Prediction Performance and Economic Efficiency of Soft Sensors for in-Line Water Content Monitoring in Fluidized Bed Granulation: PP-Based Model vs. NIRS-Based Model.

Soft sensors play a crucial role as process analytical technology (PAT) tools. They are classified into physical models, statistical models, and their hybrid models. In general, statistical models are better estimators than physical models. In this study, two types of standard statistical models using process parameters (PPs) and near-infrared spectroscopy (NIRS) were investigated in terms of prediction accuracy and development cost. Locally weighted partial least squares regression (LW-PLSR), a type of nonlinear regression method, was utilized. Development cost was defined as the cost of goods required to construct an accurate model of commercial-scale equipment. Eleven granulation lots consisting of three laboratory-scale, two pilot-scale, and six commercial-scale lots were prepared. Three commercial-scale granulation lots were selected as a validation dataset, and the remaining eight granulation lots were utilized as calibration datasets. The results demonstrated that the PP-based and NIRS-based LW-PLSR models achieved high prediction accuracy without using the commercial-scale data in the calibration dataset. This practical case study clarified that the construction of accurate LW-PLSR models requires the calibration samples with the following two features: 1) located near the validation samples on the subspace spanned by principal components (PCs), and 2) having a wide range of variations in PC scores. In addition, it was confirmed that the reduction in cost and mass fraction of active pharmaceutical ingredient (API) made the PP-based models more cost-effective than the NIRS-based models. The present work supports to build accurate models efficiently and save the development cost of PAT.

An economically and environmentally acceptable synthesis of chiral drug intermediate L-pipecolic acid from biomass-derived lysine via artificially engineered microbes.

Deficiency in petroleum resources and increasing environmental concerns have pushed a bio-based economy to be built, employing a highly reproducible, metal contaminant free, sustainable and green biomanufacturing method. Here, a chiral drug intermediate L-pipecolic acid has been synthesized from biomass-derived lysine. This artificial bioconversion system involves the coexpression of four functional genes, which encode L-lysine α-oxidase from Scomber japonicus, glucose dehydrogenase from Bacillus subtilis, Δ1-piperideine-2-carboxylase reductase from Pseudomonas putida, and lysine permease from Escherichia coli. Besides, a lysine degradation enzyme has been knocked out to strengthen the process in this microbe. The overexpression of LysP improved the L-pipecolic acid titer about 1.6-folds compared to the control. This engineered microbial factory showed the highest L-pipecolic acid production of 46.7 g/L reported to date and a higher productivity of 2.41 g/L h and a yield of 0.89 g/g. This biotechnological L-pipecolic acid production is a simple, economic, and green technology to replace the presently used chemical synthesis.

Quality control of hospital preparations: Establishment of a simple and rapid method for quantifying ulinastatin in vaginal suppositories.

Ulinastatin vaginal suppositories, used to prevent threatened premature delivery, are frequently used in hospitals. However, there is no established method for quantifying ulinastatin contained in suppositories. Therefore, we investigated a simple and efficient method for quantifying ulinastatin contained in suppositories. Our analytical method involved removal of the base; optimising the enzyme inhibition reaction time and enzyme reaction time; and measuring the absorbance. The modified method was reproducible, operation time was significantly shortened, and cost was reduced to approximately 1/17 of that of the previously reported method. This simple and rapid quantitative method could contribute to the improvement of quality control of ulinastatin vaginal suppositories as an extemporaneous hospital preparation.

A Cheap and Convenient Method of Liposome Preparation Using Glass Beads as a Source of Shear Force.

