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This feasibility study evaluates a cleaning process designed to avoid the use of detergents and reduce operator exposure to the active pharmaceutical ingredient (API). The continuous manufacturing equipment was cleaned using excipients to displace ibuprofen residues from the system. The cleaning process was performed using 3.0 kg of Prosolv® and 3.0 kg of Tablettose® 70. The impact of different volumetric feed rates of the cleaning excipient was assessed. The displacement of API and blend residues was evaluated with in-line near infrared (NIR) spectroscopy. Principal component analysis (PCA) was performed to evaluate the cleaning progress as the Prosolv® flowed through the feeder, mixer and stream sampler. In-place Raman spectra were acquired from the material sticking to detect the ibuprofen residues. The study showed that Prosolv® and Tablettose® can remove ibuprofen residues effectively from the hopper, feeder screw, mixer paddles, shaft and stream sampler. The Process Analytical Technology (PAT) system can be utilized to detect API displacement during the cleaning process. However, dismantling and manual cleaning was required to remove material sticking at the surfaces adjacent to the rotating feeder screws and mixer paddles.

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PURPOSE: This study describes the first efforts to build a spectral library to identify four cell culture media in powder form with spectra obtained with a handheld Raman spectrometer. These complex mixtures contain over 30 components and are among the most widely used cell culture media. METHODS: A total of 32 spectra were collected for the four Dulbecco's Modified Eagle Medium cell culture media and pure materials (glucose and L-glutamine) in powder form. The spectra were preprocessed using standard normal variate with second derivative, and the barcode method before performing principal component analysis (PCA). RESULTS: The PCA model differentiated the pure glucose and the cell culture media according to the glucose concentration along the first principal component. The second principal component differentiated the three cell culture media with high glucose content according to the pyruvate concentration. The correlation coefficient showed that powdered cell culture media with high glucose concentration have a higher correlation with pure glucose, when compared with the cell culture media with low glucose. CONCLUSION: The Raman spectra made it possible to differentiate the four DMEM in the cell culture media from the majority of the external samples used in the method evaluation. However, sample heterogeneity affected the predictions. Additional studies are needed to improve the method's ability to differentiate the DMEM with high glucose.

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This work aimed to evaluate the performance of a handheld NIR spectrometer in developing calibration models to quantify brix and pol at various stages of an industrial sugar production process. Because of sample variability, collected over two harvesting seasons, NIR measurements were acquired either in transmittance or diffuse reflectance. For modelling purpose, partial least squares (PLS), also combined with variable selection techniques, and support vector machine regression (SVR) were investigated. SVR was applied to handle non-linearities within the data. In general, results illustrated the best performance of SVR, that yielded lower root mean square error of prediction (RMSEP) values for brix and pol for spectra acquisition in transmittance (0.59 and 0.69%w/w) and using diffuse reflectance (1.44 and 2.44%w/w), respectively. Results from models using spectra collected in transmittance were comparable to those reported in other works where benchtop instruments were used, highlighting the cheaper and simpler employment of the portable spectrometer.

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In this investigation, the fermentation step of a standard mammalian cell-based industrial bioprocess for the production of a therapeutic protein was studied, with particular emphasis on the evolution of cell viability. This parameter constitutes one of the critical variables for bioprocess monitoring since it can affect downstream operations and the quality of the final product. In addition, when the cells experiment an unpredictable drop in viability, the assessment of this variable through classic off-line methods may not provide information sufficiently in advance to take corrective actions. In this context, Process Analytical Technology (PAT) framework aims to develop novel strategies for more efficient monitoring of critical variables, in order to improve the bioprocess performance. Thus, in this work, a set of chemometric tools were integrated to establish a PAT strategy to monitor cell viability, based on fluorescence multiway data obtained from fermentation samples of a particular bioprocess, in two different scales of operation. The spectral information, together with data regarding process variables, was integrated through chemometric exploratory tools to characterize the bioprocess and stablish novel criteria for the monitoring of cell viability. These findings motivated the development of a multivariate classification model, aiming to obtain predictive tools for the monitoring of future lots of the same bioprocess. The model could be satisfactorily fitted, showing the non-error rate of prediction of 100%.

