This is an example pharmaceutical development report illustrating how ANDA applicants can move toward implementation of Quality by Design (QbD). The purpose of the example is to illustrate the types of pharmaceutical development studies ANDA applicants may use as they implement QbD in their generic product development and to promote discussion on how OGD would use this information in review.
FDA官网中一个有关药物开发报告的实例，用以说明申请人如何实施质量源于设计(QbD)。 该实例的目的是说明ANDA申请人在其仿制药开发过程中实施QbD时，可使用的药物开发研究的类型，同时促进探讨OGD在审评中如何使用该信息。
本文主要概述了制剂的目标质量概况和溶出方法开发的关键要点。
1.3 Quality Target Product Profile for the ANDA Product
ANDA药品的目标药品的质量概况
Note to Reader: The quality target product profile (QTPP) is “a prospective summary of thequality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.” 1 The QTPP is an essential element of a QbD approach and forms the basis of design of the generic product. For ANDAs, the target should be defined early in development based on the properties of the drug substance (DS), characterization of the RLD product and consideration of the RLD label and intended patient population. The QTPP includes all product attributes that are needed to ensure equivalent safety and efficacy to the RLD. This example is for a simple IR tablet; other products would include additional attributes in the QTPP. By beginning with the end in mind, the result of development is a robust formulation and manufacturing process with a control strategy that ensures the performance of the drug product.
致读者:目标药品的质量概况(QTPP)是“从理论上达到对药品质量特性的前瞻性总结，确保预期的质量，同时兼顾药品的安全性和有效性“。
1 QTPP是QbD方法的基本要素并形成仿制药设计的基础。对于ANDAs，应在开发的早期，基于药物(DS)性质，RLD药品的特征并兼顾 RLD标签和预期的患者人口确定目标。QTPP包括需要保证与RLD安全性和有效性等效的所有产品属性。该实例适用于单一IR片;其他产品将包括QTPP中的额外属性。通过以终为始， 开发的结果是处方稳定，生产工艺的控制策略可确保药品的性能。
A critical quality attribute (CQA) is “a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.”1 The identification of a CQA from the QTPP is based on the severity of harm to a patient should the product fall outside the acceptable range for thatattribute.
关键质量属性(CQA)是“物理，化学，生物学，或微生物学性质或特点，应在适宜的限度范围内，或分布内以保证预期的药品质量”。QTPP中确认CQA是基于该属性在可接受范围 外的药品对患者伤害的严重程度。
All quality attributes are target elements of the drug product and should be achieved through a good quality management system as well as appropriate formulation and process design and development. From the perspective of pharmaceutical development, we only investigate the subset of CQAs of the drug product that also have a high potential to be impacted by the formulation and/or process variables. Our investigation culminates in an appropriate control strategy.
所有的质量属性都是药品的目标元素，应通过良好质量管理系统，适宜的处方和工艺设计及开发来实现。从药物开发的角度来看，我们仅研究也有高度可能受处方和/或工艺变量影响 的药品 CQAs 的一部分。我们的研究以适宜的控制策略告终。
Based on the clinical and pharmacokinetic (PK) characteristics as well as the in vitro dissolution and physicochemical characteristics of the RLD, a quality target product profile (QTPP) was defined for Generic Acetriptan Tablets, 20 mg (see Table 4).
基于 RLD 的临床和药动学(PK)特征及体外溶出和理化性质，确定了仿制药 20 mg Acetriptan 片的目标药品的质量概况(QTPP)(见表 4)。
Table 5 summarizes the quality attributes of generic acetriptan tablets and indicates which attributes were classified as drug product critical quality attributes (CQAs). For this product, assay, content uniformity (CU), dissolution and degradation products are identified as the subset of CQAs that have the potential to be impacted by the formulation and/or process variables and, therefore, will be investigated and discussed in detail in subsequent formulation and process development studies.
表 5 概述了仿制药 acetriptan 片的质量属性，并指出了那些属性被列为药品关键质量属性 (CQAs)。对于该产品，确定含量，含量均匀度(CU)，溶出和降解物为可能受处分和/或工艺变量影响的 CQAs 的一部分，并因此，将在随后的处方和工艺开发研究中详细研究并讨论。
On the other hand, CQAs including identity, residual solvents and microbial limits which are unlikely to be impacted by formulation and/or process variables will not be discussed in detail in the pharmaceutical development report. However, these CQAs are still target elements of the QTPP and are ensured through a good pharmaceutical quality system and the control strategy.
另一方面，药物开发报告中不详细讨论不可能受处分和/或工艺变量影响的 CQAs 包括特性， 残留溶剂和微生物限度。但是，这些 CQAs 仍然是 QTPP 的目标元素，并通过良好药品质量 系统和控制策略得到保证。
1.4 Dissolution Method Development and Pilot Bioequivalence Studies
溶出方法开发和中试生物等效性研究
Note to Reader: A pharmaceutical development report should document the selection of the dissolution method used in pharmaceutical development. This method (or methods) may differ from the FDA-recommended dissolution method and the quality control method used for release testing.
