The Future of Aseptic Processing Sterility by Design Dr. James E. Akers Technical Advisor Shibuya Kogyo, Co. LTD. 1 Japan PDA 2013
Background Sterility by Design is a concept Mr. J. Agalloco and I began developing in 2006 and has since been the subject of articles and two text book chapters now in the press. Its development was a joint effort in which we built on years of discussion and extensive collaboration on the subjects of aseptic processing, sterilization, and sterility assurance. It also was influenced by our work on the Akers-Agalloco risk analysis approach. It was further influenced by work done by Dr. Katayama and colleagues in Japan on aseptic risk and quality assessment. 2
Validation- Test? Monitor? or Design? In the 1970 s, when validation was first being introduced part of the rationale was the understanding that “quality cannot be tested into products it must be designed and built in to products. In aseptic processing the standards appear to be built on the idea that quality (sterility) can be monitored into products. The concepts central to validation included the idea that once process designs were shown to work in practice through effective design and performance qualification, less testing would be necessary. 3
The Quality by Design Concept Is not new- it was introduced by J. M. Juran in a book published in 1992. Juran thought that any new product was a “Hatchery” for quality problems. Juran focused on “Gaps” relating to what a customer actually needs, what the supplier thinks the customer needs, what the supplier designs, and finally what the supplier delivers. Juran was concerned about an understanding “Gap” between what the customer needed and what an organization tried to supply. Juran taught us that the key element of quality is fitness for use. 4
The Sterile Product Customer The customer in this case may be the healthcare provider and/or the patient. What is required are: ① Products which are effective ② Products which do not result in infections, fever, or other toxemias. ③ Is this consistent the producer’s understanding of aseptic product requirements? The regulatory requirements? 5
Are Regulations and Standards Aligned with the Customer’s Needs? To answer this question we must ask if what we do to ensure safety provides value to the customer (patient)? ① Does environmental monitoring provide safety to the patient? ② Does the sterility test provide value to the patient? ③ Do media fills provide safety to the patient? Are there other means of assuring the same or higher level of safety at a lower cost? 6
Are Sterile Products manufactured by Industry Safe? Researching back to 2001 I was unable to find any evidence of sterility failures involving sterile products manufactured by industry (pharma/biopharma). In the USA alone we average according to the Centers for Disease Control about 1. 7 million hospital acquired infections (HAIs) per year (2010 data). About 95, 000 -100, 000 of those who contract HAIs in the USA die. In Europe ~25, 000 die of HAIs each year Japan averages about 90, 000 -100, 000 nosocomial infections per year. 7
There is a big problem with patients becoming infected during medical treatment! It seems from the available data that industrially produced sterile and aseptic sterile products are not a significant source of risk. A quality expert might conclude that to serve the customer of healthcare there should be more focus on infection control in direct patient care. But spending more resources and money on controlling sterile product manufacturing is not money well spent. Perhaps, particularly in the USA and Europe we have a “quality gap” as Juran would say and we are spending too much of our resources on aspects of healthcare that can be shown to provide little customer benefit. 8
“The Regulatory Spiral” The Regulatory Spiral is a phrase coined by Mr. John Sharp in the late 1990’s while he was working for the UK Medicines Control Authority. In the Regulatory Spiral each technological advance introduced results in regulators responding to this “new state of the art” by tightening standards. The result is an ever growing and tightening spiral of as Mr. Sharp put it “increasingly demanding standards”. Mr. Sharp speculated that this spiral might be kicked-off by companies wishing to gain advantage or by over zealous inspectors. 9
The Regulatory Spiral and Aseptic Processing There has been a regulatory spiral associated with aseptic processing and it has had the following effects: ① An ongoing increase in Environmental Monitoring sample intensity ② An ongoing tightening of acceptance criteria for both EM and media fill tests. ③ Increasingly more complex air visualization studies ④ Difficult and costly validation requirements for advanced technologies in spite of their clear safety/risk reduction advantages. ⑤ And others as well! 10