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A chute was designed following the principles of the Theory of Sampling to minimize the variations in powder flow and provide all particles in the flowing blends with the same opportunity of being selected as a sample. The design also reduces the thickness of the chute to allow the analysis of a higher portion of the flowing blends by a near infrared spectrometer. The blends that flowed through the chute had Carr's index values that fluctuated between 23 and 25 percent, indicating passable flowability. A powder fowling evaluation demonstrated that there was no powder accumulation at the inspection window of the chute. The mass flow rate profiles indicated that the system achieves mass steady-state in approximately 30 s and a throughput of 30 kg/h which makes it suitable for continuous manufacturing operations. An in-line NIR calibration model was developed to quantify caffeine concentrations between 1.51 and 4.52 % w/w. The spectra obtained from each experiment had minimal baseline variation. The developed NIR method was robust to throughput changes up to approximately ±7 %. The test blends in the caffeine concentration range between 2.02 % w/w and 4.02 % w/w met the dose uniformity requirements of the Ph.Eur. 9.0, chapter 2.9.47. Variographic analysis was done to estimate the analytical and sampling errors which yielded values below 0.01 (%w/w)2. The obtained results showed that this chute could also be used in a continuous manufacturing line or other applications with flowing powders.

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Pyrazinamide (PZA), Rifampicin (RIF), Isoniazid (ISH) and Ethambutol (ETB) form the core for the treatment of Tuberculosis, today a devastating disease in low-income populations around the world. These drugs are usually administrated by fixed-dose combination (FDC) products, to favour the patient compliance and prevent bacterial resistance. PZA exists in four enantiotropically-related polymorphs (Forms α, δ, ß and γ), but only Form α is considered suitable for pharmaceutical products due to its stability and bioavailability properties. The classical approaches to address solid-state (microscopy, X-ray diffraction and calorimetry) shows limitations for quantification of polymorphs in the presence of excipients and other active components, as in the case of FDC tablets. In this work, an overall strategy was developed using near infrared spectroscopy (NIR) coupled to partial least squares regression (PLS) to quantify Form α of PZA in drug substance (raw material) and PZA/RIF/ISH-FDC tablets. For this purpose, two PLS models were constructed, one for drug substance preparing training (n = 30) and validation (n = 18) samples with a ternary composition (Form α/Form δ/Form γ), and other for FDC drug products, also including the appropriate amount of RIF, ISH and the matrix of excipients in order to simulate the environment of PZA/RIF/ISH association. The NIR-PLS models were optimized using a novel smart approach based on radial optimization (full range, 3 L V and MSC-D' and SNV-D' as pre-treatment, for raw material and FDC tablets, respectively). During the validation step, both methods showed no bias or systematic errors and yielded satisfactory recoveries (102.5 ± 3.1 % for drug substance and 98.7 ± 1.5 % for FDC tablets). When commercial drug substance was tested, NIR-PLS was able to predict the content of Form α (0.98 ± 0.01 w/w). The model for FDC tablets allowed estimating polymorphic purity in intact (0.984 ± 0.003 w/w), sectioned (0.986 ± 0.002 w/w), and powered (0.985 ± 0.004 w/w) tablets, showing the methodology could be applied to a different stage of the process (i.e premixed-powders or granulates). The suitability of the method was also verified when Form α was satisfactorily analysed in FDC fortified with Form δ and Form γ to reach 0.78, 0.88 and 0.98 w/w, Form α. This strategy results in an excellent alternative to ensure the polymorphic purity of PZA throughout the overall pharmaceutical manufacturing process.

