Blend Uniformity and Unit Dose Sampling

Process validation for solid dosage forms must include a component that demonstrates content uniformity of the final blend. As a result of a recent court ruling this aspect of validation has received increased attention from both industry and government. In particular, the court ruled that the appropriate sample size for content uniformity testing of the final blend in validation batches is three times the run weight of the finished product. Furthermore, recent FDA communications suggest that the uniformity of the final blend should be held to a higher standard than that of the tablet in order to provide reasonable assurance that the finished product will exhibit acceptable uniformity. The purpose of this article is to communicate some problems that our firm encountered during the validation of a lower strength of a currently marketed tablet. The validated process for the marketed product has a long history of providing tablets that exhibit acceptable content uniformity at the higher strength. Extensive data from three validation batches manufactured at each of two production sites demonstrate consistently and significantly lower drug content in the lubricated granulation than in the finished product. The variability of the granulation data as characterized by the standard deviation is, for the most part, acceptable and comparable to that of the tablets. Unfortunately, these batches fail validation when subjected to the acceptance criteria suggested in recent FDA communications. We attribute the lower assay values of the granulation to sampling bias that occurs when small volumes of powder are extracted from a large V-blender with a sampling thief. In order to circumvent this problem and avoid rejecting acceptable processes we recommend an alternative acceptance criteria in which the mean assay of the powder samples is not relevant, This criteria relies solely on the standard deviation of the blend.     

Unit Dose Sampling: A Tale of two Thieves

As a consequence of the United States vs. Barr Laboratories decision, pharmaceutical companies are now compelled to demonstrate the uniformity of unit dose samples of final powder blends. This investigation was initiated in response to a previously reported failed attempt to validate a process for lower strengths of a currently marketed product. This process has a long history of providing high-quality commercial tablets at the higher strength. The failure occurred because the unit dose samples of the final powder blend were indisputably subpotent. Interestingly, during the validation effort, 799 tablets of various strengths were assayed and exhibited outstanding content uniformity and potency. It was hypothesized that this failure was due to sampling bias which occurred when small (unit dose) samples were extracted with a thief from a static powder bed that was 7 orders of magnitude greater in size. The purpose of this two-part investigation was to test this hypothesis. In both of these studies, sieve analyses were conducted on samples collected from 100 kg of the final commercial blend. From these data the ratio of the coarse to fine fractions was calculated. This ratio is directly proportional to particle size and, for this product, related to the concentration of drug in the sample. Two different thieves (A and B) and a variety of sampling conditions were compared in Study 1 and the results suggest that the coarse-to-fine ratio: (a) decreases with sampling depth, (b) is generally larger for samples extracted with thief B than thief A, and (c) is larger for samples collected with a thief that is maintained in the vertical position than one held at an acute angle. The intent of Study 2, which focused exclusively on thief B, was to determine if the pronounced effect of sampling depth on the coarse-to-fine ratio was due to sampling bias or product segregation. The results of Study 2 demonstrated that coarser material was preferentially sampled from the top of the bed than from the bottom. These studies indicated that one thief used under different conditions and two thieves used under similar conditions can extract samples of different particle size from the same population. This implicates sampling bias and confirms that a thief is far from an ideal sampling device. We believe that the unit dose sampling requirement is more likely to impede the delivery of innovative pharmaceutical products to the marketplace than it is to enhance the quality of these products.     