Current aseptic standards and regulations are: Based on the premise that it is possible to both test and monitor quality into aseptically produced products. Even though risk and contamination rate data indicate that aseptic processing performance (safety) is better than ever before microbiological test requirements continue to increase. The industry is essentially being asked to test and monitor sterility into the products, perhaps more than ever before. There has been little discussion about how to use initiatives such as PAT or Qb. D in aseptic processing. The validation requirements for isolators and other advanced aseptic processing has not been reconsidered to reflect technology improvements. Validation of advanced technologies parallels the requirements for human-scale clean room aseptic processing even as those requirements continue to evolve and require more testing, validation studies and ongoing monitoring. 11
The regulatory spiral continues without consideration of the following facts: We can’t prove that sterility exists in aseptic processingthere is no amount of testing or monitoring that would enable us to prove sterility. The proof of sterility would require us to take a sample of infinite size (volume) and test it with an analytical method that had a limit of detection of zero. This method would also have to have perfect sensitivity since it would have to detect all potential contaminants. Scientific experience and wisdom informs us that this approach is a dead end. 12
It is necessary to stop and reverse the regulatory spiral We should rely on engineering to specific defined principals and demonstration of compliance with user requirements specifications in place of microbiological testing and monitoring. It is possible to define the physical performance conditions that must be present for the safety of aseptic products to be assured. With proper design, execution and validation of advanced technologies against defined specifications microbiological testing and monitoring are not required. Given the limitations of microbiological methods they do not provide useful information with most modern technologies including state of the art clean room designs. 13
Aseptic Processing is not in 2013 a difficult challenge It is not difficult to design a modern aseptic operation that provides Sterility by Design. There are only a few key factors that must be carefully specified and controlled. Where advanced aseptic processing technologies are used the major risk, human contamination, is effectively eliminated by the inherent features of the design. Therefore, all we need to is bring sterilized product, containers and closures together in a microbial contamination free environment. 14
Sterility by Design in Cleanrooms Thorough design and execution makes microbiological testing less significant. Equipment Design Facility Design Personnel Traffic Flow Disinfection Environment HVAC Equipment Storage Conditions Validation Product Personnel Practices & Training Product & Material Flow Cleaning & Maintenance Procedures Product & Materials 15 Sterilization
Microbial Proliferation- An Objectionable Condition Any proliferation of microorganisms in a facility or process is an objectionable condition. It is critical to have product knowledge regarding the characteristics of each product. Products of natural origin such as proteins or peptides can support microbial growth. Dry powders with low moisture levels, products with high ionic strength, are at p. H’s lower than about 3 or high than 9, or products that are inherently antimicrobial are generally inherently safe from microbial proliferation. 16
Microbial Contamination and Harmful Effects to Product } Microbial Contamination Could: } 1. Destroy the intrinsic quality of a product by causing damage to the product such that its efficacy is lost in part or completely. } 2. Product Harmful Side Effects in the form of potential to cause in infection or toxemia. } In order for a microbiological contamination event to cause toxin formation that could result in harmful effects to patients, or could damage product efficacy the following condition must be met: } Microorganisms must proliferate in the product or its ingredients in sufficient numbers to result in the production of toxins, or damage active ingredients resulting in degradation of the product. NO PROLIFERATION = NO TOXIN AND NO PRODUCT DAMAGE. 17 6
Conventional Aseptic Processing can produce safe products Aseptic processing has been performed since its beginnings under conditions that could never be demonstrated to be ‘sterile’. As as long as the contamination risks are understood, and measures taken to minimize them aseptic products made in human scale clean rooms are very safe. Conditions required to produce safe products are easy to understand accomplish. Safety depends on an environment in which organisms cannot proliferate, well-trained operators, equipment that is sufficiently automated so that the most difficult interventions are eliminated, an environment will HEPA filtered air at high air exchange rates, highly retentive clean room gowns. Advanced technologies, however, make it easier to design facilities and processes for aseptic manufacturing because they have inherently higher contamination control and risk mitigation capabilities. 18
