Page 9 - Shimadzu Journal vol.2 Issue1

Customer Interviews Customer Interviews

whether non-target substances are present in a particular sample, its
Unique & Innovative Functions for use enables the elucidation of HPLC conditions that provide a high
degree of reliability.
Next Generation Separation Technologies (4) Controlling the presence of impurities is an extremely important

and complex part of pharmaceutical development. Pharmaceutical
W e interviewed two customers with whom we have built good relations for over 10 years. They have advised us impurities include the impurities present in starting materials (raw
ingredients) as well as byproducts found in intermediates and APIs.
ɹɹɹduring the development of instruments and methods for pharmaceutical analyses. Recently, we released the
Nexera X2 UHPLC that features two innovative functions: i-PDeA (Intelligent Peak Deconvolution Analysis) and i-DReC Many of these impurities are similar structurally to useful components,
and their identification can be difficult when the resolving power of
(Intelligent Dynamic Range Extension Calculator). We asked them about each technology. For further information HPLC is insufficient for their quantitation. For example, uncertainty
about i-PDeA and i-DReC, please see each technical report that follows the interviews. can arise over whether to apply tangent skim or peak splitting to
determine the area of an impurity peak. i-PDeA extracts the impurity
peak with specificity to always provide objective peak integration that
i-PDeAɹ- Intelligent Peak Deconvolution Analysis - (See pp. 39-42) produces scientifically accurate results not affected by human factors.
While there is the conventional method of improving resolution by
What is the background to how the benefits of this The development of i-PDeA occurred against this backdrop, and increasing throughput time to increase separation of impurities, if Please give us your opinion of Shimadzu, and what you
technology were brought to light? originated from eluate testing that then took 24 hours to perform. would like to see from them.
i-PDeA recognizes differences between UV spectra, impurities can be
Pharmaceutical development normally entails a developmental period of We changed from using conventional HPLC to a UV-based analytical quantitated within a short period of time. In addition, when
several decades and research and development expenditures of around method, and to analysis of the derivative spectrum of UV spectra to chromatographic separation is insufficient for impurity analysis, it may The idea for i-PDeA was given to Shimadzu around five years ago. I
100 billion yen. Therefore, the development of efficient research practices ensure specificity. I also proposed the development of i-PDeA analytical be assumed that i-PDeA can be used for quantitation as long as there wonder whether Shimadzu could not have developed i-PDeA a little
is of increasing importance. Meanwhile, the efficacy and safety of software, with which spectra can be obtained instantaneously. is a difference present in UV spectra. earlier, though I suppose conventional methods were deemed good
pharmaceutical products are invariable requirements, and regulatory enough at the time, or no one raised any criticism against them.
authorities are demanding ever-stricter conditions for their approval. With Could you tell us what analytical applications and Also, because an 85-mm optical path length cell allows i-PDeA to However, it must be recognized that to stick to conventional methods
regards to regulations on quality assurance practices for pharmaceutical particular tests you see this feature being useful for? carry out highly sensitive analysis, i-PDeA is expected to be used to is a complacent approach that halts progress. We must look to the
CMC (the ICH "Q" series of guidelines), subsequent to guidelines that analyze GTIs (genotoxic impurities) at ppm levels. GTI analysis is an future in order to advance, despite the strong tendency to view the
pertain to pharmaceutical products, ICH Q11, which references active Although i-PDeA has only just been developed as a commercial essential part of process control testing and release testing that is future through the rear-view mirror of conventional wisdom. I think it
pharmaceutical ingredients (APIs), has recently been endorsed. product and it will find many applications in the future, the current performed during the phases of pharmaceutical development through is in people's nature to be conservative. While maintaining a focus on
the past can result in work getting done, you cannot expect to see any
primary focus is its use as a PAT. to commercial production. At present, highly sensitive and highly
These ICH guidelines perceive the optimization of methods for the selective LC/MS analysis methods are generally employed for this progress while doing so. The promise of progress goes hand in hand
manufacture of APIs and pharmaceutical products that occurs between In particular, the 85-mm long path length cell for the SPD-M30A analysis. However, considering its stable detection, speed, simplicity, with a certain amount of effort and hardship.
the developmental phase and the commercial production phase of detector and dynamic range extension using i-DReC dramatically and routine performance, including the ease of equipment control, I
pharmaceutical manufacture in terms of what is called a Design Space. increase the concentration range of analytes, expanding the range of think a synergistic application of chromatographic technology with the The technical capabilities exhibited by Shimadzu in their