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An innovative chute and stream sampler system for flowing powders has been developed and tested. The system is designed for representative sampling based on the principles of the Theory of Sampling (TOS). The sampling system was used in combination with near infrared (NIR) spectroscopy to determine the drug concentration of flowing powders. The system is comprised of three parts: a chute, a stream sampler and a sample collection port. The NIR spectra were obtained at the chute, before entering the sampler, and as the powder flowed through the stream sampler. Samples were also collected from the sample collection port to be analyzed using an ultraviolet-visible (UV-Vis) reference method to determine drug content. A total of eight pharmaceutical powder blends, ranging in concentration from 10.5(%w/w) to 19.5(%w/w) of caffeine, were used to test the sampling system. Materials were characterized before blends were made to provide information on flow properties. The throughput of the system was between 30 and 35 kg/h based on the flow properties of the blend. Drug concentration was effectively determined at the chute and stream sampler. The NIR calibration models showed low root mean squared errors of prediction, 0.65(%w/w) and 0.51(%w/w), for the chute and stream sampler respectively. The NIR calibration models also showed low bias values -0.36(%w/w) at the chute and 0.057(%w/w) at the stream sampler. Significant agreement was obtained between the results from the nondestructive NIR versus the destructive UV-Vis method. Variographic analysis was performed to estimate the analytical and sampling errors when determining the drug concentration at the chute and stream sampler respectively. The variographic analysis showed low analytical errors, 0.103(%w/w)2 and 0.181(%w/w)2 at the chute and stream sampler respectively. The analysis also showed that the minimum practical error (MPE) was around 0.2(%w/w)2 at both chute and stream sampler.

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Recentemente, produtos farmacêuticos e cosméticos com concentrações mínimas de parabenos e outros conservantes ganharam e apelo comercial e de segurança, devido à controvérsia sobre a segurança dos conservantes. No entanto, o uso de conservantes é essencial para garantir a conservação microbiana de produtos cosméticos e farmacêuticos durante o seu uso. Neste trabalho, desenvolveu-se um método quimiométrico de espectroscopia no infravermelho com Fourier transform near-infrared (FTIR) para prever a eficácia de sistemas conservantes em produtos farmacêuticos e cosméticos tópicos usando os conceitos de Quality by design (QbD) e Process Analytical Technology (PAT). A abordagem de QbD foi usada para determinar a eficácia antimicrobiana frente aos microrganismos: Candida albicans (ATCC 10231), Escherichia coli (ATCC 8739) e Staphylococcus aureus (ATCC 6538), em funções das concentrações de parabenos, e determinar a região de Design Space, empregando o delineamento de compóstio central (CCD) Todas as 15 formulações preparadas foram analisadas utilizando um espectrofotômetro (FTIR) equipado com aparato de Attenuated Total Reflectance (ATR). Os modelos de regressão por Partial Least Squares (PLS) para predição dos "slopes" das curvas de morte microbiana em função dos espectros ATR/FTIR foram bem ajustados, com R2 e R2-predição de 0,9937 e 0,8921, 0,9947 e 0,8783, e 0,9957 e 0,9222 para Candida albicans (ATCC 10231), Escherichia coli (ATCC 8739) e Staphylococcus aureus (ATCC 6538), respectivamente. O método FTIR proposto aplicado em uma abordagem de PAT foi capaz de prever a eficácia do sistema conservante em tempo reduzido. Este método de predição de silício permitirá um controle lote-a-lote da eficácia do sistema conservante de produtos farmacêuticos e cosméticos

Recently, pharmaceuticals and cosmetics with minimal concentrations of parabens and other preservatives have gained and commercial and safety appeal due to controversy over the safety of preservatives. However, the use of preservatives is essential to ensure the microbial conservation of cosmetic and pharmaceutical products during use. In this work, a chemometric method of infrared spectroscopy with Fourier transform (FTIR) was developed to predict the effectiveness of preservative systems in pharmaceutical products and topical cosmetics using the concepts of Quality by design (QbD) and Process Analytical Technology (PAT). The QbD approach was used to determine antimicrobial efficacy against candida albicans (ATCC 10231), Escherichia coli (ATCC 8739) and Staphylococcus aureus (ATCC) microorganisms 6538), in functions of paraben concentrations, and determine the Design Space region, employing the design of central composite (CCD). All 15 prepared formulations were analyzed using a spectrophotometer (FTIR) equipped with Attenuated Total Reflectance (ATR). The Partial Least Squares (PLS) regression models for the prediction of the slopes of microbial death curves as a function of ATR /FTIR spectra were well adjusted, with R2 and R2-prediction 0.9937 and 0.8921, 0.9947 and 0.8783, and 0.9957 and 0.9222 for Candida albicans (ATCC 10231), Escherichia coli (ATCC 8739) and Staphylococcus aureus (ATCC 6538)respectively. The proposed FTIR method applied in a PAT approach was able to predict the effectiveness of the preservative system in reduced time. This method in silico prediction will allow a batch-to-lot control of the effectiveness of the preservative system of pharmaceuticals and cosmetics