Liposomes, the biocompatible lipid bilayer vesicles, have attracted immense attention due to their distinctive features such as efficient vehicle for the delivery of a wide range of therapeutic agents, adjustable formulation properties, and high drug entrapment efficiency. In this contribution, we present a simple method for the preparation of liposomes using glass beads and compared the potential of this method with conventional methods of liposome preparation. The prepared liposomes were characterized by different analytical techniques (HPLC, DLS, TEM, differential scanning calorimetry, and in vitro drug release). Our findings revealed that the particle size of liposomes is mainly dependent on the size of the glass beads and the glass bead shearing time. An average liposome size of 67.7 ± 25.5 nm was obtained using 2-mm glass beads after 24-h incubation at 200 rpm. The liposomes prepared under the optimized conditions exhibited a high encapsulation efficiency of 92.1 ± 1.7% with 31.08% drug release after 360 min at 37°C. In conclusion, the developed method is a simple and convenient process of liposome preparation of different sizes with desirable entrapment efficiency capacity.

Using Data Exclusivity Grants to Incentivize Cumulative Innovation of Biologics' Manufacturing Processes.

The pharmaceutical market is divided into two types of compounds: small-molecule chemical compounds and large-molecule biologics. Due to biologics' molecular sizes and the current scientific state of biologics manufacturing, manufacturing facilities and processes require frequent reassessment to ensure production of safe, pure, and potent therapeutics. Manufacturers utilize patent and drug regulatory law to protect their investments and simultaneously signal where innovation and investment are lacking. The current four- and twelve-year regimented structures of the Biologics Price, Competition, and Innovation Act do not keep pace with scientific development; biologics manufacturing processes drift with time, and if a manufacturer can obtain a higher degree of process control, then it should not feel restricted to wait until their exclusivity period lapses. Currently, the FDA rarely grants market exclusivity privileges for manufacturing process improvements alone; hence, manufacturing processes--or at least large portions thereof--are typically withheld as trade secrets or strategically claimed within companion composition claims. As a result, significant opportunity exists in regulatory framework to incentivize the research and development of biologics manufacturing processes. By creating a one- to four-year data exclusivity extension opportunity, manufacturers will feel more comfortable reinvesting their returns on investment towards manufacturing efficiency, and manufacturers can capitalize on the complex-molecule nature of their biologic.

[INDENA SPA company's patent portfolio of Ginkgo biloba preparation].

INDENA SPA Company in Italy is a multi-national company that produces and sells plant extracts. Based on its own re- search advantages in the field of Ginkgo biloba preparation, the company protects its own products market effectively through building patent portfolio around the patents of its opponent. Based on the multi-angle analysis for patent portfolio of G. biloba preparation from the aspects of application time, legal status, technical development route, and patent portfolio layout, this article provides technical reference on research and development of G. biloba preparation, and the author suggest that Chinese applicants learn techniques and layout experiences of other patents fully to enhance the level of research and patent protection level.

[Analysis of projects funded by NSFC in field of processing Chinese materia medica in recent five years].

The general situation of the approved and concluded projects of National Natural Science Foundation of China in the field of processing Chinese Materia Medica in recent five years has been reviewed. The progresses and achievements of some projects have been summarized in accordance with research area such as the processing principle, the processing technology, quality evaluation, toxicity and safety evaluation, etc. The researchers and project support units of the funded projects have been analyzed, and the problems of the applications have been also summarized.

[Present situation and development strategies of Chinese medicine preparation in medical institutions].

As the actual clinical reflecting of transform Chinese medicine special curative effect, Chinese medicine preparation not only satisfies the need of hospital clinic, scientific research and teaching, but also plays an important role in deepening medical and health system reform, improving people's health level and contributing to the economic growth. However, some problems about administration and approval (tending to western medicine), contraction of the scale, lack of synchronization for clinic and scientific research, and the imbalance of regional development make Chinese medicine preparation move forwards slowly in contradiction. It has not only reduced the effectiveness of the Chinese medicine preparation in hospital clinic, but also brought bad effect on modernized development of Chinese medicine preparation. Research shows that main influencing factors of status quo of Chinese medicine preparation in medical institution include imperfect laws and regulations, high cost than income, and shortage of talents in preparation research. The analysis indicated that the necessary measures to break the contradiction, improve clinical effect of Chinese medicine, and promote the modernization development of Chinese drugs preparation were as follows: government and related departments should strengthen the supporting force in policy by adjusting the examination and approval policy, speeding up dispensing use, reforming pricing system, including into medicare reimbursement, integrating advantage resources and so on; medical institution should actively carry out research and development of traditional Chinese Medicine through drawing the traditional and modern essence, reserving professional talents, and developing characteristic preparation; companies cooperate with hospitals for complementary advantages, which can rapidly transform Chinese medicine preparation into clinical practice.

