Development Pharmaceutics and process Validation

Abstract

A resume is presented of the guideline on the data required under Part I.A.4. of the Annex to European Directive 75/318/EEC covering the choice of composition of a medicinal product, supported by data on development pharmaceutics. The broad areas of development studies cover the function and compatibility of active ingredients and excipients, the development of liquid, semi-solid and solid dosage forms and the suitability of containers.

The guideline aims also to cover general aspects of process validation. The principles laid down in the Guideline are compared with those of FDA guideline on process validation which are much more detailed, but share the same overall aim.

One of the fundamental aims of the regulatory control of medicinal products is to ensure the correct purity, potency and consistency of manufacture of each product according to the quality appropriate for its intended use. While Good Manufacturing Practice is essential for quality assurance, other factors such as product design and development may also influence quality, and therefore must be studied and controlled. With this in mind, the Regulatory Authorities of the European Community have produced a guideline to the types of studies that should be undertaken in the development of a medicinal product, and which should be presented in support of application for marketing authorisation. A properly presented section on Development Pharmaceutics at the beginning of a dossier is extremely useful, if not essential, in explaining the rationale behind a particular product and giving the reviewer a clearer understanding of the data presented in support of product quality.

Quality Assurance of every product must be demonstrated, and validation is the key to its demonstration, put simply, validation is the act of proving that a process works. Thus the manufacturing methods and controls specified in an application should follow on from the development studies, and be based on valid principles. Demonstration of the validity of the manufacturing process should be provided as should the validation of the analytical methods used to control the process and therefore the product. Thus process validation should be seen as being strongly supported on the one hand by development pharmaceutics, and on the other by analytical validation.     

Validation process and uncertainty budget: a recommended approach for performance verification

Within its Occupational Radiation Protection Programme, the International Atomic Energy Agency (IAEA) initiated and funded many international and regional intercomparison exercises, with the aim of verifying performance of the individual monitoring service providers. An important component within the quality system is the validation and uncertainty budget of the method used. Each method must be validated. This validation process must provide evidence that the method can fulfil all requirements for its intended use. A method may be regarded as validated only when it fulfils all requirements established before the validation process. This paper reviews methods recommended for different types of measurement techniques in individual monitoring.     

Validation of hot ring rolling industrial process 3D simulation

Ring rolling is a hot forming process used in the production of railway tyres, anti friction bearing races and different ring shaped work pieces for automotive energy production and aerospace applications. The advantages of ring rolling process include short production time, uniform quality, closed tolerances, good material quality and considerable saving in material cost. Despite the benefits some problems still exist according to a correct selection of the process parameters. Due to the nature of the process different rolling mills (driving, idle and axial rolls) are involved and the correct selection of the process parameters is not so feasible. Moreover an experimental approach to solve this problem risks to be more expensive. Actually FE codes are available to simulate the non linear problem that characterizes a ring rolling process. In this work a FE model, based on Deform 3D software, was tested versus experimental results acquired from an industrial plant. The accuracy of the FE model was analyzed through a dual comparison: by geometrical and by physical aspects. A good agreement was found between experimental and numerical results for both comparisons and, as a consequence, this code could be used in order to investigate and optimize the process parameters that characterize the ring rolling process in a virtual not expensive environment. The validated model will allow the studies of more environment-friend process configurations.     

Integrated Population Balance Model Development and Validation of a Granulation Process

This study is concerned with the development of an integrated three-dimensional population balance model (PBM) that describes the combined effect of key granulation mechanisms that occur during the course of a granulation process. Results demonstrate the importance of simulating the different mechanisms within a population balance model framework to elucidate realistic granulation dynamics. The incorporation of liquid addition in the model also aids in demarcating the dynamics in different regimes such as premixing, granulation (during liquid addition) and wet massing (after liquid addition). For the first time, the effect of primary particle size distributions and mode of binder addition on key granule properties was studied using an integrated PBM. Experimental data confirms the validity of the overall model as compared to traditional models in the literature that do not integrate the different granulation mechanisms.     

Dual-Material Electron Beam Selective Melting:Hardware Development and Validation Studies

Electron beam selective melting(EBSM) is an additive manufacturing technique that directly fabricates three-dimensional parts in a layerwise fashion by using an electron beam to scan and melt metal powder. In recent years, EBSM has been successfully used in the additive manufacturing of a variety of materials. Previous research focused on the EBSM process of a single material. In this study, a novel EBSM process capable of building a gradient structure with dual metal materials was developed, and a powder-supplying method based on vibration was put forward. Two different powders can be supplied individually and then mixed. Two materials were used in this study: Ti6Al4 V powder and Ti47Al2Cr2 Nb powder. Ti6Al4 V has excellent strength and plasticity at room temperature, while Ti47Al2Cr2 Nb has excellent performance at high temperature, but is very brittle. A Ti6Al4V/Ti47Al2Cr2 Nb gradient material was successfully fabricated by the developed system. The microstructures and chemical compositions were characterized by optical microscopy, scanning microscopy, and electron microprobe analysis. Results showed that the interface thickness was about 300 μm. The interface was free of cracks, and the chemical compositions exhibited a staircase-like change within the interface.     

