Spectroscopic Techniques and PAT: Roundtable

Gary Ritchie
               President
               Council for Near Infrared Spectroscopy (CNIRS)

  Mark Sullivan, Ph.D.
                Senior R&D Scientist
                Advantest America, Inc.

   Brian Marquardt, Ph.D.
                 Director
                 Center for Process Analytical Chemistry
                 University of Washington

  Claudia Corredor
                Research Investigator II
                Bristol-Myers Squibb

  Robert Chimenti
                Sr. Strategic Applications Engineer
                Innovative Photonic Solutions

How does the movement from lab-based instruments to portable tools in the industry bolster pat?

GR: More broadly, it allows measurements to be made in locations where standard lab instruments are not easily implemented, for example on loading docks, and in the fi eld. “Portable” covers a wide range, from handheld to truck-mounted. An appropriate unit should be selected, depending on the expected conditions to be encountered, including the precision and accuracy needed. Specifi cally, one of the objectives of PAT is to reduce the cycle times for batch manufacturing and release. Performing laboratory tests and waiting for the results consumes a large amount of time. Removing the in-process sampling step and being able to make measurements at the point of material processing will preserve time, and more importantly reduce the “run at risk” mode that many manufacturers practice currently.

BM: The size and cost reduction of traditional lab instrumentation into portable tools drives the expanded use of the technology to improve process control and product quality. The caveat with this argument is when smaller, faster and cheaper leads to inaccurate results or poor data. This is where I have seen the move to portable tools being a detriment to companies and PAT overall. All it takes is one person selling a bad solution into a company for all process measurements to get a bad name in that company. There are, however, many examples where small, portable Raman, NIR and IR handhelds have been eff ectively applied to improve quality. Using handheld Raman to screen raw material for use in a pharmaceutical process is an example.

Identify noteworthy advances in nir instrumentation. What are the key drivers for these advancements?

GR: “Faster, smaller, cheaper” is here! 1000 spectra per microseconds, 50 mm diameter or less sampling windows and under $1,000 is now a reality. The development of Diode-Array (DA),Charge Couple Device (CCD) and Linear Variable Filters (LVF) based instruments has led to smaller devices. Together with smaller computing technology that makes it possible to carry portable devices in a pocket (say, 2 x 4 x 8 inches), in conjunction with optical fibers to interface with all kinds of sample holders for the measurement, has greatly widened the range of conditions under which spectra and analyses can be obtained competitively (i.e. instrument performance gauged to regulatory-based qualification criteria). Technologies have evolved based on business needs (i.e. the morphing of fiber optic industries into spectrometer vendors), individuals have devoted their lives to pursuing the idea of miniature devices (Prof. Fred McClure and Dr. John Coates to name two who have had a huge impact in promoting smaller, faster and cheaper innovations), and a need to measure the sample in situ rather than bringing the sample to the instrument has been emphasized in the manufacturing, commerce and health sectors. All of these factors have converged to create the perfect storm, forcing the miniaturization of NIR instrumentation. The development of portable NIR instruments seems to have become a self-fulfilling prophecy – i.e. NIR as a rapid, non-destructive, non-invasive technique is now portable – based on the following basic factors: it has been done, there are men and woman who have pursued this innovation towards miniaturization, and there is now a real need to make NIR measurements for real time process quality control for medical diagnostics and to combat counterfeiting.

What trends and developments in Raman spectroscopy have impacted the pharmaceutical industry in recent years?

GR: Raman has also seen a proliferation of instruments of roughly the same size as the smaller NIR instruments. Advances in lasers and detectors allow Raman spectra to be obtained with less and less interference from fluorescence.

BM: The development of stable laser systems, photon efficient spectrometers/cameras, and effective probe technologies has driven the pharmaceutical Raman market recently. Improved hardware has improved stability, sensitivity, and reproducibility of Raman measurements across numerous process, development and discovery applications. A primary driver in the application of Raman in the process pharma markets has been the development of effective, non-fouling Raman immersion probes that provide stable, reproducible sample interfaces for liquids, powders, slurries and mixed phase systems. The advent of reproducible Raman immersion probes enabled the application of chemometric routines for qualitative and quantitative process Raman analysis. Once Raman measurements could be performed reproducibly from sample-to-sample without the need for refocussing, the technique could be effectively applied for process analysis.

