FDA 发布透皮和局部递药系统研发和质量考量指南草案
2020-05-06 07:01
来源：博凯明达科技
FDA 发布透皮和局部递药系统研发和质量考量指南草案
IN VITRO–IN VIVO CORRELATIONS
体内体外相关性
The term IVIVC first appeared in the pharmaceutical literature as a result of the awareness of the importance of bioavailability concepts and in vitro dissolution rate determinations. IVIVC refers to the establishment of a rational relationship between a biological property, or a parameter derived from drug plasma concentrations produced by a dosage form, and a physicochemical property or characteristic of the same dosage form. The biological properties most commonly used are one or more pharmacokineticparameters such as Cmax or AUC, obtained following the administration of the dosage form. The physicochemical property most commonly used is a dosage form's in vitro dissolution behavior (e.g., percent of drug released under a given set of conditions). The quantitative relationship between the two properties, biological and physicochemical, is an IVIVC. The most important use of an IVIVC is for predictability. In many cases the actual drug plasma concentration profile can be predicted from in vitro dissolution data.Historically, IVIVC analysis has been more successful for extended-release products than for immediate-release products. This difference probably reflects the application of specific data analysis techniques and interpretations that require dissolution rate-limited drug absorption. However some correlations with immediate-release products have been demonstrated using methods that rely on the current, broad availability of computers and nonlinear regression software, along with new correlation methods.
术语IVIVC这个词第一次出现在医药文献是对生物利用度概念和体外溶出速率测定的重要性的认识结果。IVIVC是指在制剂的生物学特性或血浆浓度参数和同一剂型理化性质或特征之间确定的合理关系。给药后获得的一种或多种药代动力学参数如的Cmax或AUC是最常使用的生物学特性。剂型的体外溶出行为中最常使用的是理化性质（例如，在给定条件下，药物释放的百分比）。这两种特性、生物学性质和理化性质之间的定量关系，是IVIVC。IVIVC的最重要的一个用途是可预测性。在大多情况下，体外溶出数据可以预测实际血浆药物浓度曲线。以前，缓释制剂的IVIVC分析比速释制剂更加成功。这种差异可能反映了具体数据分析技术的应用以及需要对溶出速率限制药物吸收进行说明。然而，已经使用了一些方法证明了速释制剂的相关性，这些方法依赖于目前计算机和非线性回归软件和新的相关方法。
General Considerations
总则
With the proliferation of modified-release products, it becomes necessary to examine IVIVC in greater detail. Unlike immediate-release dosage forms, modified-release products, particularly extended-release dosage forms, cannot be characterized using a single time point dissolution test. These products are designed to deliver drug so that a patient has a specific plasma level profile over a prolonged period, usually 12–24 h. Analysts require an in vitro means of ensuring that each batch of the product will perform identically in vivo. An IVIVC satisfies this requirement. Initially, it was thought that developing a meaningful correlation for immediate-release dosage forms would be an easier task than for extended-release products. However, because of the nature of the principles on which each type is based, analysts now believe that an IVIVC is more readily achieved for modified-release dosage forms.One expects all extended-release products to be dissolution rate limited. For these products, the formulation significantly contributes to the prolongation of drug release from the dosage form. Because of the impact of formulation on BA from an extended-release product, numerous attempts have been made to correlate one or more pharmacokinetic parameters determined from in vivo studies with the amount released in a given time during an in vitro dissolution test. Single-point correlations can indicate that increasing or decreasing the in vitro dissolution rate of the modified-release dosage form would result in a corresponding directional change in the product's performance. However, such single-point correlations reveal little about the overall plasma level curve, which is a major factor for drug performance in the patient. Rather, correlation methods that utilize all plasma drug concentration data and all in vitro dissolution data are preferred. Three correlation procedures are available that use all dissolution and plasma data, along with statistical moment analysis. Each procedure displays important differencesin the quality of the correlation. These methods are discussed in terms of the advantages of each along with its potential utility as a predictive tool for pharmaceutical scientists.