药物开发报告应记录药物开发中使用的溶出方法的选择。该方法(或这些方法)可不同于FDA推荐的溶出方法和用于释放检查的质量控制方法。
1.4.1 Dissolution Method Development 溶出方法开发
Acetriptan is a BCS Class II compound displaying poor aqueous solubility (less than 0.015 mg/mL) across the physiological pH range. As such, development of a dissolution method that can act as the best available predictor of equivalent pharmacokinetics to the RLD was pursued to allow assessment of acetriptan tablets manufactured during development. Acetriptan
在整个生理pH值范围内显示出水溶性差(低于0.015 mg/mL)，为BCS II类化合物。 因此，进行一种在预测与RLD药动学等效方面起最佳作用的溶出方法的开发，以允许评估开发期间acetriptan片的生产。
The target is an immediate release product, so dissolution in the stomach and absorption in the upper small intestine is expected suggesting the use of dissolution medium with low pH. Development began with the quality control dissolution method recommended for this product by the FDA: 900 mL of 0.1 N HCl with 2.0% w/v SLS using USP apparatus 2 at 75 rpm. Initial development formulations (Batches 1-11) exhibited rapid dissolution (NLT 90% dissolved in 30 minutes (min)) and were comparable to the RLD. It became a challenge for the team to select the formulations which might perform similarly to the RLD in vivo. The solubility of acetriptan in various media was determined (Table 6) and suggests that the solubility of acetriptan in 0.1 N HCl with 1.0% w/v SLS is similar to its solubility in biorelevant media.
目标为速释产品，因此预期在胃内的溶出和在小肠上部内的吸收，建议使用具有低 pH 值的溶出介质。该产品的开发以 FDA 推荐的质量控制溶出方法开始:900 mL0.1 N HCl 和 2.0% w/v SLS的溶出介质，用USP装置2，75 rpm转速。初始开发的处方(批次1~11)显示出快速溶出(30 分钟(min)内溶出度不低于 NLT 90%)，与 RLD 类似。对于团队来说，选择体内行为与 RLD 类似的制剂成为一种挑战。测定了 acetriptan 在各种介质中的溶解度(表 6)，显示 acetriptan 在 0.1 N HCl 和 1.0% w/v SLS 的介质中的溶解度与其在生物相关性介质中的溶解度类似。
The dissolution method selected for product development uses 900 mL of 0.1 N HCl with 1.0% w/v SLS in a dissolution apparatus equipped with paddles (speed 75 rpm) and maintained at a temperature of 37°C, followed by UV spectroscopy at a wavelength of 282 nm. Dissolution in 1.0% w/v SLS is not sensitive to medium pH (similar in 0.1 N HCl, pH 4.5 buffer and pH 6.8 buffer) (data not shown). Additionally, this method is capable of detecting dissolution changes in the drug product caused by deliberately varying the drug substance (DS) particle size distribution (PSD) (see Section 1.4.2).
产品开发选择的溶出方法使用了900 mL0.1 N HCl和1.0% w/v SLS的装备桨(转速75 rpm)的 溶出装置，温度维持在37°C，然后是波长为282 nm的UV分光光度仪。在1.0% w/v SLS中的溶出对介质pH值(类似于在0.1 N HCl, pH 4.5缓冲液和pH 6.8缓冲液中)不敏感(数据未显示)。 此外，该方法能检测出通过故意改变药物(DS)粒度分布(PSD)而引起的药品的溶出变化(见 1.4.2节)。
1.4.2 Pilot Bioequivalence Study 中试生物等效性研究
Note to Reader: For low solubility drugs, pilot bioequivalence (BE) studies are invaluable to demonstrate that the in vitro dissolution used is appropriate. When pilot bioequivalence studies are conducted, the following is an example of how they should be described in the development report to support controls on critical attributes such as particle size and to understand the relationship between in vitro dissolution and in vivo performance. Inclusion of formulations that perform differently will help to determine if there is a useful in vivo in vitro relationship.
致读者:对于低溶解度药物，证明使用的体外溶出是适宜的中试生物等效性(BE)研究是极其 宝贵的。当进行中试生物等效性研究时，以下为示范说明它们应怎样在开发报告中描述以支 持对关键属性如粒径的控制和理解体外溶出和体内性能间的相关性。包括不同行为的处方将 有助于判断是否对体内外相关性有用。
The formulation development studies identified drug substance particle size distribution as the most significant factor that impacts drug product dissolution (see Section 2.2.1.4). In order to understand the potential clinical relevance of drug substance particle size distribution on in vivo performance, a pilot bioequivalence (BE) study (Study # 1001) was performed in 6 healthy subjects (four-way crossover: three prototypes and the RLD at a dose of 20 mg).