CC: Recent developments in Transmission Raman Spectroscopy (TRS) have made this technique a potential alternative to Near Infrared (NIR) for the quantification of APIs and excipients in tablets and capsules. Several approaches to quantify APIs using TRS in combination with Multivariate Data Analysis have been published (Anal Bioanal Chem (2013) 405:3367-3379 and literature herein). The recent advent of very robust instrumentation with optimized laser excitation and collection optics allows for a larger volume of a tablet to be sampled with minimal sub-sampling effects. TRS suppresses interfering surface fluorescence and Raman signals from capsules and coatings. Other advantages are rapid analysis times (seconds or less per sample), high accuracy, and quantification of low concentration components with the use of enhancement optics. An increasing number of scientists have adopted this technique and it is now a common tool (more than 10 publications in the last two years). Although the effects of physical properties (hardness, density, tablet thickness, API properties and excipient particle size) in the TRS spectra are better understood, more research on the topic is needed and expected in the near future. This technology seems well-suited to real-time online measurements that require high speed testing.

RC: One of the most promising trends in Raman spectroscopy can be summed up in one word, “speed”. Raman is typically thought of as lumbering, requiring long integration times (several minutes per point) in order to acquire enough photons to pull the signal out of the noise. Nowadays, due to a convergence of various technologies, the technique is capable of high speed point sampling as well as rapid hyperspectral imaging. This is due to the maturation of spectrum-stabilized diode lasers that can now direct hundreds of milliwatts into a submicron spot allowing for high speed confocal imaging or, contrastively, into multi-watt line scanners for use on conveyor systems.

Not all of the speed is coming from higher power though. Taking advantage of the compact size and lower power consumption of freespace single mode sources to build smaller handheld and portable systems is an emerging trend. These systems use the Raman effect’s dependency on power density (not absolute power) to acquire data in a fraction of the time of traditional portable Raman spectrometers. These improvements in testing throughput allow for improved efficacy in drug development, quality control, and production, furthering the already rapid adoption of Raman spectroscopy in the pharmaceutical Industry.

Discuss how chemometrics contributes to a successful PAT platform.

GR: While chemometrics is not a requirement for a successful PAT implementation, (there are other non-spectroscopic systems such as rapid microbial enumeration and viability methods that do not require chemometrics), in order to “achieve process understanding”, meaning a mechanistic (or a mathematical) understanding of the manufacturing process’ impact on the process composition, the PAT Guidance suggests that users “Develop mathematical relationships between product quality attributes and measurements of critical material and process attributes”. This is broadly accepted to mean that multiple linear (perhaps even non-linear) process variables must be identified and studied to determine the relationship among these variables and find out how they may correlate to the process composition in order to predict and control final product quality attributes. This is the essence of what it means to move beyond traditional laboratory analysis. Essentially, you cannot conduct PAT very effectively using current classical linear models as they do not allow the user to predict multiple input functions simultaneously or use those inputs to affect a feed-forward or feedback control strategy in real time during manufacturing. Multivariate Analysis (MVA), strictly speaking, chemometrics, offers an approach for understanding process and product throughout the product lifecycle, from early development to market monitoring, and simultaneously measuring and controlling the final product quality attributes during manufacturing processing. Other mathematical systems certainly exist (Bayesian Statistics and Monte-Carlo Simulations are popular), however, most MVA techniques work well with smaller populations and generally fewer factors are required for modeling. The models are generally robust (if the correct factors and the correct number of factors are chosen), accurate and precise.

MS: Chemometric tools are an essential part of spectroscopy and PAT for classification, quantitative prediction and process modeling. They provide the capability to measure and ultimately control process variance. For example, chemometrics permits the rapid mapping of batch process trajectories, as well as the quantitative measurement of critical quality attributes (CQAs) of raw materials, intermediates and finished products. In fact, multivariate tools provide the relationships between process variables and CQAs that lead to process understanding. Chemometric tools are essential for routine troubleshooting because they aid in detecting analyzer faults in addition to distinguishing unexpected material and process equipment changes. Chemometric tools provide continuous validation to detect sample outliers that are outside the experience of the established methods.

