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Industry and regulatory experts discuss the challenges and benefits of implementing real time release testing in a pharmaceutical manufacturing environment.
In 2004, FDA published a final guidance for industry introducing the concept of process analytical technology (PAT) and redefining pharmaceutical manufacturing and quality assurance for the future. That guidance also addressed a concept known as "real time release," defined as "the ability to evaluate and ensure the acceptable quality of in-process and/or final product based on process data" (1). The PAT component includes, according to the guidance, "a valid combination of assessed material attributes and process controls," and builds upon the 1985 guidance on parametric release, which is used primarily in heat-based sterilization of drugs.
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A few years later, in August 2009, the parties to the International Conference on Harmonization (ICH) adopted ICH Q8(R2) Pharmaceutical Development, which used the term "real time release testing" (RTRT). The definition of this term in ICH Q8(R2) shifted the emphasis from the decision to release a batch to the measurements themselves, as follows: "the ability to evaluate and ensure the quality of in-process and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls."
There are many benefits to be gained from RTRT applications. "From an industry standpoint, RTRT approaches seem to have economic benefits from manufacturing efficiency, such as reduced inventory and lower laboratory costs," says Christine Moore, PhD, deputy director for science and policy at the FDA Office of New Drug Quality Assessment (ONDQA), which falls under the Center for Drug Evaluation and Research (CDER). "Quality can also benefit resulting in higher yields or lower rework or rejection rates. From a regulator's and a consumer's standpoint, the integrated real-time analysis and control feasible with RTRT have the potential to provide an increased assurance of product quality."
Adds Grace McNally, senior policy advisor within FDA's Division of Manufacturing and Product Quality, Office of Compliance, which also falls under CDER, "One of the benefits of on-line or at-line testing is the ability to perform rapid analysis in real-time. PAT tools typically enable nondestructive testing and provide the opportunity for enhanced monitoring during the manufacturing process, and greater product and process understanding."
Despite the potential gains that can be realized from RTRT, industry still is trying to work out the practicalities of implementing the approach, and therefore, is not yet fully benefitting from its promises. Many questions remain regarding the instrumentation to use, when and where on the manufacturing line to conduct tests, how to evaluate on- or in-line analyzers during manufacture, and what regulatory authorities expect.
Industry's hesitation toward applying RTRT was abundantly clear during the October 2010 ICH Quality Implementation Working Group (IWG) workshop, held in North Bethesda, Maryland. A breakout session on control strategy addressed RTRT controls and brought up even more questions about its application, such as what to do in case of instrumentation failure, how to differentiate between RTRT and in-process tests, how to describe RTRT in specification, and where to record RTRT information in regulatory submissions, such as the common technical document.
The issue stretches across the Atlantic. The European Medicines Agency (EMA) published a new draft guideline on RTRT just last year to replace its former guideline on parametric release (2). The new document is meant to align better with the ICH terminology and to allow for real time release tests beyond that of sterility testing, which is the most common real time release practice.
During the past nearly two years, the ICH Quality IWG has constructed and posted on its website a list of common questions and answers about the organization's quality guidelines (Q8, Q9, and Q10). The current version includes 11 Q&As devoted solely to RTRT (3). As industry moves more toward a quality-based approach, some RTRT questions may fall into place. In the meantime, Pharmaceutical Technology gathered input from industry and regulatory experts already making headway in this area.
Making the move to RTRT
Now that RTRT has moved from a concept to a realistic option for drug products, says Senior Director of Global Manufacturing Services at Pfizer Global Manufacturing Holly Bonsignore, there are many benefits for industry to take advantage of. For example, RTRT can "improve process control by generating more data while the manufacturing process is taking place, as opposed to traditional release testing conducted on small samples after batch manufacture is complete." The availability of RTRT data at the time of batch manufacture can also improve operational efficiency and inventory control by eliminating the time and resources needed to test batches in a laboratory post-manufacture.
There are a few downsides to the approach as well. Because RTRT is not yet globally accepted by regulatory agencies, explains Bonsignore, manufacturers are caught somewhat in the middle of a paradigm manufacturing shift. Some companies need to continue to use traditional batch-release testing for certain markets even if other markets have approved the approach and even if the company is ready to move full speed ahead with RTRT.
Bonsignore's colleague, Steve Hammond, a director and team leader in Pfizer Global Manufacturing's analytical sciences group, notes a more technical limitation with RTRT: testing for impurities and stability. "PAT technology is being developed that may be capable of that category of 'stability indicating' analysis, but at this time, there is a gap," he explains. "The approach at Pfizer is to propose RTRT for products for which we have a history of stability (e.g., active pharmaceutical ingredients that do not degrade due to the manufacturing process)."