[Suggestions to strengthen quality management of herbal decoction pieces--based on production chain of herbal decoction pieces].

With the development of society and the improvement of people's living standards, the effect of Chinese medicine in treatment and health care is more and more prominent. The herbal decoction pieces are the important part of Chinese medicine,it can be applied directly to clinical treatment and it's also the raw material of Chinese patent medicine. Therefore, the quality of herbal decoction pieces is quite important. The parts of the production of herbal decoction pieces are numerous, and there are possibilities of adverse effects on the quality of the herbal decoction pieces in every part. In this paper, we based on the production chain of herbal decoction pieces, analyzed the main problem that affect the quality of herbal decoction pieces in the part of selection of Chinese herbal medicines, planting, purchasing, processing, packaging, storage and transport, such as the poor quality of seed and seedlings of plant-based Chinese medicines, some plants left their place of origin and have been introduced in the place that is not suitable for this kind of plant, the insufficient growth time and the excessive harmful substances. The purchasers and the accepters lack of professional knowledge and professional ethics. The mechanism of processing is not clear, the standards can not be uniformed, and lack of qualified person in processing, etc. So we suggest: intensify the basic research of key scientific issues. Improve the quality of persons who work in herbal decoction pieces; Establish an "integration" mode of operation in herbal decoction pieces enterprise; Breeding high quality plant resources, establish the large-scale planting basement; Make the packing of herbal decoction pieces standard; Establish the modernization traditional Chinese medicine logistics enterprise.

Why is mannitol becoming more and more popular as a pharmaceutical excipient in solid dosage forms?

Various fillers/binders which are applied for the formulation of solid oral dosage forms are assessed for their benefits and drawbacks, including lactose, sorbitol, mannitol, microcrystalline cellulose and calcium hydrogen phosphate dihydrate. A focus of this work was to evaluate the application of mannitol in comparison to other common fillers/binders as it was observed that this excipient is gaining more and more attention in pharmaceutical formulation development and production. While one of the main advantages of conventional fillers/binders such as lactose, microcrystalline cellulose and calcium hydrogen phosphate dihydrate is their low price level, mannitol excels regarding its physicochemical characteristics such as a low hygroscopicity, a strong inertness towards both the API and the patient's body, its good compactibility and the ability to produce extremely robust tablets. Additionally, the suitability of mannitol for the emerging formulation technology of orally disintegrating tablets is pointed out. In summary, it is emphasized that the selection of the filler/binder is highly individual, depending, for example, on the preferred characteristics of the final solid dosage form, the applied API and the available budget. However, mannitol exhibits many strong advantages which can be expected to result in a more widespread application in the near future.

[Multi-objective optimization of extraction process for red ginseng based upon extraction efficiency and cost control].

It is the objective of this study to optimize the extraction process of red ginseng to minimize the unit cost of extracting effective ingredients. The relation between the target variables of total quantity of ginsenosides and first extraction time, first extraction solution amount, second extraction time, second extract solution amount were studied with Box-Behnken experimental design method. At the same we also considered the cost of extraction solution and energy usage. The objective function was set as unit cost of target (total quantity of ginsenosides or its purity) for the multi-objective optimization of extraction process. As a result, the optimal process parameters were found as first extraction time (108.7 min), first extraction solution amount folds (12), second extraction time (30 min), second extraction solution amount folds (8) to minimize the unit cost. It indicated that this approach could potentially be used to optimize industrial extraction process for manufacturing Chinese medicine.

[Research status and translational application of new extraction techniques of traditional Chinese medicine].

