Page 9 - Shimadzu Journal vol.2 Issue1
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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.
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