How Technology (And The People Who Use It) Will Reshape The Future Of Aseptic Processing (Part3)

 

Aseptic practices are quite difficult and skillful for handling critical area, where risk is always high in compare to other dosage forms. The very common issues comes in area due to behavioural part and handling of materials, which causes interventions in area and become major source of contamination - viable / non-viable both.

This is the 3rd and last article of series sent you for Aseptic area processing and handling. These series must have helped in various way to understand latest developments and discussion coming ahead in aseptic processing and technics.

How Technology (And The People Who Use It) Will Reshape The Future Of Aseptic Processing

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https://www.pharmaceuticalonline.com/doc/how-technology-and-the-people-who-use-it-will-reshape-the-future-of-aseptic-processing-0001

Posted By: Dr. Tarun Chugh

Growth Promotion Testing For EM

Reference Materials Critical for Ensuring Effective Environmental Monitoring Tests

Growth promotion testing of culture media is an important part of microbiological testing in support of pharmaceutical quality (1). The growth promotion test is a quality control requirement that confirms the ability of a new batch of media to support growth of a predetermined selection of representative microorganisms. All media used in a cGMP facility should be tested, including media for microbial limits, environmental monitoring and sterility testing (2,3). Growth promotion testing requirements apply to in-house and externally purchased media (3,4).

Suspension Method versus Reference Materials

Microbiological reference materials are now readily available from multiple suppliers in all major locations. They are available in many different forms, including qualitative and quantitative formats. Quantitative reference materials contain a defined number of viable microorganisms and are normally a freeze-dried or gel suspension supplied with a Certificate of Analysis (COA) specifying the number of viable microorganisms that should be recoverable. Prior to the availability of high-quality reference materials, growth promotion testing was usually performed by plating a serial diluted microorganism suspension on both a new and a previously released media batch to compare recoveries. This method proved difficult in obtaining accurate results (5). In addition, this approach is potentially flawed in that the inoculum does not come with a COA and a gradual decline in viability might not be readily detected. Testing with a reference material provides an independent and precise external calibration point. Every batch of ready-to-use reference material should come from an ISO 17034:2016 accredited manufacturer and offer quantitative data specific to the batch on the COA (6). The COA should report a mean colony forming unit (cfu) count and the standard deviation for each batch.

Certified reference materials have been widely used in analytical chemistry for many decades but have only been available for microbiologists in recent years (7). A certified reference material is a reference material characterized by a metrologically valid procedure for one or more specified properties, accompanied by a certificate that states the value of the specified property, its associated uncertainty of measurement and a statement of metrological traceability (8). Metrological traceability is the property of a measurement result whereby the result can be related to a reference through a documented unbroken chain of calibrations, each contributing to the measurement uncertainty (9). This means that when using a measurement result with metrological traceability, such as the average cfu count of a certified reference material accredited for its quantification, measurements can be meaningfully compared even when they are made at different times and places by different people or using different equipment (10). For quantitative methods such as growth promotion testing, a certified reference material that has a quantitative property value, such as cfu, would further enhance the ability to achieve comparable results as per pharmacopeia requirements.

During pharmaceutical manufacturing, each facility must perform environmental monitoring that measures and monitors levels of microbial bioburden (11). Keep in mind, the pharmacopoeias are not harmonized for environmental monitoring and each has varying requirements that demand very low initial contamination recovery rates or the detection of very low cfu levels (Tables 1 and 2). The requirements vary depending on the criticality of the manufacturing area to product sterility. Depending on the cleanroom classification, there can be very stringent requirements on the outcome of environmental monitoring. For example, in rooms such as ISO 5 and 6, the cfu counts allowable are extremely low and need to be managed very closely. In USP <1116> Microbiological Control and Monitoring of Aseptic Processing Environments, it states that suggested initial contamination recovery rates for aseptic environments in ISO 5 and ISO 6 rooms should only show contamination in control plates <1% and <3% of the times, respectively (12). This means that at least 97% of the time, there is no growth expected. Furthermore, in the “EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use Annex 1 Manufacture of Sterile Medicinal Products” it is very clear about the CFU numbers recommended as limits of microbial contamination (13).

