2007 highlights of advances in the pharmaceutical sciences: An American Association of Pharmaceutical Scientists (AAPS) perspective

The American Association of Pharmaceutical Scientists (AAPS) covers the full range of areas of expertise associated with the resolution of concerns pertaining to drugs and drug products. This editorial highlights the initiatives, issues, and challenges that are the forefront of the pharmaceutical sciences in 2007. It also provides an overview of how these difficult questions are being addressed through the programs and events associated with the AAPS 2007 Annual Meeting that will be held at the San Diego, California, Convention Center from November 11 to 15, 2007.     

智能制造理念在血液制品产业的应用研究

目的：通过分析智能制造理念下,质量源于设计（quality by design,QbD）与血液制品生产的相关性、过程分析技术（process analytical technology,PAT）在血液制品QbD中的应用以及关键质量环节的QbD实施,以期推动我国血液制品行业升级,实现血液制品的智能生产。方法：采取前瞻性研究方法,查阅、检索以"智能制造" "血液制品" "质量源于设计"过程分析技术"为关键词的文献,对智能制造理念在血液制品的应用研究进行论述。结果与结论：基于我国制药工业的自动化与信息化的水平与现状,制药工业的"智能制造"已逐步发展起来,QbD已被引入我国新版药品GMP,强调了与药品注册、上市制度的有效衔接。在科学监管的要求下,QbD理念已成为血液制品行业界的共识,实施QbD,通过基于问题的审核（question-based review,QbR）,将有助于全面提高我国血液制品的质量,提升产品的竞争力。     

我国药品首次工艺验证存在问题及探讨

通过调查研究的方法,找到我国制药企业在首次工艺验证中普遍存在的问题,借助对国内外法规及相关文献研究,并结合我国制药企业的现状,提出对问题的解决策略,该研究对我国制药企业有效开展首次工艺验证有一定的指导意义。     

基于AQbD的培植牛黄中18种氨基酸含量测定方法的建立与优化

目的 基于分析方法质量源于设计理念,建立与优化同时测定培植牛黄中18种氨基酸含量的分析方法。方法 以峰对的最低分离度为指标,采用Hunter筛选试验设计筛选影响色谱分离的关键色谱参数;然后采用中心复合响应曲面实验设计建立分析方法关键连续变量与5个关键响应指标之间的多变量回归函数,再将5个多变量回归函数整合至1个设计空间中,应用设计空间确定这些关键色谱参数的最优值和控制范围。结果 Hunter筛选试验设计确定色谱参数柱温、pH值和缓冲盐类型对响应值有显著性影响(P<0.05)。同时实验中发现有机相中甲醇和乙腈分别对不同的色谱峰对有不同的分离效果。应用中心复合响应面实验设计确定3个连续色谱变量(柱温、pH值和甲醇-乙腈比例)的最优值和控制范围。柱温接受范围为46~58 ℃,最优值为50 ℃;流动相pH可接受范围为7.7~8.7,最优值为8.2;流动相中甲醇-乙腈比例可接受范围为0.7~1.28,最优值为1.0。结论 所建立的分析方法可靠,可用于同时测定培植牛黄中18种氨基酸的含量。     

Prediction of Dissolution Profiles From Process Parameters,Formulation, and Spectroscopic Measurements

This study utilized multiple modeling approaches to predict immediate release tablet dissolution profiles of 2 model drugs: theophylline and carbamazepine. Two sets of designs of experiments were applied based on individual drug characteristics to build in adequate dissolution variability. The tablets were scanned using a near-infrared (NIR) spectrometer and then subjected to in vitro dissolution test at critical time points. Because of the inherent difference in dissolution profiles, a hierarchical modeling approach was applied for theophylline data, whereas global models were constructed from carbamazepine data. The partial least squares models were trained using 3 predictor sets including (1) formulation, material, and process variables, (2) NIR spectra, and (3) a combination of both. The dependent variables of the models were the dissolution profiles, which were presented either as parameters of Weibull fitting curves or raw data. The comparison among the predictive models revealed that the incorporation of NIR spectral information in calibration reduced prediction error in the carbamazepine case but undermined the performance of theophylline models. It suggests that the modeling strategy for dissolution prediction of pharmaceutical tablets should not be universal but on a case-by-case basis.     

