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John Wasylyk, a principal scientist at Bristol-Myers Squibb in New York, New York, has been using quality by design (QbD), Raman spectroscopy, and Fourier transform infrared (FT-IR) spectroscopy in process development as well as for at-line and on-line monitoring of active pharmaceutical ingredient (API) crystallization. Here, he discusses the advantages, limitations, and challenges of these techniques.
John Wasylyk, a principal scientist at Bristol-Myers Squibb in New Brunswick, New Jersey, has been using quality by design (QbD), Raman spectroscopy, and Fourier transform infrared (FT-IR) spectroscopy in process development as well as for at-line and on-line monitoring of active pharmaceutical ingredient (API) crystallization. Here, he discusses the advantages, limitations, and challenges of these techniques.
How does your work with Raman spectroscopy fit into your company’s approach to quality by design?
We have embraced the advantages of quality by design (QbD) and Raman spectroscopy and have reaped the benefits in terms of process knowledge, process optimization, and control. Raman plays an integral part of process development, as we have three platforms for implementation: walk-up (open access) instruments, portable laboratory instruments equipped with noncontact optics and probes for in situ data collection, and plant-based instruments. We have standardized on one laser type and manufacturer of Raman spectrometers, which enables us to transfer methods across all three platforms.
To promote QbD and the use of Raman spectroscopy to leverage our learning, we have held a series of training sessions hosted by both internal and external subject-matter experts covering topics from the basics of spectroscopy and instrument setup to more advanced principles of spectroscopy and in-line analytics. Furthermore, Raman has been key due to the ease of transferability across instruments and the availability of instruments that meet safety requirements in the US and Europe.
What are the advantages of coupling QbD with Raman spectroscopy in terms of understanding reaction kinetics and following the progression from development to manufacturing?
Regardless of the length of the time to run a reaction to completion, we can leave the Raman spectrometer in a programmable collection mode and use a variety of probes to cover the various sizes of reactors and sensitivity over a wide spectral range, all of which allow us to attain a complete kinetics profile for the reaction. Continuous data collection during QbD experiments allows us to capture the impact of parameter changes. In addition, this can include data collected during the scale-up process as well as the impact of physical-mechanical changes such as agitation rate, impeller variations, and heating and cooling rates. By using Raman spectroscopy throughout the entire development process we can obtain a broad understanding of critical reaction parameters that not only improves our speed to patients but also positively impacts the quality of our product.
Your group has also used FT-IR spectroscopy to examine foreign materials in pharmaceutical development. What types of foreign materials were found, and how was FT-IR used to determine the source of the extraneous materials?
According to the Food and Drug Administration’s (FDA) Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, we are responsible for overseeing the quality of the incoming raw materials and intermediates. If a foreign material is found in an incoming material it will lead to an investigation and may ultimately lead to the rejection of that lot. Extraneous material can range from fragments of packaging material to process equipment components such as fragments of seals or gaskets. FT-IR allows for rapid classification and, many times, identification of extraneous material. We use commercial spectral libraries for the rapid classification and identification of foreign materials.
You have been using the mid-frequency and low-frequency spectral regions of Raman spectroscopy to study the transformation of amorphous indomethacin to the g-crystalline form (1). What are some of the challenges you faced in using this technique for this research?
Low-frequency Raman spectroscopy has been around for years, and one of the challenges was the lack of commercial Raman instruments that were capable of filtering out or attenuating the Rayleigh line to the point where low-frequency spectral bands could be observed. Recent advances in filters and gratings have affordably solved this challenge. Notably, this information may include the presence or absence of amorphous material in the crystalline matrix. In addition, the increased signal intensity in the low frequency range has allowed us, in a number of cases, to identify multiple polymorphs in the crystalline matrix. Coupling low- and mid-frequency (fingerprint) ranges has led to a wealth of information on both the short- and long-range crystalline structures. The recent addition of probes to the low-frequency-enabled instruments will help drive QbD during crystallization studies. The ultimate goal will be the advent of plant-based spectrometers that have both low- and mid-range capabilities.
What are the advantages of Raman spectroscopy for at-line and on-line monitoring of API crystallization?
There are several points I want to make here. First, manufacturers have developed lasers that are stable, reliable, and, from our experience, have an exceptionally long lifetime. This long lifetime is an advantage over other techniques such as FT-near infrared (NIR), which can require periodic changes of the light source. Second, instrument-to-instrument variability from the same manufacturer is minimal. The last point is that the Raman signal can travel long distances (we have fiber runs on the order of 75 m), enabling remote analysis of processes. This remote analysis capability means that we can follow a reaction or plant process in a rated or hazardous area and locate the actual spectrometer in a safe, nonhazardous zone. This is opposed to FT-IR and FT-NIR, which are limited to fiber bundles and can have a maximum fiber length for the transfer of spectral data of approximately 3 m.
Are there limitations or disadvantages to using Raman spectroscopy for that purpose?
A universal challenge when applying Raman is the inherent fluorescence of the sample. Fluorescence, if intense enough, can saturate the detector (charge-coupled device [CCD] camera) and is more pronounced at lower laser wavelengths (532 nm > 785 nm > 1064 nm). However, one must balance the need for sensitivity with the desire to minimize the sample fluorescence. For instance, if I go to a higher wavelength laser, say, 1064 nm, it will minimize the sample fluorescence but it will also decrease the spectral band intensity, which may not be suitable to follow dilute reactions. Therefore, in certain cases, if the sample fluorescence cannot be mitigated, FT-IR, NIR, or UV may be the appropriate technique to choose.
What are the next steps in your research?
The next challenge that we are looking to tackle is to extend our application of Raman spectroscopy into the biopharma arena focusing on biologics both in processing streams to develop in-process controls, and in final isolated drug substance and formulations to develop release and quality control methods.
John Wasylyk is a principal scientist at Bristol-Myers Squibb in New Brunswick, New Jersey. For 25 years, he has worked with Chemical Development Operations and the Analytical and Bio-Analytical Department where he focuses on developing spectroscopy-based PAT methods for early- to late-stage development projects through to manufacturing, along with spectroscopy methods for reagents and foreign material investigations. He received his PhD from the State University of New York at Binghamton in Biology and an MS in Medicinal Chemistry from the University of Houston.