处方开发研究确定药物粒度分布是影响药品溶出的最重要因素(见2.2.1.4节)。为理解因为粒度分布对体内性能的潜在临床意义，在6个健康受试者内进行了一项中试生物等效性(BE)研 究(Study # 1001) (四交叉:剂量为20 mg 的3个原型和1个RLD)。
The formulation used to produce the three prototypes and the composition is shown in Table 7. The only difference between each prototype was the drug substance particle size distribution. Drug substance Lot #2, #3 and #4 with a d90 of 20 μm, 30 μm and 45 μm was used for prototype Batch 18, 19, and 20, respectively. Characterization of the drug substance lots is provided in Section 2.2.1.2, Table 19.
处方用于生产 3 个原型，组分如表 7 所示。各个原型间的唯一差异是药物粒度分布。用于原 型批 18，19 和 20 的药物批分别是#2，#3 和#4，d90 分别是 20 μm，30 μm 和 45 μm。药物 批的特征见 2.2.1.2 节，表 19。
According to the literature3, when the mean Cmax and AUC responses of 2 drug products differ by more than 12-13%, they are unlikely to meet the bioequivalence limits of 80-125%. Therefore, the predefined selection criterion was a mean particle size that yielded both a Cmax ratio and an AUC ratio for test to reference between 0.9 and 1.11. The results of the PK study indicated that a drug substance particle size distribution with a d90 of 30 μm or less showed similar in vivo performance based on test to reference ratio calculations for AUC and Cmax. A drug substance particle size distribution with a d90 of 45 μm did not meet the predefined criterion of a test to reference ratio for Cmax and AUC between 0.9 and 1.11. The results confirmed the in silico simulation data obtained during preformulation work (see Section 2.2.1.2).
根据文献，当2种药品的平均Cmax和AUC响应相差在12~13%以上时，它们不可能符合生物等效性限度80~125%。因此，预定义的选择标准是平均粒径，可产生受试与参比的Cmax 比和AUC比介于0.9~1.1之间。PK研究的结果表明药物粒度分布的d90为30 μm或以下显示出 类似的体内性能，基于计算的受试与参比的AUC比和Cmax比。药物粒度分布的d90为45 μm 不符合受试与参比的Cmax比和AUC比介于0.9~1.1之间的预定义标准。结果确认了在预处方 工作中得到的计算机模拟数据(见2.2.1.2节)。
In order to understand the relationship between in vitro dissolution and in vivo performance, the dissolution test was performed on the three prototypes and the RLD using the in-house versus the FDA-recommended dissolution method. The results are presented in Figure 4 and Figure 5, respectively. The data indicated that the in-house dissolution method (with 1.0% w/v SLS) is capable of differentiating formulations manufactured using different drug substance particle size distributions. However, the FDA-recommended dissolution method (with 2.0% w/v SLS) is not sensitive to deliberate formulation changes in the drug substance particle size distribution for this BCS class II compound.
为理解体外溶出和体内性能间的相关性，使用内部和 FDA-推荐的溶出方法，对 3 个原型和 1 个 RLD 进行了溶出检查。结果分别见图 4 和图 5。数据表明内部溶出方法(含 1.0% w/v SLS) 对该 BCS II 类化合物的药物粒度分布中的处方故意变更不敏感。
The AUC0-t ratio and Cmax ratio between the prototypes and the RLD were plotted versus the percentage of drug dissolved using both the in-house and FDA-recommended dissolution methods. The results are presented in Figure 6 and suggest that dissolution testing in medium with 1.0% w/v SLS and a 30 minute endpoint is predictive of the in vivo performance. However, the dissolution testing in medium with 2.0% w/v SLS was not able to predict the in vivo performance differences due to the drug substance particle size changes.
原型和 RLD 间的 AUC0-t 比和 Cmax 比对使用内部和 FDA 推荐的溶出方法的药物溶出率绘图。结果见图 6，表明在含 1.0% w/v SLS 的介质中的溶出检查和 30 分钟终点可预测体内性能。但是，在含2.0% w/v SLS的介质中的溶出检查不能预测体内性能差异由于药物粒径变化。
A dissolution rate of not less than (NLT) 80% in 30 minutes in 0.1 N HCl with 1.0% w/v SLS was set as the target for pharmaceutical development studies based on the fact that Batch 19 (d90 30μm) showed 80.8% dissolution in 30 minutes and demonstrated comparable pharmacokinetic profiles to the RLD in the pilot BE study.
设定在含 1.0% w/v SLS 的 0.1 N HCl 中，30 分钟内溶出率不低于(NLT) 80%为药物开发研究 的目标是基于这样的事实，批 19 (d90 30 μm) 显示在 30 分钟内溶出率为 80.8%并证明在中 试 BE 研究中药动学曲线与 RLD 类似。
参考文献：
Example QbD IR Tablet Module 3 Quality 3.2.P.2 Pharmaceutical Development，FDA，2012.