Table 1 Suggested Initial Contamination Recovery Rates in Aseptic Environments Per 1116

Table 2 EU Guidelines in Annex 1

For example, when considering contact plates for Grade A and B rooms (ISO 5 and 6), <1 and <5 colonies must be recovered. These are very small numbers of cfu, implying that the contact plates should be able to recover and grow a small number of microorganisms. Consequently, users need to be confident about the quality, especially fertility performance, of the culture media used. Recent studies performed on environmental monitoring of surfaces have shown variation in recovery of microorganisms between the surfaces sampled (14). Another study found discrepancies between the suppliers of contact plates leading to random and systematic errors (15). It is important to be highly confident about the performance of the culture media used.

What Does USP Say?

USP growth promotion testing requirements for solid and liquid microbiological growth media is described in <61> as:

"For solid media, growth obtained must not differ by a factor greater than 2 from the calculated value for a standardized inoculum. For a freshly prepared inoculum, growth of the microorganisms comparable to that previously obtained with a previously tested and approved batch of medium occurs. Liquid media are suitable if clearly visible growth of the microorganisms comparable to that previously obtained with a previously tested and approved batch of medium occurs" (1).

USP also stipulates using less than 100 cfu. A factor of 2 is commonly interpreted as a recovery of 50 to 200%, otherwise half or double the cfu count of the original growth promotion testing inoculum. In the case of growth promotion testing, this comparison is between the calculated cfu of the previously tested media and that of the new media batch, e.g., if the previous batch of tested media had 50 cfu, the new media batch must have >25 and <100 CFU to pass. This approach allows between 25 to 100 cfu which could be a variation of up to 75 cfu between agar plates and still have a passing growth promotion testing result. This wide acceptance criteria allows for variation in the inoculum, particularly if the inoculum is prepared by serial dilution.

Unless monitored closely, comparing previous batches could result in progressive decline in media performance, leading to the possible acceptance of less fertile culture media (16). For this reason, acceptance criteria that also include results based on a standardized microorganism preparation brings much more confidence to growth promotion testing results.

Conclusion

• Use an ISO17034:2016 accredited reference material for growth promotion testing
• Choose a reference material or certified reference material with the smallest standard deviation to heighten the capability to observe media fertility changes
• Select a reference material or certified reference material with batch-to-batch consistency in cfu levels
• Ensure use of a reference material able to match COA quantitative data
• Compare the specified cfu count stated on COA with the results from the growth promotion testing and set internal target recovery levels (nonselective media)
• Monitor trends in growth promotion testing results to look for discontinuities or drifts in media fertility over time

With the current availability of high quality, precise and accurate reference materials and certified reference materials, consistently accurate and precise results can be achieved to allow qualification of a new culture media batch’s performance with a high degree of confidence.

References

1. USP <61> Microbiological examination of non-sterile products: microbial enumeration tests
2. USP <1117> Microbiological best laboratory practices
3. Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice, U.S. FDA, September 2004
4. Pharmaceutical Microbiology Manual, U.S. FDA, 2014
5. Sutton, S. “Accuracy of Plate Counts.” Journal of Validation Technology 17 (2011): 42–48.
6. ISO17034:2016 General requirements for the competence of reference material producers
7. Fajgelj, A. 2000 Using Certified Reference Materials in Analytical Chemistry - Present Status, Trends and Needs. Spectroscopy 15 (2000): 19–21.
8. ISO Guide 30:2015 Clause 2.1.2
9. VIM3 Clause 2.41 metrological traceability
10. Armishaw, P. “Certified Reference Materials - A Path to Traceable Chemical Measurements.” Presented at the Australian National Measurement Institute May 5, 2016.
11. Peacos, P. “Using Contamination Rates For Environmental Monitoring Trending-It’s Not Just For Clean Rooms.” American Pharmaceutical Review (February 16, 2016)
12. USP <1116> Microbiological control and monitoring of aseptic processing environments
13. EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - Annex 1 Manufacture of Sterile Medicinal Products - 2008
14. Goverde M, et al,. “Evaluation of the Recovery Rate of Different Swabs for Microbial Environmental Monitoring.” PDA Journal of Pharmaceutical Science and Technology 71 (2017): 33–42.
15. Grosselin, J., “Quantitative evaluation of microorganisms recovery from surfaces using contact plates.” Presented at the European Microbiology Conference, Vienna, April 2018.
16. Guidelines for Assuring Quality of Medical Microbiological Culture Media. July 2012. Culture Media Special Interest Group for the Australian Society for Microbiology, Inc.

written by: Brendan Tindall, biomerieux, and Graham Vesey, Regeneus | Jan 22, 2019

Source: PDA Letter

Posted By: Dr. Tarun Chugh

Re-imagining Aseptic Processing: What Must Change?