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Near-infrared spectroscopy (NIRS) is nowadays an established analytical technique in the pharmaceutical industry. The aim of this review is to present the progress of NIRS in providing useful information for pharmaceutical particle technology. NIR methods are now developed to characterize a wide variety of materials (active pharmaceutical ingredients, excipients, co-processed powders, and physical mixtures) and pharmaceutical dosage forms (conventional, modified drug release technologies, and phytomedicines). This review also provides a number of spectra to illustrate the fundamental understanding of NIRS which has been gained. The sampling that must occur prior to the acquisition of near-infrared spectra is also discussed, as well as developments in monitoring mixing, tableting, and coating. This review will be valuable for product formulation and process engineering specialists.

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O uso de ferramentas estatísticas no ciclo de vida de um produto farmacêutico permite verificar e controlar o processo tendo como objetivo a sua melhoria contínua. No presente estudo foi avaliada a estabilidade e a capacidade estatística do processo de fabricação dos comprimidos revestidos de lamivudina 3TC e zidovudina AZT (150 + 300 mg) fabricados pela Fundação para o Remédio Popular "Chopin Tavares de Lima" (FURP). Esse medicamento, distribuido gratuitamente pelo programa DST/AIDS do Ministério da Saúde, e fabricado por compressão direta, processo rápido que permite a implementação futura da tecnologia analítica de processo (Process Analytical Technology - PAT). No Capítulo I foi realizada avaliação retrospectiva da variabilidade de atributos criticos da qualidade de 529 lotes dos comprimidos fabricados de acordo com a RDC ANVISA 17/2010 e as monografias oficiais, sendo tais atributos: peso médio, uniformidade de dose unitária e % m/v de fármaco dissolvido, antes e após o revestimento. O objetivo foi identificar eventuais causas especiais de variabilidade dos processos que permitam melhorias contínuas. No Capitulo II foi desenvolvida metodologia analítica empregando a espectroscopia no infravermelho próximo com transformada de Fourier para a avaliação da homogeneidade da mistura dos pós. Nesse estudo foram analisadas amostras de misturas dos fármacos lamivudina 3TC e zidovudina AZT e mistura excipiente, empregando como método de referência a CLAE, para a quantificação desses dois fármacos. No Capitulo I, a avaliação do processo para o peso médio revelou a necessidade de investigação das causa especiais de variabilidade, evidenciada por meio das cartas de controle. Os resultados do ano de 2015 indicaram necessidade de centralização e de consistência do processo, com redução de probabilidade de falha. As cartas de controle para uniformidade de dose unitária, no ano de 2013, revelaram menor variabilidade do processo. Porem, nesse ano, a análise estatística para a dissolução revelou processo descentralizado e sem consistência, com maior evidência para o fármaco 3TC que demonstrou menor desempenho, Cpk<1,0. A avaliação da estabilidade e da capacidade do processo de fabricação de comprimidos de lamivudina + zidovudina (150+300 mg), no período de 2012 a 2015, permitiu o maior entendimento de suas fontes de variação. Foi possível detectar e determinar o grau dessa variação e seu impacto no processo e nos atributos críticos de qualidade do produto com evidentes oportunidades de melhoria do processo, reduzindo os riscos para o paciente. No capítulo II, no desenvolvimento do método, as estatísticas de validação revelaram que os menores valores de BIAS foram observados para a 3TC, 0,000116 e 0,0021, respectivamente para validação cruzada e validação. Os valores de BIAS próximos a zero indicaram reduzida porcentagem de variabilidade do método. O presente estudo demonstrou a viabilidade do uso do modelo desenvolvido para a quantificação da 3TC e AZT por FT-NIR apos ajustes que contribuam para a elevação de R, R2 e RPD para valores aceitáveis. Valores de RPD acima de 5,0 que permitem o uso do modelo para uso em controle de qualidade

