are times when, even though everything is within limits, something in our gut says something is “off”. Knowledge should be the basis of our profession. A SOP should focus on that knowledge, but an SOP alone cannot be the basis of our knowledge.
Weeks: There are so many aspects of automation that can be beneficial to pharmaceutical microbiologists, but it’s ultimately about finding the solution that has the most meaningful impact. I think that microbiologists will be expected to increase their regulatory knowledge base and understand the expectations when choosing and implementing automation or AI at any level. Validation, implementation support, and service capabilities will be highly valued attributes from both the microbiologists and selected solutions providers. Overall, the outcome will greatly improve testing workflows, data analysis, and decision-making, allowing your microbiologists to focus on other high-value responsibilities.
Recruitment and retention of skilled microbiologists remains an ongoing challenge. What innovative approaches could help attract and develop talent in this field?
Byrd and Johnston: Recruitment and retention of skilled microbiologists remain an ongoing challenge. Nevertheless, innovative approaches to attract and develop talent in this field do include but are not limited to:
- Involvement and exposure to new technologies: By allowing microbiologists to work with cutting-edge technologies, we can attract those eager to advance their skills and stay at the forefront of the field.
- Education on the distinctions between clinical microbiology and pharmaceutical microbiology: Offering specialized education and training programs that highlight the differences and unique opportunities in clinical versus pharmaceutical microbiology can help potential recruits make informed career choices.
- Providing robust and comprehensive training: Implementing well-structured training programs that equip microbiologists with the necessary skills and knowledge can enhance their competence and confidence, making the roles more appealing.
- Mentorship: Establishing strong mentorship programs where experienced microbiologists guide and support recruits to foster professional growth and create a more engaging work environment.
- Support and guidance: Creating a supportive work environment that includes regular feedback, clear career development paths, and resources for continuous learning can help microbiologists perform well in their roles and increase job satisfaction.
Burgenson: As stated above, nothing beats knowledge and mastery of the subject. There are times when, even though everything is within limits, something in our gut says something is “off”. Knowledge should be the basis of our profession. A SOP should focus on that knowledge, but an SOP alone cannot be the basis of our knowledge. Permitting analysts to use their education when evaluating an assay allows them to apply that knowledge to evaluate the results to give a proper answer. If something is at the border of “passing”, but the error of the test could mean that the results may exceed the limit, so should be evaluated and responded to. That is the role of the microbiologist possessing the proper education, training, and experience as called for under cGMP.
Weeks: I am personally grateful to work for a company that I think is a leader in internal and external programs that foster a passion for science and skill development. Through our SPARK program and curiosity cube, recruitment starts at the youth level to showcase the great impact that microbiologists and all those in life sciences can have. Additionally, offering specialized projects, or adding specialist responsibilities to a job role can help attract more skilled microbiologists. Some may want to influence in adopting new technology, exposure to other groups within their company, or the ability to expand skills beyond routine testing that may influence retention and talent development.
Microbial contamination risks extend beyond sterile products to non-sterile drugs as well. How can risk assessment and prevention strategies be strengthened for the full range of pharmaceutical products?
Byrd and Johnston: Regarding risk assessments (RA), it is imperative to have an in-depth understanding of the lifecycle of one’s entire manufacturing process. This includes scrutinizing the supply chain; from sourced raw materials to the final product. Reviewing Certificates of Analysis and verifying the quality of sourced materials may identify potential risks early on.
Identifying risk may be achieved through regular self-audits and audits of Contract Development and Manufacturing Organizations (CDMOs) or contract laboratories. These audits, conducted internally or by neutral third-party consultants, ensure processes meet required standards and that risks are identified.
Prevention strategies are strengthened by conducting detailed investigations with clear Root Cause Analyses (RCAs) and Corrective and Preventive Actions (CAPAs). These measures identify causes of contamination and implement strategies to prevent recurrence. Partnering with knowledgeable parties and experts in the field who specialize in RA can provide valuable support. These experts refine strategies, ensuring that potential risks are identified and mitigated, enhancing the robustness of contamination prevention strategies.