Re-imagining Aseptic Processing: What Must Change?

This article is the second in a three-part series exploring the need and means to achieve improvement in aseptic processing of sterile products. 

In 2011, Dr. Janet Woodcock, director of the U.S. FDA CDER and former deputy commissioner, discussing supply shortages of critically needed medicines, noted that “By 2010, shortages nearly tripled to 178, three-quarters of which were injectable drugs...” Dr. Woodcock affixed much of the blame on industry’s inability to modernize aging facilities and processes, stating that “factors (they) cited were aging facilities, production lines crowded by manufacturers trying to produce various products, a lack of oversight over manufacturing subcontractors, and the economic downturn.”1

The sterile products manufacturing business does have unique characteristics that at times hamper the adoption of new technology. The industry is highly regulated, approval and validation of technology changes takes significant time and resources, focus on speed to market results in risk avoidance, and operating margins are relatively high, softening the incentive for technology improvement. However, as noted in Part 1 of this series, there will be pressure on the industry to ensure product availability, reduce healthcare costs, improve product quality assurance, and adapt to the challenges of manufacturing new personalized medicines. These demands on our industry for improved productivity and process control require better use of technology. This will impact how we plan and run our manufacturing operations.

Productivity Vs. Quality

Process control and productivity are improved through the use of new technology. Embracing new technology requires financial investment. The return on this investment is often regarded in terms of cost of quality. But, technology does not necessarily increase manufacturing cost. It is important to recognize that controlling manufacturing cost and improving process quality are not mutually exclusive, conflicting objectives. Investing in technology to achieve a higher level of process quality can have positive returns in both quality and productivity. Quality processes and designs result in fewer defects, failures, and investigations, higher yields, and lower costs. Higher yields are a good indicator of a well-controlled, managed, reliable quality process. Reliable quality processes and higher productivity can mitigate drug product shortages.

Here are just some examples of how aseptic processing productivity can be improved:

• Cleanrooms are designed to operate 24/7, yet today many aseptic process operations are limited to single-shift five-day production. Extending aseptic filling processes longer could increase output and productivity by 300 percent, while reducing downtime, changeovers, and the errors that result from start-ups.
• Data acquisition and analysis is available at unprecedented levels. Using manufacturing intelligence, Big Data, artificial intelligence, and PAT (process analytical technology) can provide better process understanding, control, and decisions through predictive modeling, real-time release, and process parameter and environmental monitoring trend analysis.
• Continuous process manufacturing is already used in API and solid dosage drug processes. Adopting continuous manufacturing methods for aseptic processing would eliminate changeovers, decrease human intervention, shrink the crucial aseptic manufacturing space, reduce start-up-related deviations, and eliminate opportunities for microbial contamination.
• Where processes rely on human performance, focusing on ergonomic aseptic process design, automation, and barrier technology can reduce or eliminate the source and impact of personnel-related process weakness, variability, and contamination.

Accepting New Contamination Control Strategies

Accepting new technology means taking a critical thinking approach to contamination control. Few would argue the importance of developing effective microbiological contamination control strategies. In doing so, however, it is essential to focus on efforts that will yield real benefits to product quality.

Critical, scientific evaluation of microbiological evidence may provide conclusions that are contrary to today’s approaches. Not all microorganisms detected in the environment represent the same risk of product contamination. Evaluation of the trend of microorganisms below limits can be more useful than identification of excursions beyond limits. Reaction to trends and excursions should be based on the understanding of the capability and limitations of the contamination control measures. Proper reaction to excursions and deviations can reduce unproductive efforts that distract from more impactful issues.

Where applicable, lower temperature terminal sterilization and post aseptic lethal treatments can decrease the risk of microbiological contamination and provide opportunities for real-time, parametric release of these products. To achieve this increase in sterility assurance, companies will have to reconsider container composition and capital investment in post filling treatment systems.