The use of statistical tools in the life cycle of a pharmaceutical product allows verifying and controlling the process aiming at its continuous improvement. In the present study, the stability and statistical capacity of the lamivudine coated tablets 3TC and zidovudine AZT (150 + 300 mg) manufactured by the Chopin Tavares de Lima Foundation (FURP) were evaluated. This drug, distributed free of charge by the Ministry of Health's DST/AIDS program, is manufactured by direct compression, a rapid process that allows the future implementation of Process Analytical Technology (PAT). In Chapter I, a retrospective evaluation of the variability of critical quality attributes of 529 batches of tablets manufactured was carried out, such attributes being: mean weight, unit dose uniformity and % m/v of dissolved drug substances, before and after coating. The objective was to identify possible special causes of variability of the processes that allow continuous improvements. In Chapter II an analytical methodology was developed employing the near infrared spectroscopy with Fourier transform for the evaluation of the homogeneity of the powder mixture. In this study, samples of mixtures of the drugs lamivudine 3TC and zidovudine AZT and excipient mixture were analyzed, using as reference method the HPLC, for the quantification of these two drugs. In Chapter I, the evaluation of the process for the mean weight revealed the need to investigate the special cause of variability, as evidenced by the charts. The results of the year 2015 indicated the need for centralization and process consistency, with a reduction in the probability of failure. The control charts for unit dose uniformity, in the year 2013, revealed less process variability. However, in that year, the statistical analysis for dissolution revealed a decentralized process with no consistency, with greater evidence for the 3TC drug that showed lower performance, Cpk<1.0. The evaluation of the stability and capacity of the lamivudine + zidovudine tablet manufacturing process (150 + 300 mg) in the period from 2012 to 2015 allowed a better understanding of its sources of variation. It was possible to detect and determine the degree of this variation and its impact on the process and the critical quality attributes of the product with evident opportunities to improve the process, reducing risks for the patient. In Chapter II, in the development of the method, the validation revealed that the lowest values of BIAS were observed for 3TC, 0.000116 and 0.0021, respectively for cross validation and validation. BIAS values close to zero indicated a reduced percentage of variability of the method. The present study demonstrated the feasibility of using the model developed for the quantification of 3TC and AZT by FT-NIR after adjustments that contribute to the elevation of R, R2 and RPD to acceptable values. RPD values above 5.0 that allow the use of the model for use in quality control

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Os protetores solares (PS) são os grandes responsáveis pela proteção da pele quando exposta à radiação solar, por isso a importância sanitária de se otimizar o desenvolvimento deste cosmético tipo II e monitorar para que seja eficaz em seu propósito. O principal objetivo deste trabalho é aplicar os conceitos de Qualidade por Design (QbD), ferramentas estatísticas de desenho experimental (DoE - Design of Experiments) e o conceito de tecnologia analítica de processo (PAT - Process Analytical Technology) para desenvolver uma formulação e processo produtivo de um PS de modo a modernizar os processos da indústria cosmética, fazendo as análises durante o processo e eliminando o controle de qualidade final. Trata-se de um sistema de desenvolvimento sistematizado, onde se executa as ferramentas de QbD para avaliar os dados obtidos ao longo da fase experimental. Para a fase experimental, empregou-se o desenho fatorial e desenho do compósito central (CCD - Central Composite Design) como ferramenta estatística, para a execução do planejamento de experimentos (DoE - Design of Experiments). As respostas foram analisadas através da metodologia de superfície resposta (RSM - Response Surface Methodology). Tais ferramentas são fundamentais para a determinação do desenho de concepção (design space), para se obter o PS com as melhores características físico-químicas e de processo dentro do escopo delineado. Para o desenvolvimento da metodologia de análise in line, optou-se pela utilização da espectrometria UV, utilizando-se ferramentas como análise de regressão dos mínimos quadrados (PLS) devido a praticidade em transforma-la em uma ferramenta PAT, para isto, a quimiometria foi empregada para modelar sistemas que são desconhecidos e complexos, como um PS, e trazendo respostas diretas como a aprovação do produto antes de ser embalado, por exemplo. A abordagem apresentada baseia-se na construção da qualidade ao longo do desenvolvimento e otimização de PS e torna possível o monitoramento da qualidade em tempo real