Unit Dose Sampling: A Tale of two Thieves

Abstract

As a consequence of the United States vs. Barr Laboratories decision, pharmaceutical companies are now compelled to demonstrate the uniformity of unit dose samples of final powder blends. This investigation was initiated in response to a previously reported failed attempt to validate a process for lower strengths of a currently marketed product. This process has a long history of providing high-quality commercial tablets at the higher strength. The failure occurred because the unit dose samples of the final powder blend were indisputably subpotent. Interestingly, during the validation effort, 799 tablets of various strengths were assayed and exhibited outstanding content uniformity and potency. It was hypothesized that this failure was due to sampling bias which occurred when small (unit dose) samples were extracted with a thief from a static powder bed that was 7 orders of magnitude greater in size. The purpose of this two-part investigation was to test this hypothesis. In both of these studies, sieve analyses were conducted on samples collected from 100 kg of the final commercial blend. From these data the ratio of the coarse to fine fractions was calculated. This ratio is directly proportional to particle size and, for this product, related to the concentration of drug in the sample. Two different thieves (A and B) and a variety of sampling conditions were compared in Study 1 and the results suggest that the coarse-to-fine ratio: (a) decreases with sampling depth, (b) is generally larger for samples extracted with thief B than thief A, and (c) is larger for samples collected with a thief that is maintained in the vertical position than one held at an acute angle. The intent of Study 2, which focused exclusively on thief B, was to determine if the pronounced effect of sampling depth on the coarse-to-fine ratio was due to sampling bias or product segregation. The results of Study 2 demonstrated that coarser material was preferentially sampled from the top of the bed than from the bottom. These studies indicated that one thief used under different conditions and two thieves used under similar conditions can extract samples of different particle size from the same population. This implicates sampling bias and confirms that a thief is far from an ideal sampling device. We believe that the unit dose sampling requirement is more likely to impede the delivery of innovative pharmaceutical products to the marketplace than it is to enhance the quality of these products.     

Unit Dose Sampling and Final Product Performance: An Alternative Approach

This article documents a proposed plan for validation testing for the content uniformity for final blends and finished solid oral dosage forms (SODFs). The testing logic and statistical justification of the plan are presented. The plan provides good assurance that a passing lot will perform well against the USP tablet content uniformity test. The operating characteristics of the test and the probability of needing to test for blend sampling bias are reported. A case study is presented.     

A Statistical Approach to Blend Uniformity Acceptance Criteria

Abstract

Recent Food and Drug Administration (FDA) validation guidelines and comments indicate that applying finished product content uniformity specifications to blend testing is unacceptable. The scenario the FDA has presented is one in which disorder increases as the process progresses so that blend test specifications should be more restrictive (tighter) than finished product testing specifications. In other publications, it has been suggested that finished product assay limits be applied as a blend specification along with a lower relative standard deviation value than the current USP content uniformity limit (6.0%). This approach is questionable since assay results are applied to an aggregate finished product sample rather than individual doses. A method is presented in this paper for applying statistical tolerance limits (Sib) to blend data. This procedure provides a 95% confidence level that at least 90% of the values for the entire population are within the calculated limits. These statistical tolerance limits provide an acceptable criterion that is statistically tighter than the application of USP XXIII finished product content uniformity specifications. In addition, this method involves a decision process or multiple-level evaluation based on a statistical comparison of the variance and mean for the blend and finished product. In cases where the calculated STLs are unacceptable, the decision process allows for determining if the out-of-specification values from the first level of testing are due to a true blend failure or if the cause of the aberration is due to other phenomena, which could include sampling technique, thief design, and analytical testing problems.     

A Statistical Approach to Blend Uniformity Acceptance Criteria

Recent Food and Drug Administration (FDA) validation guidelines and comments indicate that applying finished product content uniformity specifications to blend testing is unacceptable. The scenario the FDA has presented is one in which disorder increases as the process progresses so that blend test specifications should be more restrictive (tighter) than finished product testing specifications. In other publications, it has been suggested that finished product assay limits be applied as a blend specification along with a lower relative standard deviation value than the current USP content uniformity limit (6.0%). This approach is questionable since assay results are applied to an aggregate finished product sample rather than individual doses. A method is presented in this paper for applying statistical tolerance limits (Sib) to blend data. This procedure provides a 95% confidence level that at least 90% of the values for the entire population are within the calculated limits. These statistical tolerance limits provide an acceptable criterion that is statistically tighter than the application of USP XXIII finished product content uniformity specifications. In addition, this method involves a decision process or multiple-level evaluation based on a statistical comparison of the variance and mean for the blend and finished product. In cases where the calculated STLs are unacceptable, the decision process allows for determining if the out-of-specification values from the first level of testing are due to a true blend failure or if the cause of the aberration is due to other phenomena, which could include sampling technique, thief design, and analytical testing problems.     