The use of rapid and real-time microbiological detecting systems offers contamination detection and product release benefits. However, their widespread use will require a shift from traditional colony forming unit (CFU) detection to evaluation at smaller, even cellular, detection levels. Determining a practical correlation between detection and product quality and demonstrating such to regulators will be essential.

As monitoring technology is improved, the ability to detect microorganism increases. This will require a clear understanding of what levels of microbial observation constitute risks to patient health. Failure to do so will likely result in overly stringent control steps and the rejection of acceptable product, as more microorganisms are detected. Given the rising cost of healthcare products, the increasing focus on manufacturing costs, and the resulting business decisions affecting supply of needed drug products, these additional actions will be of questionable benefit to the public. One should recognize that it is often easier to make product acceptance decisions on a zero-sum, pass or fail test result basis than it is to carefully evaluate contamination-related evidence and judge conclusions based on that evidence. This will place additional burden on the quality unit and regulators, making it more difficult to choose the latter, more effective approach. Therefore, successful use of new contamination monitoring technology and contamination control strategies may depend on the automation of data acquisition, evaluation, and decision-making methods and tools.

Considering Changes In Aseptic Process Validation Approach

Using new technology means changing one’s thoughts on process validation. Today, validation is largely based on process testing and detection of failures. Many companies still see process validation largely as a regulatory demonstration exercise, rather than as a program to gain knowledge, confidence, and process improvement.

Validation and monitoring are essential process control tools. Yet detection effectiveness can be overstated. Reliance on media fills, monitoring, and product testing to assure quality, rather than relying on sound process design, is not effective. Preventing failure through process design is a better means of risk mitigation, and as such will be more useful for the design, acceptance, and use of new technologies.

There is an over-reliance on aseptic process simulations to validate aspects of the aseptic process.  Aseptic process simulations should not be the sole judge of the capability of a process, set of process steps, or personnel. Aseptic process simulations provide value by helping to uncover process weaknesses that may otherwise be missed during process control strategy design. Relying on media fills to do more than they are designed to do is ineffective and may provide a false sense of security. Aseptic process simulations should not be used to:

Determine if the process is proper and effective. Validation of the aseptic process involves a holistic, multi-faceted approach to design and qualification.2 The passage of three replicate media fill runs without an understanding or focus on process variability does not provide a substantial challenge to ensure continued process reliability and performance. Therefore, the objective of the aseptic process simulation should change from validating the aseptic process to uncovering system and process weaknesses and variables that might have been missed in or arisen after qualification.

Qualify personnel or demonstrate their proficiency. The qualification of cleanroom personnel through replicate aseptic process simulations is burdensome and ineffective. Human performance is too variable to be effectively qualified by the presence and activities of personnel during media fills. Participation in aseptic process simulations do not necessarily test their ability to perform their job using proper aseptic technique, nor does it prove their ability to perform over long durations. Instead, aseptic processes, equipment, and technology should be designed to minimize the risk and effect of human activity variability on product quality, and personnel should be trained to perform those activities understanding and using proper aseptic practice.

Validate interventions. One should not rely on uncovering flaws in the intervention technique or related process design. The chance occurrence of a microorganism finding its way into a container during the performance of an improper intervention is insufficient. Aseptic processing interventions should be designed to use first air principles, aseptic technique, and cleanroom behavior. These are best confirmed through proper design and design review. Confidence in the acceptability of interventions should change from demonstration in media fills to carefully thought-out process and equipment design. Eliminate interventions through such means as automation or minimize the impact of interventions through such means as barrier or closed processing systems.

Establish holding, filling periods, durations, or conditions. Qualification and validation runs should not be used to set process conditions or parameters. The process, including all critical conditions and parameters, should be established during process design based on manufacturing requirements. Once set, the process can then be confirmed or demonstrated during the qualification and validation studies. Sterile or decontaminated material/product holding periods should be qualified through separate studies and tests designed to challenge specific aspects of process design, such as the integrity of seals, the microbial barrier properties of the wrap material, the consistency of the wrapping and transfer procedures, and the environmental holding conditions.

Simulate operator fatigue or show effect on performance. Where operator fatigue can affect process performance and product quality, process design steps, including automation and ergonomic designs, should be taken to minimize those effects, rather than rely on aseptic process simulations to address human endurance.