随着调节释放制剂的扩散，有必要详细检查IVIVC，与速释制剂不同，调节释放制剂，尤其是延迟释放制剂，不能使用单点溶出试验来表征。这些制剂的药物释放设计目的是使患者的血浆药物浓度水平曲线范围延长，通常12-24小时。分析人员需要通过一个体外的方式来确保每批产品体内相同，IVIVC要满足此要求。最初，认为速释制剂形成有意义的体内外相关性比缓释制剂更容易。然而，由于以每种剂型的原理为基础，分析人员现在认为调节释放剂型的IVIVC相关性更容易实现。预料所有缓释制剂的溶出速度是有限的。对于这些产品，处方材料显著延长了药物的释放。由于这些处方材料对缓释制剂的BA有影响，很多人尝试将一个或多个体内研究获得药代动力学参数和体外溶出试验获得药物释放量在指定时间点相关联。单点相关性可以表明，增加或减少调节释放剂型的体外溶出速率将引起制剂性能的相应改变。但是，这样的单点相关性几乎不能表明整个血浆浓度曲线，这也是患者体内释药性能的一个主要因素。而是，利用所有血浆药物浓度数据和所有的体外溶出数据相关的方法是优选的。相关的三个程序，所有的溶出数据和血浆数据以及统计分析。每个程序表明了质量相关性的不同。讨论的这些方法都具有各自的优势，这些方法作为制剂科学家潜在应用的工具来使用。
Correlation Levels
相关水平
Three correlation levels have been defined and categorized in descending order of quality. The concept of correlation level is based on the ability of the correlation to reflect the entire plasma drug concentration–time curve that results from administration of the given dosage form. The relationship of the entire in vitro dissolution curve to the entire plasma concentration–time profile defines the strength of the correlation and, therefore, the predictability.
三级相关水平进行定义并按照质量的降序进行分类。相关级别是根据指定剂型给药后获得的整个血浆浓度-时间曲线的相关能力进行定义。因此整个体外溶出曲线和整个血浆浓度 - 时间曲线在整个的关系表明了相关强度和可预测性。
体外溶出曲线到整个血浆浓度 - 时间分布在整个的关系定义的相关性的强度，因此，可预测性。
LEVEL A
A级
This level is the highest category of correlation. It represents a point-to-point relationship between in vitro dissolution and the in vivo input rate (absorption rate of the drug from the dosage form). For a Level A correlation, a product's in vitro dissolution curve is compared to its in vivo input curve, i.e., the curve produced by deconvolution of the plasma profile. Deconvolution can be accomplished using mass balance model-dependent methods, such as the Wagner–Nelson or Loo–Riegelman methods, or by model-independent, mathematical deconvolution. In an ideal correlation, the in vitro dissolution and in vivo absorption rate curves are superimposable or can be made superimposed by the use of a constant offset value of the time scale. The equations describing each curve are the same. This procedure often is found with modified-release dosage systems that demonstrate an in vitro release rate that is essentially independent of the dissolution media and stirring speeds used in a dissolution apparatus. Superimposition is not an absolute requirement for a Level A correlation. If the dissolution and absorption curves are different and a mathematical relationship can be developed to relate the two, the plasma level profile still is predictable from the in vitro dissolution data. This relationship must be true not only at that single input rate but also over the entire quality control dissolution range for the product. Furthermore, when the dissolution rate depends on mixing speed, the two curves can be made to superimpose by either increasing or decreasing the in vitro mixing speed or some other alteration of the dissolution method.
A级是相关性的最高类别。它代表了体外溶出和体内输入速度（剂型中药物吸收速率）的点对点的关系。对于A级相关，制剂的体外溶出曲线可以与体内的输入速度相比较，也就是通过反卷积获得的血浆曲线图。使用质量平衡模型依赖方法，例如，the Wagner–Nelson或Loo–Riegelman或通过模型依赖、数学反卷积。理想的相关性，体外溶出和体内吸收速率曲线是可叠加的，或通过一个常数抵消时间范围值来完成叠加。描述每个曲线的方程是相同的。这个过程往往在调节释放剂型中发现，并证明体外释放速率基本与在溶出装置中使用的溶出介质和转速无关。叠加不是A级相关的一个绝对要求。如果溶出曲线和吸收曲线不同，数学关系式可以连接着这两个参数，体外的溶出曲线仍然可以预测血浆药物浓度曲线。不仅是在单一输入速度，而且在整个产品质量控制溶出范围中，这种关系都必须是真实的。而且，当溶出速率取决于搅拌速度时，两种曲线关系既可以通过增加或减少体外搅拌速度或溶出方法的其他变更方法进行叠加。
The advantages of a Level A correlation are as follows.