In summary, by understanding the manufacturing process and supply chain, conducting regular audits, performing detailed investigations, and partnering with knowledgeable consultants and companies, pharmaceutical firms can strengthen their RA and prevention strategies to effectively mitigate microbial contamination risks in sterile and non-sterile products.
Burgenson: Any unplanned or unexpected microbial contamination has potential detrimental effects on product quality. Such risks include product loss via microbial degradation, as well as various toxin development in the product via microbial growth. Microbial contamination should be kept as low as practicable via the ALARA (as low as reasonably achievable) concepts, and setting in-process alert and action microbial levels for the process. Proper cleaning and sanitation practices and environmental control are important for non-sterile, and critical for sterile products to reduce the risk of in-process contamination. Quality is built into the manufacturing process, and proper upstream control assures final product quality.
Weeks: Non-sterile pharmaceutical-focused regulatory guidance and FDA oversight have noticeably expanded in recent years as noted by an increase in regulatory chapters, revisions, and publicly available audit information. As more specialized medicines that may not be sterile or were produced as sterile personalized medicine are introduced into the market with unique manufacturing processes, the need for a formal and well-defined risk assessment is key. The focus for microbial contamination control as important as it is for sterile pharma must also include risk assessment at the excipient, API, and compounding levels as well. As we learn and educate ourselves more on the prevalence of objectionable organisms that are harmful to certain patient populations and continue to define mitigation and testing strategies the better the pharmaceutical industry will be for all. Non-sterile can carry some of the same risks as sterile pharmaceuticals, and in many cases can affect a greater population, especially if that product is available as an OTC. Mirroring some of the best practices that are already established in sterile pharma, such as environmental monitoring, robust bioburden testing, and material flow control will be great steps in distributing safe products.
Arakel: The manufacturing practices of sterile and non-sterile drug products differ significantly, yet many aspects from the EU-GMP Annex 1 can be applied to non-sterile manufacturing. Contamination risks in both sterile and non-sterile manufacturing are similar and include poorly designed facilities with insufficient air filtration and room pressurization, inadequate cleaning and sterilization of equipment, lack of routine maintenance of utilities such as HVAC systems, contaminated raw materials, process water or packaging, poor hygiene practices by personnel compounded by inadequate masking and gowning practices, and improper unidirectional flow and separation of materials and processes.
Adopting the two core principles of the EU-GMP Annex 1 for sterile products — Quality Risk Management (QRM) and a Contamination Control Strategy (CCS)— for non-sterile products would help set a baseline. Once risks are identified, strategies can be devised by all stakeholders and regularly reviewed to gauge the effectiveness of the agreed-upon risk control measures.
Despite non-sterile drugs being manufactured in clean, controlled environments, there is no mandated classification or grading of the clean area. Therefore, guidance on minimum requirements is crucial. Since the final quality of non-sterile drugs does not rely on release testing, strategies need to be designed to achieve targets well below microbial limits during in-process testing.
Until guidance on the harmonization of manufacturing practices can be drafted, given the similar contamination risks in sterile and non-sterile manufacturing, parallels can and should be drawn in facility design and manufacturing practices to cover all pharmaceuticals.
Author Details
Melisa Byrd- Microbiology Supervisor, Element; Renee Johnston- General Manager, Element; Allen L. Burgenson- Global Subject Matter Expert, Associate Director, Lonza Walkersville, Inc.; Anne Weeks- Senior Field Marketing Manager, MilliporeSigma; Eric Clement Arakel- Manager, Global Product Management, Reagent and Consumable Solutions, Sartorius
Publication Details
This article appeared in American Pharmaceutical Review: Vol. 27, No. 5July/Aug 2024Pages: 48-51
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