Confirm decontamination process. The aseptic process simulation does not provide a quantifiable contamination challenge to test the decontamination procedure. Decontamination and disinfection procedures should be qualified through a combination of proper equipment design, disinfectant efficacy/effectiveness studies and in situ procedure challenges.

Qualify the capability or acceptability of manufacturing equipment. Aseptic process simulations are not sensitive enough to uncover improper equipment designs, flaws, defects, wear, or poor practice use. Aseptic processing equipment, including component handling and filling systems should be designed to operate in an aseptic process, qualified in separate studies prior to inclusion in media fills, and properly maintained after qualification. Where equipment related flaws or defects are suspected, those weaknesses should be addressed through process changes, repairs, or replacement, before inclusion in media fills.

Changes In Computer System Validation

Other examples of where traditional validation approaches will need to change are automation and knowledge management. As processes become more automated and continuous, process validation will shift from a matter of process testing and replicating runs to qualification of the automated control systems that control process parameters. As manufacturing intelligence and shared data acquisition and utilization systems are used more, the notion of computer system validation based on U.S. 21 CFR Part 11 and computer software guidance may need to change.

Much of the guidance and requirements on computer system validation address closed, self-contained, stand-alone systems and were encouraged to ensure security and validity of data. Validation of computerized systems relied on confirmation of process performance and product quality results. Today, more open, cloud based, and interlinked systems are being used. Decisions will be made based on a complex set of interactive data evaluation. Automated systems will involve continuous process and quality verification and adjustment to process parameters and settings, focused on maintaining quality attributes. This will represent a shift in validation approach from confirming process parameters to confirming the ability to control product parameters to meet product quality attributes. Qualification of systems designed to address data integrity will mean more than prevention of fraudulent data recording. It will place more emphasis on prevention of the misuse and misinterpretation of data.

References:

1. Woodcock, J. and Wosinska, M., "Economic and technological drivers of generic sterile injectable drug shortages", Clinical Pharmacology and Therapeutics, Apr. 2013.
2. PDA Technical Report No. 22, Process Simulation for Aseptically Filled Products, 2011.

By Hal Baseman, COO and a principal, ValSource, LLC

Posted By: Dr. Tarun Chugh

Why Now Is The Time For An Aseptic Processing Revolution

This article is the first in a three-part series exploring the need and means to achieve improvement in aseptic processing of sterile biopharmaceutical products. Part 1 will present the current state and opportunity for improvement using innovative technology. Part 2 will further discuss some of the changes in strategy that might be needed for and result from the use and improvement of technology. Part 3 will present the impact of technology changes.

The manufacturing of sterile biopharmaceutical products using aseptic processing has not materially changed in decades, resulting in the same compliance-related issues and manufacturing challenges from year to year. While it is true that more and more companies are using isolators and barrier systems, the filling systems they encase are largely the same as conventional filling lines. The means to sterilize, transport, and fill products remains the same. Some companies are doing electronic batch records and data evaluation, but for the most part we still rely on varying levels of manual data entry with little connectivity of data gathering systems. PAT (process analytical technology), which showed promise in the early 2000s, has yet to take a foothold in aseptic processing. Operators still gown the same way. Control systems operate separately and independently, rarely exchanging information. Environmental monitoring relies on the placement, incubation, and reading of media. The result of this lack of technological advancement can be seen in:

• Lack of productivity: Today, many, if not most, companies operate largely on a four- to five-day per week, single-shift schedule, despite modern cleanrooms being designed to operate at high capacity levels around the clock.
• Lack of scientifically based decision making: Sterility assurance is based on the observation performance surrogates, such as media fills, environmental monitoring, and end-product testing, where the correlation between what is observed and the desired state of product sterility is vague.
• Underinformed decision making:We treat environmental microorganisms as direct indicators of product contamination, even though we have yet to quantify the scientific relationship between environmental conditions and product sterility.
• Human performance variation: We tend to rely on significant human intervention in filling operations, both conventional and isolator. Most material transfers and cleanroom disinfection are manual. Filling and environmental monitoring setup and performance are largely manual. We do little to consider ergonomics or process design for human error prevention, relying instead on often ineffective training methods to prevent and correct human performance issues.
• Fear to challenge: We acknowledge the need for improvement and the desire to embrace technology, but we place more emphasis on regulatory expectations than on critical and risk-based thinking, often fearing the risk of regulatory scrutiny and burden more than enjoying the benefits of innovative methods.