Extraction is the critical link during pharmaceutical process of traditional Chinese medicine (TCM), which is directly related to the quality of drugs. So the key to technology upgrading of pharmaceutical equipment in Chinese materia medica enterprise is the development of new extraction techniques, which concerns the modernization of TCM. In this paper, fundamentals, traits, and development status of new extraction technologies were firstly introduced, including ultrasound extraction, microwave extraction, super fluid extraction, semi-bionic extraction method, enzymatic treatment extraction, continuous countercurrent extraction, vacuum extraction. Then information of projects supported by the National Natural Science Foundation of China was analyzed in order to recognize the assistance and research results of new extraction techniques. The patents authorized by the State Intellectual Property Office were also summarized for the purpose of understanding the achievement transformation. The information about extraction equipments was collected and screened to acquire the characteristics and market situation. The results showed that there are still problems about new extraction technologies, such as weak basic study, hard transformation of achievements, and the disconnection between research study and practical application. It is necessary to discuss the approaches and methods for accelerating the transformation of fundamental research, which will provide references for the long-term development of new extraction techniques of TCM.

[Establishment of industry promotion technology system in Chinese medicine secondary exploitation based on "component structure theory"].

The purpose of the secondary exploitation of Chinese medicine is to improve the quality of Chinese medicine products, enhance core competitiveness, for better use in clinical practice, and more effectively solve the patient suffering. Herbs, extraction, separation, refreshing, preparation and quality control are all involved in the industry promotion of Chinese medicine secondary exploitation of industrial production. The Chinese medicine quality improvement and industry promotion could be realized with the whole process of process optimization, quality control, overall processes improvement. Based on the "component structure theory", "multi-dimensional structure & process dynamic quality control system" and systematic and holistic character of Chinese medicine, impacts of whole process were discussed. Technology systems of Chinese medicine industry promotion was built to provide theoretical basis for improving the quality and efficacy of the secondary development of traditional Chinese medicine products.

The manipulation of drugs to obtain the required dose: systematic review.

AIM: To describe the development of a systematic review protocol that maps the evidence relating to drug manipulations conducted to obtain the required dose. This process included defining a search strategy and methods to assess the quality and to synthesize the evidence retrieved. BACKGROUND: Economic constraints mean that marketed formulations may not meet the needs of all patients. Consequently, it is sometimes necessary to manipulate marketed products with the aim of obtaining the required dose. Most clinical practice appears to be guided by ad hoc approaches and informal literature reviews. METHODS: This systematic review protocol has been designed to identify the evidence available on drug manipulation. The review aims to identify what evidence is available and where the gaps appear in the current evidence. This report describes the challenges of developing a systematic review in an area that potentially involves many drugs and considers outcomes other than effectiveness. In particular, searches required the use of non-specific terms and the iterative development of a complex search strategy. The development of quality assessment criteria is also described. Funding commenced in April 2009. DISCUSSION: The systematic review described here will capture a broad selection of research about drug manipulations and may also be of interest to those conducting reviews in broad remit subject areas that are not easy to define using accepted terminology.

[Analyses on positive influence of harmonous development of traditional Chinese medicine compounds' researchs and patent protection].

Current patent protection of traditional Chinese medicine (TCM) compounds is far from being satisfactory with increasing research and development achievements. As patent protection of traditional Chinese medicine compounds is closely related with many fields such as research and development of new TCM drugs, industrial development and TCM internationalization, the development of research and harmonious development of TCM compounds and their patent protection is bound to have a far-reaching influence on domestic and even international societies.

Scalable synthesis of a prostaglandin EP4 receptor antagonist.

The evolution of scalable, economically viable synthetic approaches to the potent and selective prostaglandin EP4 antagonist 1 is presented. The chromatography-free synthesis of multikilogram quantities of 1 using a seven-step sequence (six in the longest linear sequence) is described. This approach has been further modified in an effort to identify a long-term manufacturing route. Our final synthesis involves no step requiring cryogenic (< -25 degrees C) conditions; comprises a total of four steps, only three of which are in the longest linear synthesis; and features the use of two consecutive iron-catalyzed Friedel-Crafts substitutions.

Process R&D under the magnifying glass: organization, business model, challenges, and scientific context.