A级相关的优点如下
1. It develops a point-to-point correlation. This is not found with any other correlation level. It is developed using every plasma level and dissolution point collected at different time intervals, so it reflects the complete plasma level curve. As a result,in the case of a Level A correlation an in vitro dissolution curve can serve as a surrogate for in vivo performance. A change in manufacturing site, method of manufacture, raw material supplies, minor formulation modifications, and even product strength using the same formulation can be justified without the need for additional BA-BE studies.4,5
点对点的相关。没有发现其他的相关分级。它是通过使用在不同时间间隔采集的每个血浆浓度和溶出点形成的，因此它反映出完整的血浆浓度曲线。因此，对于A级相关的体外溶出曲线可以替代体内的性能。改变生产场地、生产方法、原料供应商、处方较小改变、甚至是使用相同处方的制剂规格不需要进行额外的BA-BE研究也是合理的。
2. A truly meaningful quality control procedure that indicates in vivo performance and is predictive of a dosage form's performance is defined for the dosage form.
一个真正有意义的质量控制方法要求可指示药物的体内特性，并对制剂特性具有预测性，需要根据剂型特点确定。
3. The extremes of the in vitro quality control standards can be justified either by convolution (simulating the plasma levelprofile from the dissolution curve) or by deconvolution (using the upper and lower confidence interval limits).
通过卷积（通过溶出曲线模拟血浆浓度曲线）或反卷积（使用置信区间的上限和下限）调整体外质量控制标准的极端。
LEVEL B
B级
This correlation uses the principles of statistical moment analysis. The mean in vitro dissolution time is compared to eitherthe mean residence time or the mean in vivo dissolution time. As with a Level A correlation, Level B uses all of the in vitro and invivo data but is not considered a point-to-point correlation. It does not correlate the actual in vivo plasma profiles but rather a parameter that results from statistical moment analysis of a plasma profile component such as mean residence time. Because a number of different plasma profiles can produce similar mean residence time values, one cannot rely on a Level B correlation alone to predict a plasma profile from in vitro dissolution data. In addition, in vitro data from such a correlation cannot be used to justify values at the extremes of quality control standards.
这种相关性使用的是统计分析矩原理。体外溶出时间的平均值既可以与体内溶出时间的平均值也可以与平均滞留时间进行比较。与A级相关一样，B级相关使用了所有的体外和体内数据，但不用考虑点对点的相关。不相关实际是体内的血浆曲线而不是来源于血浆曲线组分，比如平均滞留时间的统计矩分析结果的a-参数相关。因为许多不同的血浆曲线能产生相似的平均滞留时间值，不能独自依靠B级相关来从体外溶出曲线预测血浆曲线。而且，这种相关的体外数据不能用来证明质量控制标准的极端值。
LEVEL C
C级相关
This category relates one dissolution time point (t50%, t90%, etc.) to one pharmacokinetic parameter such as AUC, Cmax, or Tmax. It represents a single-point correlation and does not reflect the complete shape of the plasma profile, which best defines the performance of modified-release products. Because this type of correlation is not predictive of actual in vivo product performance,generally it is useful only as a guide in formulation development or as a production quality control procedure. Becauseof its obvious limitations, a Level C correlation has limited usefulness in predicting in vivo drug performance and is subject to the same caveats as a Level B correlation in its ability to support product and site changes as well as justification of the
extreme values in quality control standards. The FDA Guidance “Extended-Release Solid Oral Dosage Forms—Development,Evaluation, and Application of In Vitro/In Vivo Correlations” (www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070239.pdf) states that manufacturers can obtain biowaivers based on multiple Level C correlations. (www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070239.pdf) The guidance shows how manufacturers can achieve this correlation.The FDA also indicates that if such a correlation isachievable, it is likely that the development of a Level A correlation is also feasible.