Adds Terry Redman, product manager for particle-system characterization at Mettler-Toledo AutoChem, "It is not always feasible or cost-effective to implement direct measurement of all critical process parameters (CPPs) and critical quality attributes (CQAs) with RTRT. In many cases, gaps in measurement technology must be filled with inferred measurements that must be proven statistically reliable," he says. However, that may change in the coming years. New measurement technologies are on the horizon that will improve industry's ability to monitor process control and provide analytical measurements for quality control.
The key, according to many industry experts, is going to be increased product and process knowledge—a fundamental concept of quality by design (QbD) and the harmonized ICH quality guidelines. As Tim Freeman, director of operations at Freeman Technology, points out, "Although RTRT is the future for efficient, safe and competitive pharmaceutical manufacturing, it relies on capturing more information about the materials being processed and the equipment and configuration employed during manufacturing."
FDA's Moore offers a specific example. "By understanding your process and controlling its associated risks through a PAT system, you can monitor and control the process at the most important points," she says. "Some critical quality attributes, such as dissolution, cannot be measured directly by a specific probe. Instead, to utilize a RTRT approach, you need to understand the relation between the desired product attribute and relevant material attributes and process parameters and then monitor and control them accordingly."
Selecting appropriate unit operations
In terms of gaining knowledge before applying RTRT to a manufacturing process, pharmaceutical firms may need to determine which operations, from blending and compaction to tablet coating, are conducive to its use. The good news, according to Pfizer's Hammond, is that PAT applications are now well developed for most all unit operations. "For most products, nearinfrared (NIR) can handle a high proportion of unit operations, and the emergence of light-induced fluorescence instruments with an order of magnitude greater sensitivity than NIR has taken PAT into low-dose products," he says. In addition, he notes that technologies such as terahertz spectroscopy are emerging for coating monitoring and control, but says that further development is required in this application area.
In terms of tableting and powder processing, Freeman says he has come across several advances in measurement technologies that are driving material and process understanding toward an RTRT approach. "There are now GMP suites for continuous manufacturing of tablets that rely heavily on PAT and that function with real-time, closed-loop feedback on parameters such as size, moisture content and blend uniformity," he says. "For this reason, RTRT has become much more of a reality in the last couple of years. However, there are many material properties that are still not measured routinely at-line or on-line, even though they will influence final product quality."
According to FDA's Moore, "Many of the sensors used for in-process measurements of pharmaceutical technologies have been well established in other similar industries, such as the chemical or food processing industry. Undoubtedly, there is a sensor available that could be used at every unit operation of tablet or other dosage form manufacturing. Monitoring every step does not necessarily add value though." She adds, "The challenge is to perform the right measurement, at the right time, and at the right location. Furthermore, you want the right control systems in place to make appropriate and timely adjustments to the process based on the information collected."
Managing sampling plans
Another big challenge to using RTRT is how to approach sampling plans, specifically when and where to take a sample, how much of a sample to take, and whether compendial or risk-assessment issues need to be considered. Explains Alon Vaisman, applications manager of pharmaceuticals for Malvern Instruments, "Usually PAT instruments access larger amounts of sample than would be used for lab analysis. On-line instrumentation would typically utilize automated sampling, in contrast to traditional off-line techniques that tend to rely on grab sampling at the end of the process. Sample preparation is usually relatively limited for PAT systems since this is necessary to achieve the measurement rates required for continuous monitoring."
As for where to do sampling on themanufacturing line, Real-Time Analyzers President & CEO Stuart Farquharson suggests that RTRT is not limited to tablet or pill manufacturing, but also encompases drug synthesis. In this case, the best place to monitor synthesis is in-situ, or inside the reactor. This allows monitoring and ultimately controlling the reaction rate, reaction end-point, and yield. "This can be accomplished using a long rod fiber-optic probe. However, efforts must be made to keep the probe head clean. In-situ measurements allow for true real-time monitoring, which is significantly better than traditional grab sampling, primarily used to determine when the end point had been reached," he explains.
According to FDA's McNally, "Manufacturers must determine appropriate sampling for their processes. It is important to remember that compendial tests are standards that any compendial drug must meet if tested. Applicants should consider the claims and disclaimers made by each compendium they reference.
"The current US Pharmacopeia (USP 33–NF 28 Reissue), for example, notes that their compendial standards are not intended to make inferences about the larger group of units from which the sample was obtained. The General Notices section also states, 'In all cases, statements about whether the compendial standard is met apply only to the units tested. Repeats, replicates, statistical rejection of outliers, or extrapolations of results to larger populations, as well as the necessity and appropriate frequency of batch testing, are neither specified nor proscribed by the compendia.' So, manufacturers must ensure sampling sizes and plans are statistically sound and representative of the batch. A quality risk-management approach can be useful to develop an appropriate sampling plan."
Moore adds that the agency is willing to work with applicants to ensure appropriate acceptance criteria for large sample sizes.
