Process Analytical Technology (PAT) Impact
The pharmaceutical industry is in rapid transition from a supply-driven market to a demand and service-driven market where manufacturing efficiency and responsiveness will play a critical role in future success. Pharmaceutical manufacturers generously allocate funds to research and marketing, but they as a whole lags behind other automated industries in one key aspect: manufacturing quality analysis. To overcome this there is growing enthusiasm in the industry for the many potential gains offered by process analytical technology, a new FDA initiative that aims to foster improvements in manufacturing efficiency and quality analysis. Pharma Industry is facing growing demands for increased productivity and reduced manufacturing costs and also has to meet the evolving need for higher quality standards and higher drug expectations The regulatory area appears to be rapidly evolving, with PAT initiative to be the first major change in the GMP's in over 25 years that is based on increased scientific understanding and less on an empirical based approach. The underlying premise of process analytical technology is that quality cannot be tested into products; instead it should be built-in or should be by design. Along with benefits there are numerous technical, cultural, organization and regulatory hurdles on the PAT path.
This article provides an outline of Process Analytical Technology expectation and pioneering work on PAT by pharma Industry and positive impact of PAT in the pharmaceutical industry. This editorial highlights the issues that are the forefront of the process analytical technology (PAT) in pharma industry.It frankly highlights the issues and concerns of implementing PAT, including a discussion of limitations, risks and rewards.
Process Analytical Technology – Historical, Business & Regulatory Perspective
Pharma industry goal is to improve formulations so as to provide patients innovative and more efficient solutions, and thus achieve commercial breakthrough. For this, improvements in existing technologies are required. The emerging PAT strategy is to guide the drug industry in achieving these goals. Process Analytical Technologies involve the use of raw material properties, manufacturing parameters, process monitoring, and chemometric techniques to produce finished products of acceptable quality. It facilitates and encourages the Introduction of innovative approaches. However, it is difficult to consider potential technological alternatives without critical review to replace well established techniques.
Historical View of Process Analytical Technology (PAT):
Because they have been used for many years, existing experimental methods and manufacturing processes are considered well established and trusted to generate few errors and make only modest contributions to process variation. Historically, pharma lab develops a product, describe the product, describe the process materials and methods in great detail in the regulatory filing, and validate the process through consecutive batches. The quality of the product would remain consistent as long as nothing was changed. With this data industries are having little pressure to improve manufacturing efficiency.
Business view of Process Analytical Technology (PAT):
To pharma with its paper-based control systems PAT is alien technology, but it is old hat to industries such as food and beverage, petrochemicals and semiconductors. US drug companies have had the ability to use process control for 20 years, but they have not used it because it’s expensive in term of the cost of the equipment, the cost to develop qualification, validation and quality systems. There are no industry leaders yet demonstrating the value of PAT, so pharma companies are approaching PAT with uncertainty.
Although PAT increase production efficiency, this may not be viewed from a business standpoint as a strong impetus for change due to the perception that the implementation costs may outweigh the return on the investment in some cases, especially for small pharmaceutical companies that are already struggling with tight or nonexistent margins. With limited available capital, equipment, and talented human assets, maximizing asset utilisation and return on assets is becoming vital to future success and survival.
Although benefits of PAT in the long-term are generally recognized, the short-term uncertainty and risk, at least in these early days of the FDA guidance, boil down to how much time and resources a company should invest in a pharmaceutical product that faces an uncertain future in terms of clinical efficacy, regulatory approval, and commercial success.
Accounting pros and cons of technology companies should determine when the investment in process development does benefits the company and when it does not make any business sense. For example, a process step is not under any time constraints, does not represent a potential bottleneck, does not consume costly reagents and resources, and does not pose a risk of contamination or introduction of impurities, then there may be little justification for investing in the monitoring, control, and optimization of that particular process step. As quoted by Anurag Rathore, associate director of process development at Amgen -A PAT-like scheme is not applicable in all cases—it useful only when real-time data offers benefits.