Absolute Sterility The regulatory spiral over the last 20 years makes it appear that absolute sterility has been a regulatory objective. We know though that absolute sterility can certainly not be attained in clean rooms with direct human intervention. This raises the question as to whether products filled on aseptic processes only capable of the historically required 0. 1% contamination rate pose a medical risk. The answer seems to be no- provided of course there is no microbial growth in the product container. The data regarding product contamination and medical risk makes in reasonable to ask if some regulatory ideas are cost effective given their limited effect on patient risk? 19
Examples of Requirements that are unlikely to reduce risk to patients. Air visualization studies using various types of smoke generation in ISO 5 environments- no relationship has been scientifically make with contamination risk mitigation. Placement of cap seaming systems for vials in EU Grade A, or ISO 5 environments, because this has never been identified as a source of contamination in process simulation tests. Increasing EM sampling frequency and sampling locations- because there is no evidence that more EM corresponds to better contamination risk management. In ISO 5 environments contamination rates do not vary with exposure and are typically >99% negative (zero CFU) Larger media fill samples and processing times, because the increases in media fill sample size to sometimes 20, 000 or more and longer run times has not resulted in more positive units being observed. 20
Sterility Assurance-Points to Consider-1 Sterility is the absence of organisms capable of replicating- given statistical limitations there is no way to directly demonstrate sterility. Sterility assurance is by convention the probability that the condition of sterility exists in a material- in terminal sterilization we can calculate a true SAL in aseptic processing we cannot we can only estimate a minimum rate of contamination. 21
Sterility Assurance Points to Consider-2 There are three ways we attempt to evaluate “sterility assurance” in aseptic processing: ① Process simulation or media fill tests ② Sterility testing which is severally limited statistically and in terms of analytical sensitivity. ③ Environmental Monitoring which does not directly test product and is limited both statistically and in terms of analytical sensitivity. All three listed methods are attempts to test or monitor sterility into the process and are not acceptable proofs of sterility assurance no matter how intensive we make the testing or how low we try to push analytical sensitivity. In spite of much discussion Rapid Microbial Methods will only get results faster, they will only marginally (if at all) improve sensitivity. 22
Engineering Product Safety (sterility assurance) Design and Construction of Manufacturing facilities and environment Selection, Design and Construction of aseptic processing systems based on appropriate technologies Package engineering of drug delivery systems and containers. Formulation development and sterilization of product prior to fill Design of product filtration skids, storage vessels and product delivery to aseptic fill system including CIP/SIP. 23
Containers and Closure Systems Quality is often Overlooked Higher AQLs for defects can result in fewer component feed faults and fewer interventions/adjustments 24
Sterility by Design Engineering of quality into process as described by J. M Juran is not a new idea. However, the risk assessments we are doing in industry are not built on an engineering platform that will result in better outcomes. We do not need risk assessment based upon unscientific models we need risk mitigation based upon process and product knowledge and sound engineering principles. We are wasting time, resources and money attempting to test sterility into our aseptic processed drugs and biologics With newer advanced aseptic technologies testing and monitoring will become even less significant. We must find more efficient approaches relying on the establishment of sound physical operational principles based upon URS derived from sound engineering and scientific principles 25
Concluding Thoughts FMEA based risk analysis is a popular concept now, but it has contributed nothing new to aseptic processing technology. This is because the assumptions often made for risk levels and criticality are based upon incorrect concepts. This can readily be seen by the comparatively high risk seen associated with for example isolator decontamination which is actually a minor risk component. Improvements in aseptic processing will come from better engineered processing systems and we will not be able to measure these improvements using media fills or EM. 26
Improvements in Aseptic Processing always come from: Utilizing automation to reduce reliance on personnel for routine and corrective interventions. Applying separative technologies such as barriers or isolators to eliminate human contamination from the critical production zone. It follows that the future of aseptic processing rests with full separated and fully automated systems that can be run from a control room with no direct human interaction with the process during aseptic filling, packaging or assembly. 27
Thank you for your kind attention! 28
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