《药物制剂设备与车间工艺设计》的教学探讨

《药物制剂设备与车间工艺设计》是药物制剂专业的一门重要专业课程,将药剂学的理论与生产实践紧密结合的重要学科。通过对本学科的了解和教学中的深刻体会,结合教学实践,对教学内容、教学方法、教学实践和学生动手操作能力的培养等方面提出了个人的见解,从而培养学生的学习和实践能力,全面提升学生的综合素质。     

Pharmaceutical Quality by Design: Product and Process Development, Understanding, and Control

PURPOSE: The purpose of this paper is to discuss the pharmaceutical Quality by Design (QbD) and describe how it can be used to ensure pharmaceutical quality. MATERIALS AND METHODS: The QbD was described and some of its elements identified. Process parameters and quality attributes were identified for each unit operation during manufacture of solid oral dosage forms. The use of QbD was contrasted with the evaluation of product quality by testing alone. RESULTS: The QbD is a systemic approach to pharmaceutical development. It means designing and developing formulations and manufacturing processes to ensure predefined product quality. Some of the QbD elements include: Defining target product quality profile; Designing product and manufacturing processes; Identifying critical quality attributes, process parameters, and sources of variability; Controlling manufacturing processes to produce consistent quality over time. CONCLUSIONS: Using QbD, pharmaceutical quality is assured by understanding and controlling formulation and manufacturing variables. Product testing confirms the product quality. Implementation of QbD will enable transformation of the chemistry, manufacturing, and controls (CMC) review of abbreviated new drug applications (ANDAs) into a science-based pharmaceutical quality assessment.     

A Workshop on Smoking Cessation for Pharmacy Students

Objective. To develop, implement, and evaluate a targeted educational intervention focusing on smoking cessation with final-year undergraduate pharmacy students.Design. A smoking-cessation educational workshop entitled Smoking Cessation in Pharmacy (SCIP) was designed on the principles of adult learning and implemented with a full cohort of final-year undergraduate pharmacy students at the University of Sydney. A previously validated questionnaire testing the knowledge and attitudes of respondents was administered both before and after implementation of the designed workshop to evaluate changes resulting from the intervention. Informal feedback was obtained from students.Assessment. Pre-course mean total knowledge and attitude scores calculated were 65.8±9.1 and 86.4±12.1, respectively. The post-course mean total knowledge score was 74.9±8.1, and the attitude score was 88.8±9.1 Improvement in knowledge and attitudes was significant (p<0.05).Conclusion. Educational interventions for pharmacy students designed with careful attention to pedagogic principles can improve knowledge about evidence-based smoking-cessation strategies and enhance positive attitudes to pharmacist roles in smoking cessation.     

过程分析技术在药品生产过程中的应用

生物医药在医药行业中占比逐渐增大,现代生物制药对产品质量和一致性控制提出了更高的要求,越来越多的过程研究工作致力于此。过程分析技术基于研发生产人员对产品属性及生产工艺的充分理解,融入到质量源于设计理念中,代表着未来生物医药行业的发展趋势。从质量源于设计理念及智能制造角度出发,阐述了过程分析技术在生物制品上游工艺、收获阶段、下游工艺、成品制备等过程中的最新应用研究。从微生物发酵、细胞培养、离心、复性、层析、配制、灌装、冻干等环节分析了过程分析技术应用的难易程度,并提出过程分析技术应用的挑战与前景。

     

风对药品生产区和生产厂房的影响

良好的生产区和生产厂房的环境是提高药品质量的条件之一。主导风向是设置生产区的重要参考条件 ,以降低来自环境的不良影响。本文分析了不同风向和强度对不同生产厂房环境带来的影响及其原因 ,并从理论上探讨了药品生产区和不同净化级别厂房的设置方法。     

