Contamination Control Roundtable

• Microbiological Consulting, LLC
• Bio Products Laboratory Ltd
• Excellent Pharma Consulting

In general, what are some current issues or problems pharm/biopharma companies are dealing with in regards to controlling contamination in their facilities?

Tony Cundell, PhD, Principal Consultant, Microbiological Consulting, LLC: The usual suspects are aging facilities, the incomplete implementation of barrier technologies, sterile products being aseptically filled when they are candidates for bioburden-based terminal sterilization, poor product failure investigations and corrective actions, and the general lack of manufacturing excellence.

Paula Peacos, Senior Consultant, ValSource, Inc.:

1. Lack of specific regulatory requirements and guidance for many of the emerging technologies that are neither traditional aseptic processing operations nor true nonsterile operations is a problem. This basically put the onus on the firm to determine the requirements, and some are more proficient in that than others.
2. In my opinion, the industry in general is still learning how to appropriately apply QRM to their operations. QRM is quickly being incorporated, but not all programs are well-designed or sufficiently robust. For example, some risk assessments are still justifying current practice as opposed to identifying potential contamination risks. This is a particular problem where specific regulatory guidance or requirements are lacking.
3. Lack of new microbiological monitoring methods. Detecting/recovering microbial contamination is still done using antiquated methods that are known to be relatively inefficient, highly variable, and extremely limited. A very well designed and robust EM and trending program helps to offset that, but we are still working with estimates of what might be actually present. There are many developments in technologies allowing faster turnaround times to obtain results, but most of these still utilize the old sample collection methods (i.e., contact plates, settle plates, and viable air sampling methods).

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Tim Sandle, PhD, Head of Microbiology and Sterility Assurance, Bio Products Laboratory Limited: The problems will vary between different facilities, and these will center on the different sources of contamination in relation to people, air, water, transfer of items, equipment cleanliness, and bioburden of starting materials. The most difficult challenges are invariably around people: how personnel behave in cleanrooms, how they are gowned, and whether they follow the correct procedures. Although the regulations around personnel have largely remained unchanged, its noticeable that the number of warning letters and other regulatory citations have increased. The reason for this must rest with training, knowledge and with time (in terms of allowing operators sufficient time to carry out their duties and to clean and disinfect effectively).

Keeping track of data is also a challenge. With large facilities in particular, assessing microbial and particulate trends remains important so that appropriate actions can be taken promptly. Furthermore, it is important to understand when the process is leaning out of control, to enable personnel to be alerted to a potential change in the process. To aid microbiologists, there are a number of powerful databases on the market which provide graphical illustration of trends and which meet data integrity requirements.

Jeanne Moldenhauer, Vice-President, Excellent Pharma Consulting:

1. Some of the control problems result from the establishment of unrealistic limits for types of contamination, e.g., setting a zero-tolerance level for molds.
2. Another concern with contamination control is the reluctance of companies to use/implement newer technologies that actually prevent microbial growth.

Looking at the latest in contamination control products and solutions, can you tell us about some new technologies and/or processes that are available now that you are excited about?

Cundell: With all aseptic processes, removing human interventions is a key design and operation strategy for improving contamination control. Automation will continue to be emphasized. Equipment like depyrogenation tunnels, multiple-container filling and stoppering stations, vision systems for defect detection, online container-closure integrity testing, and robotic lyophilizer loading and unloading are now commonplace in sterile product manufacturing facilities.

The ability to exclude people from aseptic processing has a hierarchy of risk: laminar flow hood > biological safety cabinets > restricted assess barrier systems > open isolator systems > closed isolator systems with gloves > gloveless isolator systems. Robotic systems are uniquely suitable for inclusion in barrier systems like gloveless isolators. Remember, robotic systems will automate standard manipulations, exclude people from critical aseptic processing areas, and do not look or move like humans.

Peacos:

1. I am a huge fan of single use/disposable technologies that minimize the amount of product exposure to human intervention because they are very effective and relatively easy and inexpensive to implement. A firm can greatly reduce their risk of contamination in a short amount of time through the use of these technologies as opposed to having to do new construction or retrofitting. Examples include the use of sampling apparatus that can be sterilized in place, pre-assembled and/or pre-sterilized parts and components, welded connections etc. These can go a long way to aid in contamination control for small firms that simply don’t have the capital to convert their operations to, for example, isolator technologies.
2. Technologies such as the Growth Direct, which decrease the turnaround time for obtaining microbiological data (colony counts). Environmental excursions and contamination risks are often not detected until 3-7 days after sample collection using traditional processing methods. Meanwhile, manufacturing operations are continuing. Furthermore, this method is nondestructive, meaning microbiologists can culture and identify the organisms to allow for appropriate investigation. Some rapid detection methods destroy the organisms or do not allow for recovery, which in my opinion significantly lowers their value.

Sandle: With aseptic processing, ideal technologies are those that separate people from products, such as isolators, and which can replace the need for humans for carry out operations, as with the use of robotics. An advantage with automation is that processes can be stopped if there has been a shift in environmental conditions, such as an increase in particle counts.