Content Uniformity of a Low Dose Pharmaceutical Product

ABSTRACT

Optimum homogeneity and physical stability for a Roche compound (RO) low dose formulations (0,125 and 0.250 mg Tablets i.e. 0.07 to 0.14% w/w drug load, respectively) were achieved. Direct compression powder formulations were prepared by mixing the active drug substance with Starch 1500 (ST) to form an active pre-mix. Other ingredients were added subsequently. The final powder mix was subjected to a vibration of 4 Hz frequency using a specially designed segregation unit and content uniformity was assessed for these formulations. ST was considered superior to both lactose anhydrous and Avicel PH 102 in preparing homogeneous and physically stable mixes. Production-size batches of the product were successfully manufactured (Mean Drug content = 98 100%, RSV = 2%).     

高速并行采样中时间非均匀性测试与校准方法

并行交替采集系统中, 由于各采样通道间时间延迟不一致引入的偏差使得输出采样序列非均匀, 严重地降低了系统性能. 现有盲估计算法计算量大, 无法实现工程应用. 通过分析采样样本统计变化趋势, 提出了一种计算量更小的采样通道延迟估计算法, 并采用分数延时滤波器完成校正, 降低了设计难度与成本, 系统校正性能和实时性高, 适于工程实现.     

一种非均匀采样系统采样均匀性的评价新方法

提出了在多A/D合成采样系统中采样均匀性的评价方法;通过使用正弦波激励系统,将各个子A/D的数据分别抽取形成子抽样序列,使用最小二乘正弦波曲线拟合法,获得各个子抽样序列初始相位间的差异,该差异对应的时间差即为各个子A/D间的采样延迟时间,它们的一致性就是系统的采样均匀性。在一组仿真数据上验证了方法的正确性。在数字存储示波器的实测数据上进行了实验验证,获得了有效的测量结果,验证了方法的可行性。该方法可以用来评价非均匀采样系统的采样均匀性。     

吹塑级热塑性弹性体制备中的共混均匀性研究

热塑性弹性体应用广泛,利用其进行吹塑制得的成品可应用于体育器材、汽车等行业中。从理论、工艺和设备等方面综述了热塑性弹性体在吹塑前的共混改性,提高共混体系均匀性的方法,并展望了吹塑级热塑性弹性体的应用前景。     

RSD Requirement for Different Sample Size for Blend Sampling

A formula for calculating the equivalent relative standard deviation (RSD) for different sample sizes other than the Office of Generic Drugs (OGD) draft guidance was derived. These critical values vary with the population RSD and the sample size and guarantee the same confidence of passing a batch similar to the OGD blend uniformity test. Simulation results showed that the normal approximations give very close results to the simulation results. An assessment of the proposed OGD blend uniformity criteria against the first-stage USP content uniformity (CU) criteria for tablets was also made.     

Some Future Perspectives for Unit Dose Inhalation Aerosols

Unit dose inhalation aerosols fail to achieve optimal lung deposition even though this can be achieved by dispersing 1-5 µm aerodynamic diameter particles in air. Dry powder generators require rapid inhalation for actuation and fail to deaggregate and release much of their powder charge because of high particulate adhesion forces. Conversely, pressurized metered dose inhalers (MDIs) fail because emergent propellant droplets are too large and travel too fast. The present unreliable dosimetry associated with the MDI stems from a desire to administer the whole of the metered dose. Rational design should concede on this point and concentrate on reducing primary droplet size and preventing emission of non-respirable large droplets. The loss of a constant proportion of each metered dose in the device and not the patient would be a major achievement. Improved inhalation dosimetry will facilitate future formulation developments designed to sustain local activity in the lung. This may be achieved by reducing particle dissolution rates in the airways.     