Analytical Quality by Design Approach in RP-HPLC Method Development for the Assay of Etofenamate in Dosage Forms

By considering the current regulatory requirement for an analytical method development, a reversed phase high performance liquid chromatographic method for routine analysis of etofenamate in dosage form has been optimized using analytical quality by design approach. Unlike routine approach, the present study was initiated with understanding of quality target product profile, analytical target profile and risk assessment for method variables that affect the method response. A liquid chromatography system equipped with a C₁₈ column (250×4.6 mm, 5 μ), a binary pump and photodiode array detector were used in this work. The experiments were conducted based on plan by central composite design, which could save time, reagents and other resources. Sigma Tech software was used to plan and analyses the experimental observations and obtain quadratic process model. The process model was used for predictive solution for retention time. The predicted data from contour diagram for retention time were verified actually and it satisfied with actual experimental data. The optimized method was achieved at 1.2 ml/min flow rate of using mobile phase composition of methanol and 0.2% triethylamine in water at 85:15, % v/v, pH adjusted to 6.5. The method was validated and verified for targeted method performances, robustness and system suitability during method transfer.     

Real-time imaging as an emerging process analytical technology tool for monitoring of fluid bed coating process

Abstract

A direct imaging system (Eyecon^TM) was used as a Process Analytical Technology (PAT) tool to monitor fluid bed coating process. Eyecon^TM generated real-time onscreen images, particle size and shape information of two identically manufactured laboratory-scale batches. Eyecon^TM has accuracy of measuring the particle size increase of ±1?μm on particles in the size range of 50–3000?μm.

Eyecon^TM captured data every 2?s during the entire process. The moving average of D90 particle size values recorded by Eyecon^TM were calculated for every 30?min to calculate the radial coating thickness of coated particles. After the completion of coating process, the radial coating thickness was found to be 11.3 and 9.11?μm, with a standard deviation of?±0.68 and 1.8?μm for Batch 1 and Batch 2, respectively. The coating thickness was also correlated with percent weight build-up by gel permeation chromatography (GPC) and dissolution. GPC indicated weight build-up of 10.6% and 9.27% for Batch 1 and Batch 2, respectively.

In conclusion, weight build-up of 10% can also be correlated with 10?±?2?μm increase in the coating thickness of pellets, indicating the potential applicability of real-time imaging as an endpoint determination tool for fluid bed coating process.     

Design and In-line Raman Spectroscopic Monitoring of a Protein Batch Crystallization Process

Raman spectroscopy was used to design and monitor a lysozyme protein batch crystallization process in a lab scale study to facilitate the design of a pharmaceutical protein manufacturing process. A D-optimal design that consisted of 18 experiments was performed to elucidate the effect of temperature, concentration of the precipitating agent, time of crystallization, and possible interactions between these three factors on the Raman scattering changes. A polynomial mathematical model was calculated relating the scattering of the lysozyme solutions measured at individual Raman shifts to the significant factors obtained in the previous crystallization experiment. The 2,940-cm⁻¹ band provided the highest correlation values indicative of small prediction errors and good predictive ability for the crystallization model. Raman scattering signals obtained during the experiments were used as input to obtain a response surface for the factors studied and elucidate the relationship between the crystallization process conditions and the crystals obtained. The main factors affecting the crystallization process were the sodium chloride concentration and temperature.     

基于QbD理念的对乙酰氨基酚双释双层片制备工艺的设计及优化

目的：基于"质量源于设计"（QbD）理念设计并优化对乙酰氨基酚双释双层片（简称为"双层片"）的制备工艺。方法：采用Plackett-Burman考察法确定双层片制备工艺的关键工艺参数（CPPs）;采用Box-Behnken响应面设计,以缓释层的释放度、速释层的溶出度作为关键质量属性（CQAs）,优化双层片的最佳处方、工艺参数;在二次多项式回归模型的基础上建立双层片工艺设计空间,并加以验证。结果：对乙酰氨基酚双层片最佳工艺为：崩解剂量所占比例为9.5%,制粒目数为22目,缓材比例为5∶1;设计空间以Overlay plot方式展示,并加入95%置信区间,设计空间工艺稳定可靠。结论：所制定的工艺对乙酰氨基酚双释双层片制备工艺简单,制剂稳定,适合大工业生产。     