Validation of microparameters in discrete element modeling of sea ice failure process

A GPU-based discrete element method (DEM) with bonded particles is investigated to simulate the mechanical properties of sea ice in uniaxial compressive and three-point bending tests. Both the uniaxial compressive strength and flexural strength of sea ice are related to the microparameters in DEM simulation including particle size, sample size, bonding strength, and interparticle friction coefficient. These parameters are analyzed to build the relationship between the material macrostrengths of sea ice and the microparameters of the numerical model in DEM simulations. Based on this relationship, the reasonable microparameters can be calculated by given macrostrengths in the applications of simulating the failure processes of sea ice. In this simulation, both uniaxial compressive strength and flexural strength of ice increase with the increasing ratio of sample size and particle size. The interparticle friction coefficient is directly related to the compressive strength but has little effect on the flexural strength. In addition, numerical simulations are compared with experimental data to show the performance of the proposed model, and a satisfactory agreement is achieved. Therefore, this microparameter validation approach based on macrostrengths can be applied to simulate the complicated failure process of sea ice interacting with offshore platform structures.     

声屏障的发展历程及其发展趋势

伴随着交通运输业的快速发展,交通噪声已经引起大家的关注,有效处理交通噪声的办法之一就是使用声屏障。对于声屏障的研究国外起步较早,国内相对较为落后。总结了国内外声屏障的发展历程,简述了声屏障的工作原理和声屏障的类型,并指出今后声屏障发展的趋势和方向,为今后声屏障的发展提供参考意见。     

Development and Validation of HPTLC Method for Estimation of Tacrolimus in Formulations

A new, simple, and rapid high-performance thin-layer chromatographic method with a derivatization procedure was developed and validated for quantitative determination of tacrolimus. Tacrolimus was chromatographed on silica gel 60 F₂₅₄ TLC plate using toluene–acetonitrile–glacial acetic acid (6:4:0.1, by volume) as mobile phase. Tacrolimus was visualized using a derivatization reagent containing anisaldehyde–sulfuric acid in absolute alcohol and quantified by densitometric analysis in the reflectance mode at 675 nm. The method was found to give compact spots for the drug (R_f?=?0.40?±?0.03). The linear regression analysis data for the calibration plots showed good linear relationship with r²?=?.9989 in the concentration range 100–800 ng/spot. The method was validated for precision, recovery, repeatability, and robustness as per the International Conference on Harmonization guidelines. The minimum detectable amount was found to be 28.90 ng, whereas the limit of quantitation was found to be 97.04 ng. Statistical analysis of the data showed that the method is precise, accurate, reproducible, and selective for the analysis of tacrolimus. The method was successfully employed for the estimation of equilibrium solubility and quantification of tacrolimus as a bulk drug and in commercially available capsules and in-house developed self-microemulsifying formulations.     

玄武岩纤维全缠绕压力容器的研制与验证

选用玄武岩纤维为增强材料,制备了NOL环试样,进行了湿热处理和剪切试验验证。根据网格理论,针对2.4 L玄武岩纤维缠绕气瓶进行了复合层设计,确定了纤维缠绕厚度和缠绕角度,对所制样品进行了疲劳及爆破试验验证。结果表明:玄武岩纤维复合材料较玻璃纤维复合材料具有更优的界面粘结和湿热老化特性,所制备的气瓶经过0-21~(+0.2)-0 MPa压力循环的10 000次疲劳实验后未发生泄漏;爆破压力为77.1 MPa,验证了设计的合理性。     

微塑性成形技术的研究进展

介绍了塑性微成形技术的发展背景及其基本特点,综述了尺寸效应及其对微塑性成形工艺的影响、微型构件微塑性成形工艺以及微成形装置的研究现状,并对其发展趋势进行了预测.     

手机游戏用户体验评价量表开发与验证

目的开发适用于手机游戏的用户体验评价量表。方法基于心流理论和游戏平台的固有特性确定初始量表,招募380名在校学生和企业职工作为被试,通过手机APP问卷星和现场填写两种形式收集问卷,分析其信效度。结果量表包括22个题目,分为6个维度,累计方差解释率67.28%。量表的结构拟合度较好(NFI=0.920,IFI=0.976,TLI=0.970,RMSEA=0.046)。各维度内部一致性系数在0.876-0.927之间,组合信度均在0.854-0.947之间,平均抽取方差的平方根均大于各维度间的相关系数。将量表应用于两款手机游戏(皇室战争H和地铁跑酷D)用户体验评价,结果表明游戏H用户体验水平优于游戏D,在反馈、沉浸、挑战和社交4个维度及用户体验总得分上均表现出显著性差异,而在移动和控制两个维度上不存在显著性差异,这与游戏本身分析结果相一致。结论新量表适用于手机游戏用户体验评价,为后续手机游戏用户体验研究打下良好基础。     