The sunscreens are great responsible for the skin protection when it is exposed to direct sunlight, so it means a great importance of health to optimize the development of type II cosmetic and monitor for it to be effective in its purpose. The objective of this work is to apply the concepts of Quality by Design and statistical tools of experimental design (DoE - Design of experiments), as well as applying the process analytical technology (PAT - Process Analytical Technology) concept for formulation and manufacturing process development of a topical sunscreen being able to modernize the cosmetic industry processing, including real time analyses and eliminating quarantine step, which waits analysis approval performed by the quality assurance, and then release the product for sale. As it is a systematic development, where critical quality attributes and risk assessment were performed to evaluate over obtained data. During experimental phase, the factorial design was used as a statistical tool for design of experiments implementation, and the responses were analyzed by response surface methodology (RSM - Response Surface Methodology). This mapping is critical to determination of the product design (design space), i.e. get sunscreen with the best physical and chemical characteristics and processing within the outlined scope. For in line methodology development, UV spectrometry was opted to be used due to less effort in sample preparation and due to great easiness to turn it into a PAT tool. For this, chemometrics was used, which brings together chemical and statistical elements to obtain three main elements: empirical modeling, multivariate modeling and chemical data, making it able to model systems that are unknown and complex, as a sunscreen, getting direct answers as product release approval before being packed, for example. The presented approach was based on the construction of quality throughout the sunscreen development and optimization making possible the real time quality monitoring

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In this work, near-infrared spectroscopy (NIRS) method was used to evaluate the uniformity of dosage units of three captopril 25 mg tablets commercial batches. The performance of the calibration method was assessed by determination of Q value (0.9986), standard error of estimation (C-set SEE = 1.956), standard error of prediction (V-set SEP = 2.076) as well as the consistency (106.1%). These results indicated the adequacy of the selected model. The method validation revealed the agreement of the reference high pressure liquid chromatography (HPLC) and NIRS methods. The process evaluation using the NIRS method showed that the variability was due to common causes and delivered predictable results consistently. Cp and Cpk values were, respectively, 2.05 and 1.80. These results revealed a non-centered process in relation to the average target (100% w/w), in the specified range (85-115%). The probability of failure was 21:100 million tablets of captopril. The NIRS in combination with the method of multivariate calibration, partial least squares (PLS) regression, allowed the development of methodology for the uniformity of dosage units evaluation of captopril tablets 25 mg. The statistical process control strategy associated with NIRS method as PAT played a critical role in understanding of the sources and degree of variation and its impact on the process. This approach led towards a better process understanding and provided the sound scientific basis for its continuous improvement.

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This study examines the factors that may cause systematic errors in the manometric temperature measurement (MTM) procedure used to evaluate product temperature during primary drying. MTM was conducted during primary drying using different vial loads, and the MTM product temperatures were compared with temperatures directly measured by thermocouples. To clarify the impact of freeze-drying load on MTM product temperatures, simulation of the MTM vapor pressure rise was performed, and the results were compared with the experimental results. The effect of product temperature heterogeneity in MTM product temperature determination was investigated by comparing the MTM product temperatures with directly measured thermocouple product temperatures in systems differing in temperature heterogeneity. Both the simulated and experimental results showed that at least 50 vials (5 mL) were needed to give sufficiently rapid pressure rise during the MTM data collection period (25 seconds) in the freeze dryer, to allow accurate determination of the product temperature. The product temperature is location dependent, with higher temperature for vials on the edge of the array and lower temperature for the vials in the center of the array. The product temperature heterogeneity is also dependent upon the freeze-drying conditions. In product temperature heterogeneous systems, MTM measures a temperature close to the coldest product temperature, even, if only a small fraction of the samples have the coldest product temperature. The MTM method is valid even at very low product temperature (-45°C).