What will the pharmaceutical industry look like in 2020? Paul Pluta, Associate Professor of Biopharmaceutics, College of Pharmacy at University of Illinois, Chicago and Editor in Chief of the Journal of Validation Technology and the Journal of GXP Compliance, sees a need for immediate change. “You ask where we should be in six years. I’d prefer to consider what we have to do to get to where we ought to be today. For example, when people don’t determine their worst case compound or identify the actual residue on the equipment, when people use illogical cleaning agents, when people fill a tank half full of water and a ‘scoop’ of cleaning agent without controlling concentration, when people say something like: ‘I had our people clean the equipment three times today so we’ll pass validation’—we have a long way to go. Organizations need to develop a cultural change regarding cleaning. The cleaning process must be respected as a manufacturing process—and not just doing whatever is necessary to get the job done.”
Life cycle—not just validation
Pluta observes that “industry needs to take a lifecycle approach to cleaning following the FDA lifecycle approach to process validation. This means that we have to plan rather than go by the seat of the pants. Lifecycle means 1) proper design and development of the cleaning process; 2) proving it works by validation; and 3) maintaining the process by periodic review of performance. By this method, deficiencies will be noted and continuous improvements should occur.”
Richard Forsyth of Forsyth Pharma Consulting, Philadephia, predicts that by 2020, regulators will expect explanations of, and evidence for, the rationale of cleaning, not just a documented process validation.
Destin LeBlanc, Consultant at Cleaning Validation Technologies in Winter Haven, Fla. expects that “by 2020, most manufacturers will have adopted FDA process validation guidance that includes the three phases of design/development, qualification protocols, and validation maintenance for cleaning validation.”
LeBlanc notes that validation maintenance depends less on repeating validation protocols and “more on collecting routine monitoring data. For cleaning this would include monitoring temperature, time, concentration, and rinse water conductivity to demonstrate a controlled cleaning process. There will also be more trending of data, particularly with automated processes, looking not just at residue limits but also at process control.”
I (Barbara) recall that action and/or alert levels were a given for esoteric clinical testing back in the 1970s—so what took pharmaceuticals so long? LeBlanc responds that part of the problem is that process cleaning is low on the totem pole.
Rizwan Sharnez, Scientific Director at Amgen in Longmont, Colo. explains that a relatively small investment in small-scale characterization can reduce the amount of time and resources required for validation at full scale by over eighty percent. The underlying principle here is that “good science leads to less work in the long run.” He predicts that in a few years biopharma will fully leverage this approach.
Risk assessment
Sharnez hopes that by 2020, methodologies for assessing risk will be based more on scientific understanding of the phenomenological aspects of the cleaning process. For example, during cleaning and sterilization most biologicals denature and degrade into fragments that are pharmacologically inactive. If this is verified during the characterization, the acceptance limit for the process residues should be set based on the inactive fragments instead of the active ingredient.
LeBlanc explains that the rule of thumb of 0.001 of a dose for API (active pharmaceutical ingredient) residue is being challenged. Recent ISPE (International Society for Pharmaceutical Engineering) and EMA (European Medicines Agency) documents refer to toxicological-based determinations for setting allowable API. This approach would enable manufacture of highly hazardous pharmaceuticals in a shared facility in lieu of using dedicated equipment.
Sharnez opines that basing the criteria for bioburden on 0.001 of the dose is arbitrary. “The monoclonal antibody does not survive the cleaning process or sterilization. The protein would be denatured. A denatured protein may have different issues. However, we need to understand and characterize the residue to obtain meaningful acceptance limits for fragmented and degraded protein.”
However, LeBlanc is concerned that these toxicological limits could lead to allowable limits that were significantly less stringent than limits based on the 0.001 dose criterion for non-highly hazardous drugs. “While the toxicity of the API is importance, other issues of residue removal are of concern. This difference could be resolved by the FDA weighing in.” LeBlanc expects that by 2020 we will know the direction to be taken and will have implemented changes. “A reasonable approach,” concludes LeBlanc, “would be to stay with 0.001 dose for traditional drugs, and use the toxicological approach for highly hazardous ones.”