BM: From my perspective chemometrics is a driver for effective implementation of accurate and reproducible sensors and analyzers. Without efficient data analysis protocols and models, it would be nearly impossible to handle the volume of data being produced. Chemometric routines provide the ability to quickly reduce data sets to pertinent information that can be used for further understanding or control.

CC: Chemometrics is one of the key enablers of PAT. It plays an important role during PAT method development, specifically the creation of models based on latent variable techniques such as Principal Component Analysis and Partial Least Squares Regression. Timely and robust predictions based on robust models are a requirement in the successful implementation of the PAT platform. Through the use of chemometrics, which encompasses DOE, multivariate calibration and multivariate data analysis, it is increasingly common to look at more complex approaches to support development of a formulation, process or product. Multi-factorial analyses, which encompass the interpretation of large amounts of data from multiple PAT probes and sources, are replacing One-Factor-At-a-Time approaches. New software functionality enables the industry to apply chemometrics broadly and integrate results into the ICH Q8 concepts (risks assessment and design space). Chemometrics is also a key enabler of new software applications for trending analysis for process monitoring and/or control. To reach the desired state of pharmaceutical manufacturing (mechanisticallyand scientifi cally-driven development with multivariate experimental designs, science-driven operation and validation, continuous process verifi cation and in-, at- or on-line analyses), proper chemometrics and PAT tools need to be in place

RC: In order to implement and maintain a successful PAT program, the role of design of experiment can never be understated. As a result, chemometric analysis is an invaluable tool in the process analytical chemist’s toolbox when used within a well-defi ned analytical method. By utilizing multivariate statistical techniques, chemometrics allow for the collection and analysis of vast amounts of chemical data and quickly process it to fi nd hidden trends in the data. Some common PAT applications for chemometric analysis are monitoring particle size and drying using NIR, polymorphic and other molecular transitions with Raman, and complex analyte concentration using UV/Vis.

One very interesting trend gaining momentum in PAT is the use of orthogonal testing techniques which can be fed into a single chemometric method. This increases the robustness of the process, such as combining broadband reflectance with Raman spectroscopy to get a more complete picture of the chemical changes in the process. Additionally, groups such as Maddux et. al. from the University of Kansas have conducted encouraging research in the exploration of methods of combining data acquired from techniques as diverse as calorimetry and intrinsic fl uorescence into a unifi ed multivariate model.

Describe ways in which NIR and raman help to ensure regulatory compliance.

GR: Ensuring regulatory compliance is such a huge job requirement for tools that are primarily intended to assess quality, so what I will respond to is: “How do NIR and Raman help to ensure quality?” The agency itself has struggled with trying to defi ne what they mean by ‘quality’, so attempting to defi ne a role that these tools play in ensuring quality is a bit of a slippery slope as well. Surveillance seems to be on many minds right now. Assessing what quality metrics should be used and at what step they should be used in is a question that has been at the forefront. As previously mentioned, NIR and Raman can help to ensure quality by providing data rapidly, non-invasively, non-destructively, and allow users to bring the instrument to a larger number of samples and not rely on smaller sample sets. Since it is now possible to take many more measurements of samples, the idea of providing surveillance data on fi nished product, rather than providing prediction data, may have a greater impact on ensuring quality of the fi nished product in the future.

What are the advantages of using spectroscopy as an analytical tool over other techniques?

GR: Probably the single greatest advantage is the capability for non-contact measurement, which provides several application benefits:

  1. Portability often makes it easier, simpler, faster, and cheaper to bring the instrument to the sample or sampling point, rather than bringing the sample to the instrument. Samples may be too large, delicate, dangerous, sensitive, or may be changed if surrounding conditions change, to bring them to the laboratory.
  2. Materials can be measured in hostile conditions (hot, cold, wet, etc.) since the instrument does not have to be in those conditions itself.
  3. Samples can be measured in sterile conditions, obviating the need to break the sterile seal to make the measurement.