Further available analyzers are not suitable for pharma industry which requires instrument development .The sensors available as analysis tools are not compatible with the process( not CIP and SIP). Analyzer dependability (what if tools fails in production run?),having small expertise in high specialized technology,inadequate validation of analyzer/software add with all these makes PAT associated risks too high and creates hesitance over change and remains as big hurdles for PAT implementation.
But business models are changing and the importance of manufacturing’s role in the financial performance of pharmaceutical companies are important. While the cost of restructuring production lines may be daunting to smaller companies, the savings gained from more efficient use of resources, reduced waste, faster product approvals and a lower risk of product recalls would outweigh the cost to implement PAT.
Regulatory View of Process Analytical Technology (PAT):
A major contributor to inhibition of PAT adoption is concern over how regulatory agencies will react to the technology during a facility review. If the technology requires the agency to develop an understanding of the potential impact on the product, this could result in a protracted approval of the facility and thus delay the introduction of a new product to the market.Pharma industry’s are accepting new technology on the R&D side, “it lags behind on the manufacturing side for fear of delaying approval,” says Rick Cooley, manager of the process analytics center of excellence at Dionex. There is concern within the industry that there is lack of worldwide harmonization of regulatory expectations relative to PAT that could lead to PAT being accepted by one regulatory agency while another might not share the same level of acceptance, resulting in quality control strategies that are specific to a given market. However FDA has participated in international conferences as a means of creating harmonization on the PAT approach. These types of activities should also be conducive to harmonization on the PAT approach. The agency’s intention was not to dictate how companies should implement PAT, but rather to create a flexible regulatory process that would involve regular meetings with regulators, at which time companies could present and discuss individual strategies and innovative approaches says Ajaz Hussain, Ph.D., VP and global head of biopharmaceutical development, and former deputy director for science in the U.S. FDA’s Center for Drug Evaluation and Research
FDA does not intend to inspect research data collected on an existing product for the purpose of evaluating the suitability of an experimental process analyzer or other PAT tool. FDA’s routine inspection of a firm’s manufacturing process that incorporates a PAT tool for research purposes will be based on current regulatory standards (e.g., test results from currently approved or acceptable regulatory methods). Also companies are mostly considering utilizing PAT to show that their products are okay using existing processes, rather than redesigning and optimizing their processes, contends Dr. Koch. Ph.D., director of the Center for Process Analytical Chemistry at the University of Washington, Seattle .
The pharmaceutical industry has been hesitant to introduce new technologies and innovative systems for a number of reasons one of which often cited is that— in the FDA’s own words—“The existing regulatory system is rigid and unfavorable to the introduction of new technology.”
Industry's concern is that an increased amount of process data may highlight problem in a product. The more in depth process assessment by on-line analytical measurements may lead to an increased number of products failing to meet their release criteria. These same products might not have failed utilizing the current off-line methods of analysis.
Another concern is redefining the product specifications considering the more accurate statistical data provided by on-line measurement techniques. This is necessary due to the fact that even a 6σ process will theoretically have 3.4 individuals per million that fall outside the specification limits.
Though PAT is not regulatory law, the FDA pretty much insists that it be adopted. FDA introduces guidelines, which are not legal documents, but they want you to follow the guidelines. Numerous analysts have commented that regulatory guidelines have a tendency to become laws, and it is probably better for companies to try to stay ahead of the curve by taking a proactive stance.
With the discussed technology, regulatory, and business issues, have there been changes that will encourage the implementation of process analytical technology? The answer to this question is yes.