深圳市药品,生物制品生产车间洁净度监测结果及分析

本文对深圳市药品、生物制品生产车间洁净度监测结果进行了分析，并对发现的问题提出了相应的对策。     

A Tutorial for Developing a Topical Cream Formulation Based on the Quality by Design Approach

The pharmaceutical industry has entered in a new era, as there is a growing interest in increasing the quality standards of dosage forms, through the implementation of more structured development and manufacturing approaches. For many decades, the manufacturing of drug products was controlled by a regulatory framework to guarantee the quality of the final product through a fixed process and exhaustive testing. Limitations related to the Quality by Test system have been widely acknowledged. The emergence of Quality by Design (QbD) as a systematic and risk-based approach introduced a new quality concept based on a good understanding of how raw materials and process parameters influence the final quality profile. Although the QbD system has been recognized as a revolutionary approach to product development and manufacturing, its full implementation in the pharmaceutical field is still limited. This is particularly evident in the case of semisolid complex formulation development. The present review aims at establishing a practical QbD framework to describe all stages comprised in the pharmaceutical development of a conventional cream in a comprehensible manner.     

Developing a quality by design approach to model tablet dissolution testing: an industrial case study

Abstract

This study applied the concept of Quality by Design (QbD) to tablet dissolution. Its goal was to propose a quality control strategy to model dissolution testing of solid oral dose products according to International Conference on Harmonization guidelines. The methodology involved the following three steps: (1) a risk analysis to identify the material- and process-related parameters impacting the critical quality attributes of dissolution testing, (2) an experimental design to evaluate the influence of design factors (attributes and parameters selected by risk analysis) on dissolution testing, and (3) an investigation of the relationship between design factors and dissolution profiles. Results show that (a) in the case studied, the two parameters impacting dissolution kinetics are active pharmaceutical ingredient particle size distributions and tablet hardness and (b) these two parameters could be monitored with PAT tools to predict dissolution profiles. Moreover, based on the results obtained, modeling dissolution is possible. The practicality and effectiveness of the QbD approach were demonstrated through this industrial case study. Implementing such an approach systematically in industrial pharmaceutical production would reduce the need for tablet dissolution testing.     

质量风险管理在药品固体制剂车间的应用

目的：降低在药品固体制剂车间多品种共线生产中的质量风险,确保产品质量。方法：根据药品固体制剂生产的主要操作工序大致相同的特点,运用质量风险管理的方法和工具,建立药品固体制剂车间的质量风险管理模型。结果与结论：通过对固体制剂车间多品种共用厂房、设施、设备生产中可能存在的风险进行评估,对风险高的环节采取有效的控制措施,使多品种共线生产所产生的质量风险降低到可以接受的水平,保证药品质量。     

Modeling of Semicontinuous Fluid Bed Drying of Pharmaceutical Granules With Respect to Granule Size

In the transition of the pharmaceutical industry from batchwise to continuous drug product manufacturing, the drying process has proven challenging to control and understand. In a semicontinuous fluid bed dryer, part of the ConsiGma? wet granulation line, the aforementioned production methods converge. Previous research has shown that the evolution of moisture content of the material in this system shows strong variation in function of the granule size, making the accurate prediction of this pharmaceutical critical quality attribute a complex case. In this work, the evolution of moisture content of the material in the system is modeled by a bottom-up approach. A single granule drying kinetics model is used to predict the moisture content evolution of a batch of material of a heterogeneous particle size, where it is the first time that the single granule drying mechanism is validated for different granule sizes. The batch approach was validated when the continuous material inflow rate and filling time of the dryer cell are constant. The original single granule drying kinetics model has been extended to capture the granules’ equilibrium moisture content. Finally, the influence of drying air temperature is captured well with a droplet energy balance for the granules.