Other advantages include speed, the ability to handle irregular sample types, and so on.

MS: Spectroscopic measurements have a higher degree of specificity for subtle changes in chemical structure and physical form than many other analytical techniques. Spectroscopy often requires little or no sample preparation and is, therefore, fast and non-destructive. Because spectroscopic techniques are noncontact, many types of samples can be analyzed directly through a container or other packaging, thus preserving sample integrity. The non-destructive, non-contact nature of spectroscopy also makes it adaptable for on-line measurements and many important applications have been demonstrated for monitoring continuous processes. Another important advantage of spectroscopy is that spatial images can be obtained to quantify the compositional uniformity of blends and the distributions of components in solid dosage forms.

BM: There are many advantages to a spectroscopic solution over other traditional analytical approaches. As a prelude to my arguments for spectroscopic solutions, I make the assumption that both the spectroscopic and traditional solutions are equal in their performance. The primary differentiator in most cases is the cost and labor associated with traditional analytical systems like chromatography. A typical process spectroscopic solution has very low cost of ownership after installation. For example, the typical service for a process Raman instrument is laser replacement after two years. In comparison, an HPLC requires consumables that consist of solvents and columns as well as an operator to collect and inject samples or fill vials for an auto sampler. An argument can be made that a Raman instrument costs three times what a typical HPLC costs. However, when you look at the cost of ownership for operating a Raman solution vs. an HPLC solution over two years, it has been shown that the process spectroscopy solution costs less in the long term. Beyond the cost savings of a spectroscopic solution, there are other advantages in both accuracy and reproducibility that result from not having to physically collect and inject samples for analysis.

What does the future hold for spectroscopic tools in pharmaceutical processing?

GR: We are now in the age of Big Data. These tools have evolved to a point that allows data to be gathered at a faster and cheaper rate without losing the quality of information coming out of that data. It is crucial for the end user to remain vigilant when asking the two key questions that, throughout the evolution of regulations of the food and drug industries, have not changed even as regulations have undergone continual improvement. These questions are: “What is it that I want to know about the system being measured?” and “When do I want to know it?” The way in which the answers are obtained has the potential to change the outcome. Spectroscopic tools have the ability to obtain those answers throughout the development and manufacturing lifecycle of the drug and drug product so that timing is always a big challenge for users of these tools. And because some of the uses of these tools may require multivariate analysis (MVA) for designing experiments, data measurement and control, data archival and retrieval, and data analysis, the increased application of statistical tools will have an impact on how Big Data coming out of pharmaceutical manufacturing will complement evolving regulatory requirements for defining product quality. In essence, now that we can make measurements anywhere in the lifecycle of the product, measurements must be made so that the quality being surveyed really measures an attribute with both adequate impact on the product and the customer, as well as meaningful impact so that the value to the customer can be measured, not just monitored or predicted. Thus, the future will focus on redefining and linking Big Data in pharmaceutical manufacturing to final product quality attribute and determining what that value-added quality metric will be to the customer.

MS: There is a wealth of experience in deploying vibrational spectroscopy tools such as NIR and Raman in pharmaceutical processing and many of the challenges of integrating analytical instrumentation into control systems and managing big data have commercial solutions from a number of sources. One new area of interest on the horizon is spectroscopy in the terahertz frequency range with commercial systems operating from 5-150 cm-1. Terahertz waves have a higher depth of penetration into many pharmaceutical materials than NIR which provides more representative sampling for bulk analysis and the ability to do depth profiling of multilayered tablets and coatings. Terahertz spectroscopy can be used to measure the densities of solid compacts and is uniquely sensitive to changes in crystallinity and crystalline form due to polymorphism and hydration.

BM: The future will show that high information content spectroscopic tools will continue to capture market share from more traditional analytical technologies. These changes will be driven by improved performance, less cost of ownership, reduction in skilled operator labor required, and the ability to effectively incorporate spectroscopy online for improved process control that will lead to improved product quality. I feel that with effective process spectroscopy solutions, we can design quality into pharmaceutical products and not have to test quality out as we have in the past with traditional methods.

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