This Design Space approach requires the scientific validity for process applications to high-sensitivity and high-concentration sample analysis. Nexera X2 and the analytical specificity of i-PDeA would be adequate commercialization of i-PDeA within six months of deciding to proceed
conditions defined at each process operation be included in an application I believe this will further increase the potential range of applications for this purpose. I believe there is an extremely wide range of with the project are both admirable and astonishing. And I feel that
for approval. In other words, this approach requires that quality be built in for i-PDeA. applications for i-PDeA, and I would like to see further data be the timing of this commercialization of i-PDeA is apposite for those
to the product development lifecycle. This change has brought about a accumulated in support of this. who work in pharmaceutical development. I believe applications for
major reform in research practices pertaining to chemistry, manufacturing In addition to applications such as (1) real-time eluate testing and (2) i-PDeA will continue to appear, and think it certain that i-PDeA will, as
and control (CMC). The evidence that becomes the scientific basis for quantitative monitoring of target products from synthesis reactions, I Could you talk about any functionality you think should be a PAT, become a groundbreaking technology with respect to the
process optimization is analytical data, where an enormous amount of think i-PDeA can be used for (3) verifying specificity (peak purity) included in i-PDeA, or other matters that could be improved? manufacturing process control required by regulatory authorities.
analytical data is used to form the basis of the optimization of each during HPLC analytical method validation and (4) HPLC used for Thanks go to all those involved who listened to users and answered
process operation. Consequently, a major focus of optimization is the impurity testing. I believe we need to see improvements in hardware performance and their queries.
speed and power of the analyses performed to obtain this data. Analytical for new devices to be developed to better support the use of i-PDeA
methods necessary for the optimization of process operations at the (1) For eluate testing, i-PDeA is extremely attractive as drug specificity in a variety of sampling methods, including the eluate testing and
commercial production scale need to incorporate three important can be identified easily using instantaneously obtained UV spectra. reaction monitoring I mentioned earlier. Thank you for giving us your valued opinions.
elements: speed, simplicity, and accuracy. An outcome of this is the Using i-PDeA is both quick and simple, and provides quantitative
importance of working towards analytical methods that work in real time, analysis in real time. In the future, I think i-PDeA will see fruitful
or what is also called process analytical technology (PAT). application as an analytical technique suited to manufacturing process i-DReCɹ- Intelligent Dynamic Range Extension Calculator - (See pp. 43-46)
control that is geared towards optimizing the method of
manufacturing pharmaceutical products, or in other words as a PAT.
Mr. Takeuchi, based on your evaluation of the i-DReC
(2) For synthesis reactions, as long as there is no interference from the function, could you share some background on why you
reaction solvent in terms of UV absorption, i-PDeA can be used for were interested in the wide dynamic range of the i-DReC,
real-time monitoring of reaction progress. Also, because reaction what types of samples were giving you problems, and so on?
liquids become extremely concentrated, for cases in which dynamic
range extension (i-DReC) can be applied, i-PDeA is likely to become a One of the things we do is use LC for quantitative analysis in
groundbreaking development for API manufacture. Also, the 85-mm early-stage drug discovery work. Unlike many physics, chemistry, and
long path cell can be used for analysis of trace components, and can drug-manufacturing departments, where analysis is performed using
probably be used for monitoring the presence of degradation validated instruments or measurements are made for application
products and byproducts during a reaction over time. processes, we focus not only on data quality and accuracy, but also on
analytical efficiency to process as many compounds as quickly as possible.
(3) HPLC analytical method validation encompasses specificity testing,
where a required degree of peak purity in the chromatogram is The samples Shimadzu tested for us contained high concentrations of
Dr. Naoki Asakawa, Eisai Co., Ltd. employed as a means of verification. Because i-PDeA easily determines compounds that would normally be diluted before quantitation.
Mr. Takahiro Takeuchi, Teijin Pharma Ltd.
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Pretreatment processes such as dilution can affect accuracy. In
addition, dilution and some other pretreatment processes require
considering the solvent used, which takes additional time. Highly viscous
solvents, moreover, require separate consideration. For example, the
sample quantity available for administration tests is often very limited, so
we were already looking for ways to eliminate such negative factors by
measuring concentrated samples directly without pretreatment.
However, typical PDA detectors have a limited dynamic range.
Eventually, we considered using MS or another detection method with a
wide dynamic range, but MS requires dealing with matrix effects and
considering internal standard correction. It was at that point that we
were introduced to the i-DReC and provided samples. I thought the
technology was theoretically possible, but after seeing the good range
and linearity of calibration curve results, I realized that this was truly a
useful function.