Technologies which help to show that tasks are being conducted correctly are important, such as glove stations which can indicate how often and for how long hands have been sanitized for, and tracking technologies that indicate that cleanrooms are being disinfected for the appropriate time periods are useful for helping to address personnel related contamination control issues.

Other technologies of interest are the spectrophotometric particle counters, which can be used to differentiate between inert particles and those which are biologic. Although there are still some factors to overcome in terms of screening for false positives, taking samples over a sufficiently long time period provides useful data for benchmarking. Such data can then be used to assess changes in a facility, such as the impact of maintenance work or to assess the impact of increased numbers of personnel in an area.

A further area that’s receiving increased coverage is with air decontamination units with HEPA filters. These offer an additional technology to destroy a a range of airborne microorganisms.

Moldenhauer:

1. There are many new water-based technologies that are antimicrobials, e.g., increased oxygens (ozonated) and electrostatically charged hydrogens. These products have sporicidal properties without leaving residues and without damage to stainless steel surfaces or employees.
2. There is also an increased focus on products that prevent growth, both in building materials, coatings, paints and the like. For example, nanotechnology infused products.

In the past few years have regulatory expectations from the FDA and other global agencies resulted in more scrutiny placed on contamination control efforts? Can you elaborate? Do inconsistent or different global regulations place a regulatory strain on pharmaceutical companies?

Cundell: Contamination control during aseptic processing has always been scrutinized by regulatory agencies. From 2014 through 2017, 48% of the U.S. sterile drug recalls were for visible particles, 31% for lack of sterility assurance, 8% for labeling issues, 3% for container defects and 10% for other reasons (Johns et al, 2018). The biggest disruption presently is the publication of the revision to the EU Good Manufacturing Practice, Annex 1 that contains rules that differs from current industry practice and the 2004 FDA Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice. Gap analysis will reveal many procedural changes and capital improvements that may be necessary when the revision becomes official. This will consume many resources.

Peacos:

1. Inspectors in general are increasing the depth of their knowledge of microbiology, spending more time in the labs and delving deeper into contamination control procedures and programs. We see the evidence of this in the citations that are issued. Site microbiologists are addressing technical questions that they have not been asked before. I think this is appropriate given some of the findings that have come out in recent years, some truly egregious, that could impact patient safety.
2. Inconsistent or ambiguous regulations are a big problem in my opinion. When the regulations are ambiguous, they are subject to interpretation. Sometimes the firm’s interpretation is not in lock step with that of the inspectorate, particularly when it concerns the finer details. It is this room for interpretation that can make it difficult for a firm to ensure compliance.

Sandle: Inspectors are asking more questions about contamination control activities and this is reflected in the content of warning letters and the number of items raised in warning letters. One area that stands out is with cleaning and disinfection. Inspectors are asking for evidence that disinfectants have been adequately qualified, against a range of different surfaces, for example, and that sporicides are being used where appropriate. A related area of importance is with demonstrating the absence of residues that might interfere with disinfectant products.

Regulators are also coming down heavily on evidence of poor disinfection practices, such as the continued recovery of fungi or spore forming bacteria, which signal ineffective practices, such as linking with cleaning and disinfection frequencies or poor application techniques.

A unified approach to contamination control would be very useful to the pharmaceutical community, especially when receiving inspections from different inspectorates. The forthcoming changes to EU GMP Annex 1 could signal that; however, there are now variances between some of the FDA guidance and that from Europe. An example is with the design of aseptic process simulations and the acceptance criteria.

Moldenhauer:

1. One of the biggest changes is the draft of Annex 1 which has a complete section on the requirements for a Contamination Control Strategy/Program.
2. There are no clear differences in programs across regulatory agencies today.

What advice would you give to a pharmaceutical company struggling with their contamination control efforts? Is there a top 5 list of items you would suggest to these companies to help them?

Cundell: Concentrate on the knitting! My top 5 items to improve contamination control are as follows:

1. Hire and retain experienced microbiologists who are as home in the manufacturing areas as in the laboratory.
2. Apply the tools of Quality Risk Management to formulation and packaging development, manufacturing process design, and routine aseptic processing.
3. Embrace single-use processing equipment, barrier systems, robotics, and continuous bioburden, environmental and water monitoring.
4. evelop skills in expert systems, machine learning, and big data management to better control your processes.
5. Look for the best opportunities for the implementation of rapid microbiological methods.