这种分类将溶出时间点与药动学参数比如,AUC、Cmax, 或Tmax联系在一起。它代表单点相关，不能反映完整的血浆曲线，是调节释放制剂特征的最好描述。因为这种类型的相关性不能预测产品体内的实际性能，通常在指导制剂开发或产品质量控制过程中是有用的。因为它存在明显的局限性，C级相关限制了对体内药物性能的预测，在支持产品和生产场地改变和质量控制标准极值合理性同样需要进行B级相关说明。说明生产商根据多个水平的C相关可以获得生物豁免。该指导原则说明了生产商如何才能做到这个相关性。FDA的指导原则“延长释放口服固体剂型-开发、评估和体内外相关性的应用” (www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070239.pdf)。表明根据多说明的C级相关生产商可以获得生物豁免。 (www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070239.pdf)，这个指导原则表明生产商怎样能够完成这个相关。FDA还表明，如果这种相关性可以实现，发展A级相关也是可行的。
Establishment of Dissolution Specification Ranges
溶出规格范围的建立
It is relatively easy to establish a multipoint dissolution specification for a modified-release dosage form. The dissolution behaviorof the biobatch can be used to define the amount that will be released at each time point. The difficulty arises in thevariation that will be allowed around each time point. In the case of a Level A correlation, this can be done in two ways, bothof which use IVIVC: convolution and deconvolution.
调节释放剂型多点溶出规格释放确定相对容易。生物批次的溶出行为用于确定在每个时间点的溶出量。出现的困难是允许每个时间点出现变化。在A级相关的情况下，可以用两种方法进行，这两种方法都用到了IVIVC：卷积和反卷积。
CONVOLUTION
卷积
Reasonable upper and lower dissolution values are selected for each time point established from the biobatch. Historically,dissolution specifications have been selected by using the average dissolution of the development batches, with a range of ±2.5–3 standard deviations. It is now expected that the average dissolution values be approximately the same as those of thebiobatch. The dissolution curves defined by the upper and lower extremes are convoluted to project the anticipated plasma level curves that would result from administration of these formulations to the same patients to whom the biobatch was administered. If the resulting plasma level data fall within the 95% confidence intervals obtained in the definitive BA-BE study,these ranges can be considered acceptable. An alternative acceptance approach that can be used after the therapeutic window for a drug has been defined, is to establish whether the upper and lower limits of the convolution results fall within the therapeutic window, even if they fall outside the confidence interval. If they fall outside the window, a more limited range must be established. This procedure should be continued until the predicted values meet the desired ranges.
生物利用度批次每个时间点选择溶出值合理的上限和下限。以前，使用开发批次的平均溶出值选择溶出规格，标准偏差范围2.5-3。目前预计的平均溶出值与生物批次的大致相同。如果血浆浓度数据结果明确落在BA-BE研究中95％置信区间范围内，这些范围认为是可以接受。药物治疗窗确定后，即使在置信区间外，可用替代的接受方法确定卷积结果的上限和下限是否落入治疗窗内。如果在治疗窗外，必须确定更有限的范围。继续进行这个过程直到预测值满足需要范围。
DECONVOLUTION
反卷积法
An acceptable set of plasma-level data is established both for a batch of material demonstrating a more rapid release and for one demonstrating a slower release than that of the biobatch. These can be selected by using the extremes of the 95% confidence intervals or ±1 standard deviation of the mean plasma level. These curves are then deconvoluted, and the resulting input rate curve is used to establish the upper and lower dissolution specifications at each time point. In the case of Level B and C correlations, batches of product must be made at the proposed upper and lower limits of the dissolution range, and it must bedemonstrated that these batches are acceptable by a BA-BE study.
可接受的血浆浓度数据确定原料批次是较快释放以及与生物利用度批次相比为较慢释放。使用95%的置信区间或血浆平均浓度±1标准偏差进行选择。然后这些曲线进行反卷积，输入速率曲线结果用于确定每个时间点的上下溶出规格。在B级和C级相关的情况下，制剂产品的批次必须在溶出推荐的上下限范围内进行，这些批次通过BA-BE研究证明是可以接受的。
Immediate-Release Dosage Forms
即时释放剂型
GENERAL CONSIDERATIONS
总则
Because the mechanisms for drug release from modified-release dosage forms are more complex and variable than thoseassociated with immediate-release dosage forms, one would anticipate that an IVIVC would be easier to develop with the latterformulations. Unfortunately, most of the correlation efforts to date with immediate-release dosage forms have been based onthe correlation Level C approach, although there also have been efforts employing statistical moment theory (Level B). Althoughit is conceivable that the same Level A correlation approach can be used with immediate-release dosage forms, until data have been gathered to support this concept, Level B and Level C are the best approaches that can be recommended with these dosage forms.