The future improvement of aseptic processing lies in better use of technology to meet the requirements of existing products and new therapies. Aseptic processing would benefit from automation, virtual reality, artificial intelligence, machine learning, and predictive modeling. These could lead to technology advances in contamination control using barrier systems, such as isolators and closed RABS (restricted access barrier systems), closed container filling, post aseptic lethal treatments, lower temperature terminal sterilization, rapid microbiological monitoring and testing methods. Continuous process manufacturing and parametric or real-time release for sterile products could bring higher productivity. Facilities of the future could be modular, with a trend to smaller, less complex, and easier to control critical product exposure spaces. All these technologies exist today and could benefit the industry.

However, despite huge advances in technology in other industries, aseptic processing of sterile medicinal products has struggled to adopt new technologies. There are many reasons for the reluctance of companies to embrace innovative aseptic processing technology, including regulatory questions and expectations, more burdensome qualification, additional time for pre-approval change notification, risk aversion, lack of knowledge about the technology, fear of the unknown, capital and operating costs, and lack of defined benefit. Whether these concerns are more perception than reality, they are all obstacles and barriers to innovation. Overcoming these obstacles has not been easy.

However, conditions in the industry are changing. This may be the right time for a technology revolution.

Regulators are ready.

Globally, health authorities and regulators are encouraging new approaches. EMA, PIC/S, and the FDA are suggesting and expecting the use of risk-based approaches to process design and control. This can be seen in the recent release of the EMA proposed revisions to Annex 1 (Manufacture of Sterile Medicinal Products), prepared by an international PIC/S working group that included representatives from Europe, the U.S. FDA, Australia, and Japan. The revision contains 43 specific recommendations for risk approaches, with many more implied. This opens the door for the industry to consider and propose new approaches.

The financial incentive is there.

Many of the blockbuster healthcare products are sterile injectable or implantable, produced by aseptic processing. This provides a strong business and financial driver for improving the productivity and efficiency of aseptic processes, and the rationale for modernizing aged facilities, including those used for manufacturing outsourcing.

The control strategies we have may no longer fit what we need.

The future will involve sterile ATMP (advanced therapy medicinal products), cell and gene therapy products, and personalized medicine. These new therapies require aseptic processing. Current aseptic processing approaches do not adequately address the unique needs of the manufacturing of autologous sterile products on the requisite small scale. New (and improved) science and risk-based approaches are needed. The tight release criteria and timeline for these products will provide the opportunity for rapid microbiological testing and in-process, real-time release of sterile products. These advancements will require and lead to changes in regulatory guidance, acceptance of new approaches, and use of innovative methods.

It is the right thing to do.

The effectiveness of biopharmaceutical products and therapies, the demand for these products from emerging growth markets, the cost of healthcare in the U.S., and product shortages have placed an emphasis on product availability and affordability. Life-changing and lifesaving therapies are only useful if they are available and affordable. This, coupled with shareholder pressure for better returns and performance, will add emphasis to the need for manufacturing process efficiency and productivity improvement.

Industry 4.0 is here and waiting.

There is a significant opportunity to acquire and link data at unprecedented levels. This information and knowledge can be used to better model, predict, and control aseptic processes. Virtual reality and simulation can be used to design facilities, plan and address problems in simulation without putting at risk actual plant operations, provide more effective training, more expeditious qualification, and higher levels of worker awareness. Artificial intelligence and machine learning can use data to optimize processes and process control.

The workforce is changing.

It is becoming more difficult to attract, train, and keep technical resources. The lack of enough skilled, qualified manufacturing personnel will result in the use of more automation, continuous process manufacturing, and smaller, less complex plants. In addition, innovation and cutting-edge technology will help attract the young technical talent needed by the industry.

The Opportunity For Aseptic Process Manufacturing Improvement

For the industry to meet the needs the future will demand, it must improve its use of technology. Critical thinking and science-based decision making will lead to better selection, adoption, and use of technology for aseptic process improvement. Critical thinking means making reasoned judgments that are logical and well thought out. It is a way of thinking in which one does not accept all arguments and conclusions but asks why and why not. To overcome the reluctance to use new technology, the industry must consider that:

• Traditional approaches to process control by monitoring and detection may be ineffective and should be reevaluated.