As a direct consequence of the "cGMPs for the 21st Century" initiative, the pharmaceutical industry is experiencing pressure from the regulator to address concerns around limited process understanding, process inefficiencies and continuous process improvement through the adoption of PAT. Since FDA released its PAT initiative, few pharmaceutical companies are willing to talk about their efforts to implement PAT. To encourage industry for PAT implementation FDA introduced the "safe harbor" or "research exemption" concept which is designed to encourage the industry to investigate tools that will provide increased process information without the fear of having a negative impact on the ability to release products that meet all aspects of the company's current quality control strategy. Technology vendors says that many of their pharma customers are in the planning stages of adopting PAT, but few have actually implemented new manufacturing technology and they are in testing phase. Novartis is running sensor technology side-by-side with the old process and doing lot of pioneering cutting edge work. Once a company learns how to apply the key fundamental types of analytical control technologies effectively to one process and product then the knowledge can be transfered to others.
TechniKrom has implemented PAT in critical liquid handling/blending steps, such as buffer supply, pH adjustment, LC gradient elution, and solvent feeds. The company helps clients monitor process operations and demonstrate that variability in feeds leads to variability in production yields
Eli Lilly researchers presented some ideas about the analytical methods that could be adapted for real-time analysis of steps in the pharmaceutical manufacturing process.
These methods include Fourier transforms infrared (FTIR) spectroscopy for reaction analysis, Near-IR (NIR) spectroscopy to measure product dryness and uniformity, HPLC, GC, NMR spectrometry, and MS for reaction analysis and product identity, Ultrasound to measure sample granularity.
NIR use has been increasing in PAT-style testing and has been particularly useful in on-line analysis. Multiple measurements is possible with a single NIR instrument and will able to follow a variety of processes in a chemical reaction simultaneously such as changes in reactant concentration, byproduct formation, and product generation which further allows to make minor adjustments to the process on the fly.
Likewise, strong differences in the NIR spectra of various polymorphs of a single API allow scientists to quantify polymorph formation during both preformulation and formulation processes. This ability is critical to a drug’s success, because subtle changes in form can result in significant differences in drug behavior in vivo.
Scientist Jonas Johansson and Uppsala University Associate Professor Staffan
Folestad, both working at AstraZeneca’s PAT Centre of Excellence, described how new Raman spectroscopy instrumentation is making extensive inroads into the pharmaceutical manufacturing sector.
According to them it is a highly selective method that allows researchers to easily and accurately determine the active pharmaceutical ingredient (API) content of a formulation while largely ignoring the physical parameters of the samples or sampling conditions. As an example, they cite a study in which aspirin tablets were assayed for both the API and the main degradation product, salicylic acid. The study compared the results obtained using Raman spectroscopy with those achieved using more standard HPLC method and found a good correlation between the two methods.
To understand or know what PAT is, one has to look outside pharma to the chemical industry which offers an excellent resource for process analyzer expertise. They’ve been doing simulation and in-line sensing forever, and they know how to model their processes. As the business mature, process instrumentation manufacturers are looking to expand their markets. They have been traditionally associated with the petrochemical industry are now expanding their instrumentation lines to include features as well as new measurement techniques to make their instrumentation more attractive to the pharmaceutical industry. In addition, the pharmaceutical industry is realizing that the chemical industry offers an excellent resource for process analyzer expertise.
Scientists at Sigma-Aldrich Biotechnology used a DOE approach to develop a cell culture medium optimized for a variety of Chinese hamster ovary (CHO) cell lines, which biopharmaceutical firms use to produce protein-based biologics.
The researchers used statistical software to identify the best-performing culture media in their arsenal and develop methods to further increase cell growth and productivity.
Pharmaceutical industry should look to vendors to see what they’re doing with customers in chemical, petrochemicals and refining industry. Vendors like Aspen Technology,C therm technologies and Pavilion Technologies have a great play on the pharma side with analysis tools.
Process Analytical Technology (PAT) Expectation:
Process analytical technology is a framework for innovative pharmaceutical development, manufacture and quality assurance. Through this framework FDA is encouraging pharmaceutical manufacturers to adopt innovative technologies without fearing validation risks and production delays. In the PAT initiative, the FDA wants pharma industry s to adopt a system for “designing, analyzing and controlling manufacturing through timely measurements (during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality.” To be clearer, adopt 21st century manufacturing technology and cut waste and improve quality.