由于调释制剂的释放机理与速释制剂相比更加复杂和可变，因此其IVIVC比后者更容易些。不幸的是，迄今为止，速释制剂是根据C级方法相关。虽然已经努力使用统计矩理论（B级）。尽管可以想到相同等级的相关性方法可以在速释剂型中使用，只要已采集的数据支持这一概念，B级和C级是这些剂型所推荐的最佳方法。
Establishment of Dissolution Specification Ranges
溶出规格范围的建立
It is relatively easy to establish a multipoint dissolution specification for a modified-release dosage form. The dissolution behaviorof the biobatch can be used to define the amount that will be released at each time point. The difficulty arises in thevariation that will be allowed around each time point. In the case of a Level A correlation, this can be done in two ways, bothof which use IVIVC: convolution and deconvolution.
调节释放剂型多点溶出规格释放确定相对容易。生物批次的溶出行为用于确定在每个时间点的溶出量。出现的困难是允许每个时间点出现变化。在A级相关的情况下，可以用两种方法进行，这两种方法都用到了IVIVC：卷积和反卷积。
CONVOLUTION
卷积
Reasonable upper and lower dissolution values are selected for each time point established from the biobatch. Historically,dissolution specifications have been selected by using the average dissolution of the development batches, with a range of ±2.5–3 standard deviations. It is now expected that the average dissolution values be approximately the same as those of thebiobatch. The dissolution curves defined by the upper and lower extremes are convoluted to project the anticipated plasma level curves that would result from administration of these formulations to the same patients to whom the biobatch was administered. If the resulting plasma level data fall within the 95% confidence intervals obtained in the definitive BA-BE study,these ranges can be considered acceptable. An alternative acceptance approach that can be used after the therapeutic window for a drug has been defined, is to establish whether the upper and lower limits of the convolution results fall within the therapeutic window, even if they fall outside the confidence interval. If they fall outside the window, a more limited range must be established. This procedure should be continued until the predicted values meet the desired ranges.
生物利用度批次每个时间点选择溶出值合理的上限和下限。以前，使用开发批次的平均溶出值选择溶出规格，标准偏差范围2.5-3。目前预计的平均溶出值与生物批次的大致相同。如果血浆浓度数据结果明确落在BA-BE研究中95％置信区间范围内，这些范围认为是可以接受。药物治疗窗确定后，即使在置信区间外，可用替代的接受方法确定卷积结果的上限和下限是否落入治疗窗内。如果在治疗窗外，必须确定更有限的范围。继续进行这个过程直到预测值满足需要范围。
DECONVOLUTION
反卷积法
An acceptable set of plasma-level data is established both for a batch of material demonstrating a more rapid release and for one demonstrating a slower release than that of the biobatch. These can be selected by using the extremes of the 95% confidence intervals or ±1 standard deviation of the mean plasma level. These curves are then deconvoluted, and the resulting input rate curve is used to establish the upper and lower dissolution specifications at each time point. In the case of Level B and C correlations, batches of product must be made at the proposed upper and lower limits of the dissolution range, and it must bedemonstrated that these batches are acceptable by a BA-BE study.
可接受的血浆浓度数据确定原料批次是较快释放以及与生物利用度批次相比为较慢释放。使用95%的置信区间或血浆平均浓度±1标准偏差进行选择。然后这些曲线进行反卷积，输入速率曲线结果用于确定每个时间点的上下溶出规格。在B级和C级相关的情况下，制剂产品的批次必须在溶出推荐的上下限范围内进行，这些批次通过BA-BE研究证明是可以接受的。
Immediate-Release Dosage Forms
即时释放剂型
GENERAL CONSIDERATIONS
总则
Because the mechanisms for drug release from modified-release dosage forms are more complex and variable than thoseassociated with immediate-release dosage forms, one would anticipate that an IVIVC would be easier to develop with the latterformulations. Unfortunately, most of the correlation efforts to date with immediate-release dosage forms have been based onthe correlation Level C approach, although there also have been efforts employing statistical moment theory (Level B). Althoughit is conceivable that the same Level A correlation approach can be used with immediate-release dosage forms, until data have been gathered to support this concept, Level B and Level C are the best approaches that can be recommended with these dosage forms.
由于调释制剂的释放机理与速释制剂相比更加复杂和可变，因此其IVIVC比后者更容易些。不幸的是，迄今为止，速释制剂是根据C级方法相关。虽然已经努力使用统计矩理论（B级）。尽管可以想到相同等级的相关性方法可以在速释剂型中使用，只要已采集的数据支持这一概念，B级和C级是这些剂型所推荐的最佳方法。