• Safe, tried-and-true traditional methods for process control may not represent the most effective way to provide process and product quality confidence.
• Requirements and activities with little or no value waste resources and reduce the ability to perform more important efforts, and therefore may pose a risk to public health.
• Risk-based thinking should be unbiased, scientifically sound, data-based, and avoid predetermined outcomes, and where that occurs, regulators should be open to alternate risk-based approaches.

Embracing New Technology Through A Partnership Of Manufacturers, Suppliers, And Regulators

The future of technology in the aseptic processing of sterile medicinal products will depend on and require three principle parties to work in a true partnership: sterile product manufacturers, health authority regulators, and technology suppliers. To be successful, all parties must recognize their respective roles and work in concert.

The role of sterile product manufacturers, as the users of technology, should be to identify manufacturing improvement needs. To do this effectively, sterile product manufactures must be willing to:

• Use critical, risk-based thinking to set useful design requirements and specifications.
• Not accept technology design risk, when better designs can mitigate that risk.
• Take chances and be willing to move out of their comfort zones, away from traditional approaches.
• Consider manufacturing reliability and technology to address areas where improvement is needed.
• Use the tools that may already be available, rather than wait for the “perfect solution.”
• Think ahead in plant and process designs and plan for future innovation.
• Share (nonproprietary) technology information and experience with others in the industry.
• Be open to health authority concerns, but resist looking to regulators for all the answers.

Once needs are identified, the role of technology suppliers is to provide technology to meet those needs. To do this effectively, the developers and suppliers of innovative technology must be willing to:

• Listen to user needs and regulator concerns.
• Be willing to modify existing products to meet user needs and address regulator concerns.
• Research innovative approaches that go beyond existing products.
• Strongly promote and communicate new ideas.
• Go beyond limitations, strive for perfection.

Once technology is offered, the role of regulators and health authorities is to judge whether the approach to using and controlling that technology is appropriate. To do this effectively, health authorities must be willing to:

• Share expectations, criteria for acceptance, and technology successes with the industry.
• Encourage and reward innovation through such means as PAC (post approval change) relief.
• Avoid discouraging new approaches and overburdening new technology efforts with unique and less-than-value-added requirements.
• Help navigate and facilitate innovative efforts through the regulatory process (e.g., the FDA’s ETT [Emerging Technology Team]).
• Be open to well thought out risk-based alternate approaches, when presented by industry.

By Hal Baseman, COO and a principal, ValSource, LLC

Posted by: Dr. TarunChugh 

Do Sterility Test Isolators Need To Be So Complicated?

In an article called “Paradise Lost” written by Jim Agalloco, president of Agalloco & Associates, Jim talks about the intent of early simple isolators for use in the pharmaceutical industry and how that expected “paradise” was never fully realized as isolator designs became more complex. He sums up his article by saying, “No regulator has mandated that isolators be designed to cleanroom standards, and the more we devoid ourselves of that misdirection the easier it will be to implement what should be the globally acknowledged superior technology of isolator”.

A good example of how simple isolators have been made complicated can be found in sterility test isolators. Isolators have been around the pharmaceutical industry since the early 1980s and in the nuclear industry (glovebox technology) since the 1950s. Isolators are used to create an airtight barrier or enclosure around a piece of equipment or process to provide absolute separation between the operator and product. The operator can perform tasks through half-suits or glove ports. Isolators provide a specific environment inside the isolator using HEPA filters. The environment can be positive pressure or negative, can have humidity control, oxygen control, use unidirectional airflow, and can either protect the product from the operator (as with aseptic processes) or protect the operator from the product (as with potent product handling).

The earliest uses of aseptic isolators were for sterility testing. Sterility test isolators make up most of the aseptic isolators in use and are available in many different sizes and configurations. Sterility test isolators do not need to be installed in a classified area. No formal requirement exists for a Grade D environment, but the area should be controlled to allow only trained personnel. The room should also have temperature and humidity control. The simple sterility test isolator shown in Figure A has a positive pressure blower, an inlet and outlet HEPA filter and operates under turbulent airflow. This unit also utilizes a PLC, which very early isolators did not have. However, since the introduction of hydrogen peroxide decontamination generators, automated communication between the isolator and generator are needed. 