Pfizer's Hammond seems to agree that there is work to be done in the area of sampling. "There is the potential to sample very frequently or to take large numbers of units for a measurement," he explains. Pfizer uses a risk-based approach to determine sampling frequency, including looking at how the data is used, what calculations are performed, and what statistics are used for setting a specification.
"There is agreement that conventional statistics do not apply when larger data sets are under consideration. The so-called 'large n' approach is needed. Industry and regulators have been debating the best approach for a while now and some sensible approaches seem to be evolving from this discussion," adds Hammond.
He references a recent PQRI paper published, with FDA input, that describes three possible "large n" approaches. "In terms of sampling of blends during analysis using probe systems, careful control of the amount of sample that contributes to a spectrum is important. Generally the illumination characteristics are engineered to ensure that approximately one unit dose weight of blend contributes to a spectrum. Analysis of tablet cores is generally via transmission of light, through the tablet, thus ensuring that most of the material in the tablet core contributes to the spectrum collected."
Overall, the primary purpose of RTRT, and any PAT or QbD application for that matter, is to understand and control one's product and processes in a manner that ensures quality final product.
Sampling needs to be sufficient to facilitate real-time control, generate knowledge to allow the control of the next manufacturing step, and measure critical material attributes. With end-of-line testing, according to one expert, the purpose of sampling is to assess what the quality is, and the testing of samples has two roles: one enables control, and another validates the control system and strategy. Within RTRR, therefore, sampling's role is to assure that the controls are appropriate.
Dealing with equipment failures
Of great concern among industry is what to do in the event of an equipment or instrumentation failure while an RTRT process or analysis is being run. "Generally, it is not acceptable to discount PAT measurements and return to a conventional approach simply because the PAT fails a batch," says Pfizer's Hammond. "It must be proven that the equipment has malfunctioned in some way. As most PAT instruments now have very sophisticated self-diagnostic procedures, it is better to have the PAT device automatically cease to function if any of the internal diagnostics fail. Thus, suspect results are not generated."
Furthermore, a manufacturer applying an RTRT test that fails might also use a risk-assessment process to decide how to proceed. "The possibility of using the traditional analytical procedures that are registered for the product is something the industry needs to make PAT a viable proposition. All mechanical electrical systems can malfunction, and pharmaceutical manufacturing needs a way to ensure business continuity if a PAT system does break down," says Hammond.
According to FDA's McNally, "In the event of on-line or in-line equipment breakdown, the control strategy provided in the application can include the use of alternative tests or monitoring in case of equipment failure. The alternative approach could involve use of in-process and end product testing or other options, while maintaining an acceptable level of quality."
Of note, EMA's new draft guideline on RTRT includes very similar language with regard to dealing with equipment failure (2). Overall, both regulatory authorities seem to agree that testing or monitoring equipment breakdown needs to "be managed in the context of a deviation under the quality management system and can be covered by GMP" (2).
This may be particularly important for those PAT systems that can produce false negatives, such as those using spectroscopy and chemometric methods, adds McNally. "The manufacturer should ensure an effective calibration program is in place. This includes procedures to follow in the case of an out-of-specification (OOS) result from a PAT tool and steps to be taken to maintain and recalibrate the calibration model."
Some of the ICH questions and answers on real time release address this issue in more detail (3).
To date, the pharmaceutical sector seems to be moving forward with RTRT but at a slow pace. The concept "is no longer treated as an unobtainable goal," says Malvern's Vaisman. "Many companies in industry and in academic research centers are making significant inroads in implementing continuous manufacturing trains and RTRT. That said, RTRT is not yet the norm," he adds.
Cost may be a factor in the rate of implementation, point out GE Analytical Instrumentation's Richard Godec and Jonathan Yourkin, new product development manager, and global pharmaceutical product manager, respectively. Because analytical tools are still being developed and many companies' senior management and quality teams are not yet on board, RTRT is a bit of a double-edged sword. "The main advantage of RTRT is the cost-effective control of the manufacturing process to meet all quality and product specifications. The main disadvantage, however, is that there is an initial investment required to achieve RTRT of finished drug products," they say.
On the regulatory side, FDA "has reviewed and approved several applications using RTRT approaches, but the numbers are still small," says Moore. "The applications containing RTRT approaches have been challenging to review; they not only include new science but also have new approaches to fulfilling regulatory requirements. We (the FDA) are still learning, and every application has different nuances. We strongly recommend that companies looking to implement RTRT request a meeting with the FDA to discuss their proposal prior to submission."
1. FDA, Guidance for Industry: PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (Rockville, MD, September 2004).
2. EMA, Guideline on Real Time Release Testing (formerly Guideline on Parametric Release), draft, February 2010.
3. ICH, Quality Implementation Working Group on Q8, Q9, and Q10 Questions and Answers (Nov. 11, 2010), www.ich.org.
4. FDA, Draft Guidance for Industry, Process Validation: General Principles and Practices (Rockville, MD, November 2008).