Development and Validation of a Novel Bird Strike Resistant Composite Leading Edge Structure

A novel design of a fibre-reinforced composite Leading Edge (LE) of a Horizontal Tail Plain (HTP) is proposed. The development and validation approach of the innovative composite LE structure are described. The main design goal is the satisfactory impact resistance of the novel composite LE in the case of bird strike. The design concept is based on the absorption of the major portion of the bird kinetic energy by the composite skins, in order to protect the ribs and the inner LE structure from damaging, thus preserving the tail plane functionality for safe landing. To this purpose, the LE skin is fabricated from specially designed composite panels, so called ‘tensor skin’ panels, comprising folded layers, which unfold under the impact load and increase the energy absorption capability of the LE. A numerical model simulating the bird strike process is developed and bird strike experimental testing is performed, in order to validate the proposed layout and prove the capability of the structure to successfully withstand the impact loading. The numerical modelling issues and the critical parameters of the simulation are discussed. The present work is part of the European Aeronautics Research Project, ‘Crashworthiness of aircraft for high velocity impact – CRAHVI’ [1].     

Multivariate Methods in the Development of a New Tablet Formulation: Optimization and Validation

In a previous study of the development of a tablet formulation approximately 100 excipients were characterized in screening experiments using multivariate design. Acceptable values for important responses were obtained with some of the formulations. The relationships between the properties of the excipients and the responses were evaluated using PLS. In this study additional experiments were performed in order to validate models obtained from the screening study and to find a formulation of suitable composition with desired tablet properties. A formulation with the desired disintegration time was found with the additional experiments and the agreement between observed and predicted values was fair for the tablets that did disintegrate. A limitation of this study was that tablets from four experiments did not disintegrate within the set time limit. The lack of agreement between observed and predicted values of these four experiments was probably due to the nature of one of the factors in the design. Considering the reduced experimental design the results are still encouraging.     

Development of the IMX double direct process

The purpose of this work is to develop a new explosive based on eutectic blends of ammonium nitrate with ethylenediamine dinitrate and its homologues, and to assess the safety and performance characteristics of these formulations. Various processes for making these formulations were attempted and will be described. Mixes have been scaled from several grams to 30 kilograms. Additives were introduced for stabilization, energy enhancement and sensitization. The neat eutectic is very insensitive so various additives were used to ensure detonation. A historic problem has been that of phase stabilization; this problem has not been solved to everyone's satisfaction, but it does not appear to be insurmountable. Formulations were evaluated from the standpoint of processing, performance, and sensitiveness. These materials appear to have great potential as military explosives because of their good performance, low cost, safety, ease of processing, and compatibility with current Army melt-cast ammunition loading plants.     

Development of the EIA process in Cyprus

It is expected that Cyprus will join the European Union (EU) during the next enlargement (anticipated 2003-2005) and will therefore need to incorporate various European legislation, regulations and standards into existing legal, administrative and operational frameworks, including environmental impact assessment (EIA) as set out in Directives 85/337/EEC and 97/11/EC. This paper evaluates the Cyprus EIA provisions and makes a number of suggestions and recommendations as to how the Cyprus EIA process may be improved. Provisional EIA legislation in Cyprus includes some, but not all, of the European EIA requirements. The Cyprus EIA process in practice is highly variable, in some instances struggling to achieve the requirements of existing Cyprus legislation, and in others going beyond even Directive 97/11/EC. The findings of this study can be used to assist in updating the current Cyprus EIA system to reach the EIA standards set by the EU.     

Development and Validation of a Rapid HPLC Method for the Determination of Ketotifen in Pharmaceuticals

ABSTRACT

In the present study, a simple, sensitive, rapid, and stability-indicating high performance liquid chromatographic (HPLC) method with ultraviolet detection for the analysis of ketotifen was developed and validated. The method was applied to the determination of ketotifen in pharmaceutical formulations (tablets and syrups). The HPLC method utilized isocratic elution technique with a reversed phase C8 column, detection at 297 nm and a mixture of methanol, triethylamine phosphate buffer (pH 2.8; 0.04 M), and tetrahydrofuran (43: 55: 2, v/v/v) as mobile phase at a flow rate of 1.2 mL/min. Total analysis time was about 7 min with typical retention time of ketotifen of about 5 min. The method was validated for selectivity, linearity, accuracy, and precision following International Conference of Harmonization, 1996 (ICH) recommendations. Due to its simplicity and accuracy, the method can be used for routine quality control analysis.     

自增压流程空分设备的研究与应用

介绍了液氧自增压流程的原理 ,分析了常规流程与自增压流程的不同特点 ,阐述了自增压流程的优势和适用场合 ,以及杭氧在自增压流程空分设备上的应用进展