The US Pharmacopeia 1208 discusses the design of sterility test isolators. It states that the isolator must meet Class 100 conditions at rest but does not need to meet this classification during operations. Nor does the isolator need to meet an air velocity or air exchange rate criteria. Therefore, turbulent airflow is acceptable in a sterility test isolator; laminar airflow (unidirectional) is not required. 

EU GMP Annex 1 focuses on the manufacture of sterile medicinal products where a Grade D background environment, at minimum, is required. Laminar airflow is needed inside the isolator for manufacturing. No mention is made of sterility test isolators. 

Unidirectional airflow in sterility test isolators is not needed. It may help with distribution of decontamination vapors but this can be achieved with the proper number and placement of distribution fans inside the isolator.  In some instances, half-suit isolators (See Figure B) are needed due to the size of product being tested.  Unidirectional airflow would be disrupted by the half-suit. 

Is particulate control needed in a destructive test? Should the test environment duplicate the filling environment?  Certainly viable monitoring should be conducted in a sterility test isolator so that it can be shown there is no contamination inside the isolator during testing. This was particularly of interest in the past when a work station isolator, often equipped with a single or double half-suit due to its size, was meant to maintain “sterility” over weeks and sometimes months at a time.

A transfer isolator full of product and test supplies would be decontaminated daily and then connected to the work station isolator via a Rapid Transfer Port (RTP) as shown in Figure B. Materials would pass securely from the transfer isolator into the work station isolator without breaking the “containment” of either isolator. The work station isolator would be monitored daily for viable organisms using simple settle plates. The more sophisticated viable monitoring systems of today were not available. Yet the simple method was effective.

Non-viable monitoring wasn’t done in a sterility test isolator until a few years ago. Is it really necessary to know how many non-viable particles are in an isolator when the product is to be discarded? If passing sterility test results without knowing the non-viable counts in the sterility test isolator of 20 years was acceptable then, it certainly could be acceptable now.

Another “nice to have” on an isolator is an airlock. Airlocks are used to enter additional items or exit waste and finished media for incubation out of the isolator. Things to consider with airlocks are the size, number of glove ports needed and the environment. The environment of an airlock can be that of a neutral chamber with no pressure control and no airflow. It can also be positive pressure with turbulent airflow through HEPA filters or unidirectional airflow. Finally, the environment might need to be decontaminated with hydrogen peroxide or another agent. If many tests are being conducted in a day/week where the objective is to keep the main testing chamber “sterile” the airlock(s) can enter and exit materials by first adding the materials into the airlock, then decontaminating the airlock. Once the airlock decontamination cycle is complete (usually in much less time than a larger chamber) and the airlock reaches the appropriate positive pressure and airflow, the door to the main chamber is opened and materials transfer is performed.

However, if testing is done once per day or a few times per week the airlock can be replaced with a good checklist and SOP. Here the main chamber hatchback window is opened and all test materials, product media, etc., is stored on the wire rack shelves in the isolator. Shelving size can easily be determined by simply placing all items needed for sterility testing on a lab bench and “taping” off the footprint of the shelves. This will help determine if a 4-glove isolator is sufficient or if a longer 6-glove isolator (Figure C) is needed. Once all items are in the isolator, the checklist is reviewed to ensure nothing has been forgotten.

The hatchback window is closed and the decontamination cycle is initiated. Once the cycle is complete and the isolator is in run mode under positive pressure HEPA filtered air, testing can begin. At conclusion of testing, the hatchback window is opened and test samples are taken to the incubator and waste removed. The isolator is cleaned and is ready for the next sterility test. An isolator with no airlocks saves equipment cost and validation expenses.

In conclusion, an effective sterility test isolator for low-volume testing can be a 4-glove isolator with a main chamber in 316L stainless steel with a safety glass hatchback window. The isolator will operate under positive pressure, with turbulent airflow through inlet and outlet HEPA filters. A PLC will control the isolator and also communicate with decontamination generators for an automatic decontamination. It can also include stainless steel wire rack shelving for supplies. For high-volume testing a similarly operated isolator with 6 gloves or even half-suits can be used. A transfer isolator can be employed as in the past to bring test materials to the work station isolator. The transfer isolator will also operate as a positive pressure, turbulent flow isolator. These simpler systems achieve the goal of eliminating false positives during testing and a lower cost.

Source: Extract Technology

By Gary Partington, Extract Technology

Posted By:  Dr. Tarun Chugh