Peacos:

1. Minimize human intervention wherever possible. Invest in single use/disposable technologies and barrier/closed system technologies etc. While this can be expensive to implement, it must be weighed against the risk to the patient as well as the capital, labor and logistical costs of rejected batches. Even small reduction in human interventions can have a big impact.
2. Good trending involves more than just reporting data from quarter to quarter. It involves data analysis and interpretation of that analysis which leads to better, science-based decision making. I would strongly recommend they invest in a good trending software that allows them to quickly and effectively analyze a large amount of data. The ability to do this is critical to good, reliable contamination control.
3. The entire staff, including quality, facilities and manufacturing floor staff, should be trained in basic, practical microbiology. This training should focus on the way microbes enter and move through a facility, and more importantly, how each individual has a role in an effective contamination control program, and how their performance of their roles impact its success. If the staff doesn’t not have the knowledge to recognize a problem that is right in front of them, the most robust, well designed program will likely fail.
4. The Micro staff should thoroughly understand the manufacturing processes they support. It will improve the quality and efficacy of the contamination control program, as well as root cause analyses etc. They cannot effectively investigate something they don’t really understand. The Micro staff also needs to spend time on the shop floor as this will enable them to make appropriate adjustments to the elements of the contamination control program programs (EM, trending, etc.) to maximize value.
5. The Contamination Control Program needs to be a living, dynamic program. It needs to be flexible and able to adapt quickly and easily to changes in the environment or processes etc. to maintain effective control. To that end, the program itself and supporting risk assessments and procedures etc. need to be revisited and reassessed on a relatively frequent basis and updated or supplemented as needed. This is especially critical for new processes, new facilities and new technologies which are still evolving.

Sandle:

1. Contamination control requires an understanding of the microbial entry points and the various routes that can be taken to arrive where they are undesired. Hazard identification is key and then assessing how the contamination might end up impacting on a process. This involves understanding the sources of contamination and how contamination can be transferred. The risks associated with the different sources of contamination and the potential impact should be assessed, in terms of the severity of contamination (should it occur) and the likelihood of a contamination event occurring (probability). This enables an organization to focus on risk mitigation and then to put in place appropriate detection systems to ensure that the contamination risks remain within a level of control.
2. Extending the principles of quality risk management to microbiological sampling is also important, to ensure that the samples taken are meaningful and relate to the primary contamination risks. The use of HACCP (Hazard Analysis and Critical Control Points) can be employed to determine microbiological environmental monitoring locations.
3. There also needs to be a greater focus on the training of cleanroom personnel and implementation of more robust training programs defining aseptic technique, pharmaceutical microbiology and so on.
4. Keeping track of process variations is important. If the process is as validated, then the standard sample set will be sufficient. However, if the process is different, such as having a longer process hold, then additional samples should be considered to assess bioburden and endotoxin risk.
5. Having less paperwork in cleanrooms sounds simple but this minimizes contamination and leads to better control over processes and samples. With this, electronic systems offer a number of advantages for environmental monitoring and for completing batch records

Moldenhauer: The biggest recommendation is to know what is causing your contamination issues, i.e., identify the contaminants and learn all you can about these organisms to try and find the root cause.

What do you see as the major industry critical issues over the next five years in regards to contamination control?

Cundell: Clearly major issues surround gene and cell therapies and the following quote illustrates this. “The key to making gene therapy accessible to patients will be better manufacturing processes”, Peter Marks, Director of FDA’s Center for Biologics Evaluation and Research (CBER), told attendees at the Galien Forum in New York City on Oct. 25, 2018, in a panel discussion on gene therapy. “At this point, the FDA has approved one directly-administered and two cell-based gene therapies”, Marks said, “but the Agency has received over 700 investigational new drug (IND) applications in the gene therapy field”. As the FDA points out, there is a large gap between R&D, clinical supplies, and routine commercial production. Perhaps the biggest challenge in gene and cell therapies is cell viability, but the best approaches to microbial contamination monitoring and control have not been established.

The revisions to 21 CFR 610.12 Sterility to allow for more flexibility in sterility testing biologics was helpful. The proposed USP general informational chapter <1071> Microbial contamination detection/sterility testing of short life products: A risk-based approach may contribute to the discussion in the industry.

Peacos:

1. I see a general push in the industry for firms to more quickly incorporate available contamination control strategies such as the use of isolator technology, automation, single use/disposable technologies and closed systems to replace traditional aseptic processing lines. These technologies reduce the amount of human intervention required, which is the main source of microbial contamination. New construction should ideally have these technologies built in as part of the design. A lot of firms are still using the old traditional methods where better technology is available and has been for some time.
2. I also see a shift from “standard industry practice” to risk based controls specifically tailored to the product and processes in question. New technologies are emerging faster than the regulatory bodies can issue specific requirements. The current lack of specific guidance for so-called “low bioburden processes”, which have elements of both aseptic processing and nonsterile manufacturing is a good example of this. This basically put the onus on the industry, and will require firms to have very strong, science-based and holistic QRM programs.

Sandle: It is interesting that compendia appear to be removing limits, such as recommended levels of bioburden and endotoxin for excipients and raw materials, and placing the need for an assessment with manufacturers to assess the risk in relation to their own processes. There is a similar expectation with ‘objectionable microorganisms’; things have shifted from prescribed lists to the need for pharmaceutical manufacturers to deploy scientific decision making as to which microorganisms, potentially present in the manufacturing environment, present a risk to a product (which involves understanding the physicochemical properties of the product) and to the patient population for which the product is intended.

Moldenhauer: I see the industry working towards a climate of prevention of contamination rather than reaction to contamination.