Initially, the aim is to provide the big picture illustrating the as is situation in the pharmaceutical industry: a lack of productivity resulting in too few products reaching the market; a loss of billions in revenue over the next few years as some of the major megabrands go off patent; a spiraling cost for developing new drugs and taking them through clinical and safety studies. Following on, a look deeper into the organization will offer an insight into the state-of-the-art in a technical function accountable for chemical Process R&D (with a remit to develop scalable, robust, and cost efficient processes for small molecules). The vast majority of compounds already launched in the form of drug products on the market or still being pursued through the phases of discovery and development, fall within the category of small molecules (as opposed to biopharmaceuticals, e.g., proteins, monoclonal antibodies). This typically means molecular weights of <1000Da and puts organic synthesis in the widest sense of the word at the forefront of technologies needed to support R&D programs in the pharma industry. Understandably, the demands on Medicinal Chemistry are quite different to what applies in a Process R&D (PR&D) organization. In the former, making large numbers of potentially interesting molecules, many of which are discarded after testing, is a key driver and for this virtually any synthetic methodology will suffice. For PR&D, however, homing in on selected compounds there is an expectation that the best synthetic routes will be delivered that meet a number of tough criteria, for instance from an environmental and safety point of view, allowing operation on large scale, offering cost competitiveness, avoiding patent infringements, showing sustainability for long-term production, etc. The intention is to focus on issues to be addressed during this transition by providing examples of changes that had to be put in place in order to make the supply of larger amounts of material feasible. At the end some forward looking conclusions will be shared.

Validation of a simple, rapid and cost effective method for the estimation of caprylic acid and sodium caprylate from biological products using NEFA-C kit.

The method for the determination of caprylic acid and sodium caprylate from biological products was systematically validated using NEFA-C kit. The results obtained demonstrated that the kit method was simple, rapid, reliable, sensitive, reproducible and cost effective in comparison to the current methods i.e. colorimetric, High Performance Liquid Chromatography (HPLC) and Gas Chromatography (GC) methods. The assay exhibited excellent linearity, accuracy, precision and robustness. Mean recoveries ranged between 95 and 101.3% (n=6). The proposed method was linear over the concentration range of 0.05-10mM of caprylate with values of coefficient of regression being>0.99. Method showed sensitivity of 0.05 mM (7.21 microg/ml for caprylic acid and 8.31 microg/ml for sodium caprylate). The % Relative standard Deviation (%RSD) for intra and interprecision studies was less than 5%. In conclusion the validated method was successfully used in monitoring of processed bulk and final products generated during production of biological products thus laying emphasis on strict control of release criteria for biological products fractionated using caprylic acid.

A novel rapid quantitative analysis of drug migration on tablets using laser induced breakdown spectroscopy.

There have been few reports wherein drug migration from the interior to the surface of a tablet has been analyzed quantitatively until now. In this paper, we propose a novel, rapid, quantitative analysis of drug migration in tablets using laser induced breakdown spectroscopy (LIBS). To evaluate drug migration, model tablets containing nicardipine hydrochloride as active pharmaceutical ingredient (API) were prepared by a conventional wet granulation method. Since the color of this API is pale yellow and all excipients are white, we can observe the degree of drug migration by visual inspection in these model tablets. In order to prepare tablets with different degrees of drug migration, the temperature of the drying process after tableting was varied between 50 to 80 °C. Using these manifold tablets, visual inspection, Fourier transform (FT)-IR mapping and LIBS analysis were carried out to evaluate the drug migration in the tablets. While drug migration could be observed using all methods, only LIBS analysis could provide quantitative analysis wherein the average LIBS intensity was correlated with the degree of drug migration obtained from the drying temperature. Moreover, in this work, we compared the sample preparation, data analysis process and measurement time for visual inspection, FT-IR mapping and LIBS analysis. The results of the comparison between these methods demonstrated that LIBS analysis is the simplest and the fastest method for migration monitoring. From the results obtained, we conclude that LIBS analysis is one of most useful process analytical technology (PAT) tools to solve the universal migration problem.