Some Future Perspectives for Unit Dose Inhalation Aerosols

Abstract

Unit dose inhalation aerosols fail to achieve optimal lung deposition even though this can be achieved by dispersing 1-5 µm aerodynamic diameter particles in air. Dry powder generators require rapid inhalation for actuation and fail to deaggregate and release much of their powder charge because of high particulate adhesion forces. Conversely, pressurized metered dose inhalers (MDIs) fail because emergent propellant droplets are too large and travel too fast. The present unreliable dosimetry associated with the MDI stems from a desire to administer the whole of the metered dose. Rational design should concede on this point and concentrate on reducing primary droplet size and preventing emission of non-respirable large droplets. The loss of a constant proportion of each metered dose in the device and not the patient would be a major achievement. Improved inhalation dosimetry will facilitate future formulation developments designed to sustain local activity in the lung. This may be achieved by reducing particle dissolution rates in the airways.     

光探测器响应度均匀性的自动测量装置

本文讲述了一种由光学系统、扫描平台、微机为核心组成的光探测器响应度均匀性的自动测量装置。光学系统产生φ0.2mm光斑;在微机控制下,平台可作X,Y方向的25mm平移及绕中心旋转,最小平移进退间距0.01mm,最小旋转角间隔1/24度。测量系统稳定性达0.05%,扫描系统的重复性在0.05%以内,被测探测器定位及光入射角调整误差0.23%,装置的总不确定度0.26%。     

State Primary Standard of the Unit of Absorbed Dose and Unit of Absorbed Dose Rate of Beta Radiation in Tissue-Equivalent Material Get 9-2018

Measurement Techniques - The composition of the State Primary Standard of the unit of absorbed dose and unit of absorbed dose rate of beta radiation in tissue-equivalent material, GET 9-2018, is...     

Examination of Components of Variance for A Production Scale, Low Dose Powder Blend and Resulting Tablets

A study was performed to quantify the contributions of the different components comprising the total variance term observed following the analysis of content uniformity testing of powder blends and tablets. A full scale (400 kg) blend study was performed on a low dose tablet formulation (drug content = 0.13%). Content uniformity samples were pulled from throughout the blender using a pocket type probe thief in a manner which allowed the blend to be assessed for both homogeneity and sample to sample variability at a given location. Tablets were compressed from the batch and assayed for content uniformity. Sampling error accounted for approximately 75% of the variance observed following analysis of drug content in the powder blends. The estimated total variance for the powder blend was approximately twice that observed for tablets compressed from the mixture. The analytical contribution to the total variance term was minor. The difference between the estimated total variance terms for powder blend and tablets was attributed to the superior sampling efficiency of the tablet press versus the sample thief. The results of the study support the use of wider specifications for powder blends than the tablets compressed from the mixture.     

Examination of Components of Variance for A Production Scale,Low Dose Powder Blend and Resulting Tablets

Abstract

A study was performed to quantify the contributions of the different components comprising the total variance term observed following the analysis of content uniformity testing of powder blends and tablets. A full scale (400 kg) blend study was performed on a low dose tablet formulation (drug content = 0.13%). Content uniformity samples were pulled from throughout the blender using a pocket type probe thief in a manner which allowed the blend to be assessed for both homogeneity and sample to sample variability at a given location. Tablets were compressed from the batch and assayed for content uniformity. Sampling error accounted for approximately 75% of the variance observed following analysis of drug content in the powder blends. The estimated total variance for the powder blend was approximately twice that observed for tablets compressed from the mixture. The analytical contribution to the total variance term was minor. The difference between the estimated total variance terms for powder blend and tablets was attributed to the superior sampling efficiency of the tablet press versus the sample thief. The results of the study support the use of wider specifications for powder blends than the tablets compressed from the mixture.     

Tables for Determining Expected Cost Per Unit under MIL-STD-105D Single Sampling Schemes

When a MIL-STD-105D sampling scheme is used for a long period, some lots will be subjected to normal, some to reduced, and some to tightened inspection. This paper provides for several single sampling plans and various quality levels, the expected fraction of lots rejected, the expected sample size per lot, and the expected number of lots to be processed before sampling inspection must be discontinued. Equations are given to calculate the long term cost of sampling inspection using these expected values and appropriate cost parameters.