Positive Impact of Process Analytical Technology (PAT):
From a business perspective, increasing operational efficiency in manufacturing is clearly of interest. This may occur through cycle time reductions and increasing process yields. There is strong belief that variability reduction will be added by increased process capability and by minimized risk of producing out of specification product. Because whenever process variables deviate from the specifications, the result will be the loss of one or several batches and an extensive investigation process, which all adds up to very long cycle times. All of these identified issues can be positively impacted through the use of process analytical technology. . Designing in PAT upfront can offer substantial, long-lasting benefits for optimizing productivity across an organization.
Process analytical technology (PAT) is a key enabling technology to deliver huge savings. It has been estimated that reducing inventory levels across the pharmaceutical industry to those already achieved by the very best pharmaceutical manufacturing facilities could deliver a one-off cash release of $76 billion.
The key components of this knowledge-based approach are better understanding of the product manufacturing process, data analysis, process analytical tools, process monitoring, and continuous feedback during the manufacturing process
The prominent techniques of PAT is online monitoring, which means it’s not only recording information, but it’s also closing the loop and making adjustments to the process as the product is being manufactured. In other words, the ability to analyze the production stream is pointless if you can’t respond to what the results are telling you.
While process monitoring traditionally involved temperature, pressure, flows, pH and other physical parameters, PAT focuses on the use of in-line testing using near infrared, Raman, or other physiochemical techniques as a primary means of process monitoring. The data retrieved would provide information on the properties of blends, cores, and other stages in the process. Through the use of probes in the process, uniformity, drying, and mixing endpoints, and other targeted stages can be pinpointed to a high degree of certainty. Sampling error would be minimized with in-line probes placed strategically through out the production process.
Unlike the batch processing common on today’s drug manufacturing, PAT will allow continuous process streams to be digitally measured, monitored, and controlled.
By reducing the need for trial and error, FDA regulators expect that PAT will allow companies to more easily improve the manufacturing process and thereby reduce product development times.
Without strong manufacturing operations, many of the new drugs will produce less revenue than their full potential as a result of longer-than-necessary process start-up and scale-up times, too many lost batches, process instability and quality problems, and fines and recalls. PAT contributes in offering solution to these issues to greater extent.
With PAT system Bacterial Endotoxin Testing (BET), microbial growth and presence testing, ion chromatography, etc can be converted to on-line or at-line testing methods with no human intervention. Labor-intensive laboratory preparation and testing will be Outmoded as the automation sequencing is refined and standardized.
The increased process information with PAT will lead to increased process understanding and better product.
Future of Process Analytical Technology :
The challenges for the pharmaceutical sciences are expanding over time as we seek to address increasingly complex medical needs and health care expectations.
Technical innovation in the pharma industry’s manufacturing sector has moved at a snail’s pace, with many methods technicians use for process analysis remaining largely unchanged for the past three or more decades.
The implementation of Process Analytical Technology is set to change this by bringing real-life benefits and improvements to many pharmaceutical processes. The aim of PAT is to generate product quality information in real-time. The advantages of PAT are many and varied.
One thing required by companies is they must be convinced that PAT makes good business sense before they will adopt organization-wide changes that, from a process and regulatory perspective, will change the way they do business. Perhaps the most persuasive argument for introducing PAT is a sense of inevitability. As can be seen in the above discussion, the use of PAT techniques can be a huge benefit to those who choose to use the technology.
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Mr.Kirupakar .B.R earned his master degree on Pharmacy from The Ramakrishna institute of paramedical sciences affiliated to The Tamilnadu Dr.MGR Medical university ( India ). Presently he is working for Strides Arcolab Limited., Bangalore.
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