Science
Paul Lopolito, Technical Service Manager at Steris Corp., St. Louis, sees increasing emphasis on scientifically-based decisions in the cleaning process, in the impact of cleaning on surfaces. “There will be increased monitoring. This includes evaluating the cleaning agent chemistry, understanding rinsibility, assessing the toxicity risk of the API, and assuring that the overall cleaning process is robust.
Requirements for quantitative consistency will increase. “Not only will you have to be below the pass/fail,” explains Forsyth, “you have to clean to the same level consistently all the time. If pass/fail is 100, and you are usually at 1, you should be getting to 1 consistently.”
Part of assuring a robust process includes monitoring. Lopolito sees not only TOC (total organic carbon), conductivity, and in-line UV monitoring but also routine use of advanced techniques such as UHPLC (ultra high performance liquid chromatography). In contrast with current high performance liquid chromatography, UHPLC analysis could be run in perhaps five minutes, so in-line monitoring could be practical.
Elevating cleaning
While some see cleanroom cleaning as completely separate from product contact cleaning, others take a more integrated approach. “Who cleans the floor?” asks Pluta. “The lowest one on the totem pole. That should change. We have to say: ‘We will train you. We will have competent personnel do the training. We will pay you appropriately.’ That would be fantastic!”
Pluta adds that “one company combined site maintenance, with equipment, with environmental (bacterial) monitoring. They called it the Cleaning Science department. This was brilliant! That elevated it.” Pluta suggests that the pharmaceutical industry consider combining cleaning product contact cleaning with microbial control and facility cleaning—all cleaning should be approached by a scientific and technical approach. He adds that personnel who do cleaning must understand the importance of their responsibilities.
Lopolito favors on-site training. “There will be more SME [subject matter expert] training to address CAPA [corrective and preventative action] issues. The idea is to create site experts through high-level training of a few individuals.” Lopolito favors using outside experts because it is hard to benchmark internally; you have to get the perspective of other companies. He states that if there are too many people involved in training, it becomes too general, that it is preferable to train the internal trainers. In our own experience, we find that sometimes technicians need direct education. It depends on the application. Perhaps, in 2020 we will see more customized training and education.
Catalysts and game-changers
Like many chemical reactions, change may require a push, either a level of discomfort, or a positive opportunity. LeBlanc notes that for pharmaceuticals, while some changes occur slowly, blatant, well-publicized failures can result in more rapid change, citing failures that prompted cleaning equipment validation. Pluta predicts that the great increase in organisms with drug resistance will heighten awareness of cleaning. “Not a day goes by without some report of contamination in industry, hospitals, cruise ships, food packages, and so on—the world is becoming more and more aware of the importance of cleaning.” Sharnez hopes for newer guidelines from the FDA. He sees increasing synergy between industry and the regulatory community. “I predict that by 2020 regulations will be based more on the potential impact to the patient, including the impact of degraded protein on the patient.”
New developments could change the picture. Marc Madou, Professor of Biomedical Engineering at the University of California, Irvine suggests the potential for therapeutics and diagnostics to come together on a single platform, a single device, like a compact disc. If that happens, if we put desirable biofilms onto a disc, “there will be an evolution. We will have to look at different materials for cleaning, at different techniques for cleaning; and manufacturing will have to be done in a more well-defined, cleaner environment.”
Barbara Kanegsberg and Ed Kanegsberg (the Cleaning Lady and the Rocket Scientist) are experienced consultants and educators in critical and precision cleaning, surface preparation, and contamination control. Their diverse projects include medical device manufacturing, microelectronics, optics, and aerospace. Contact: [email protected]
This article appeared in the March 2014 issue of Controlled Environments.
