Jorge Quiroz

Relative Precision of Inhaler Aerodynamic Particle Size Distribution (APSD) Metrics by Full Resolution and Abbreviated Andersen Cascade Impactors (ACIs): Part 1

The purpose of this study was to compare relative precision of two different abbreviated impactor measurement (AIM) systems and a traditional multi-stage cascade impactor (CI). The experimental design was chosen to provide separate estimates of variability for each impactor type. Full-resolution CIs are useful for characterizing the aerosol aerodynamic particle size distribution of orally inhaled products during development but are too cumbersome, time-consuming, and resource-intensive for other applications, such as routine quality control (QC). This article presents a proof-of-concept experiment, where two AIM systems configured to provide metrics pertinent to QC (QC-system) and human respiratory tract (HRT-system) were evaluated using a hydrofluoroalkane-albuterol pressurized metered dose inhaler. The Andersen eight-stage CI (ACI) served as the benchmark apparatus. The statistical design allowed estimation of precision with each CI configuration. Apart from one source of systematic error affecting extra-fine particle fraction from the HRT-system, no other bias was detected with either abbreviated system. The observed bias was shown to be caused by particle bounce following the displacement of surfactant by the shear force of the airflow diverging above the collection plate of the second impaction stage. A procedure was subsequently developed that eliminated this source of error, as described in the second article of this series (submitted to AAPS PharmSciTech). Measurements obtained with both abbreviated impactors were very similar in precision to the ACI for all measures of in vitro performance evaluated. Such abbreviated impactors can therefore be substituted for the ACI in certain situations, such as inhaler QC or add-on device testing.

Polyomavirus JC Urinary Shedding in Kidney and Liver Transplant Recipients Associated with Reduced Creatinine Clearance

BACKGROUND Polyomavirus reactivation can cause significant morbidity in solid organ transplant recipients, particularly BK virus (BKV) in kidney transplant patients. Less is known about dynamics of John Cunningham virus (JCV) in nonkidney organ transplant patients. METHODS We examined the frequency of urinary shedding of polyomaviruses BKV and JCV and their relationship to creatinine clearance (CrCl) in a longitudinal study of 41 kidney and 33 liver transplant recipients. RESULTS Any polyomavirus urinary shedding was more frequent in liver than kidney recipients (64% vs 39%; P= .03). JCV was excreted more frequently by liver than kidney recipients (71% vs 38%), whereas BKV was shed more often by kidney than liver patients (69% vs 52%). Mean JCV loads were significantly higher than those of BKV in both patient groups (P< .0001). Lower mean CrCl values were significantly associated with JCV shedding in both kidney and liver recipients (P< .001). CONCLUSIONS These findings suggest that BKV and JCV display different patterns of reactivation and shedding in kidney and liver transplant patients and that JCV may have a role in renal dysfunction in some solid organ transplant recipients.

Relative Precision of Inhaler Aerodynamic Particle Size Distribution (APSD) Metrics by Full Resolution and Abbreviated Andersen Cascade Impactors (ACIs): Part 2—Investigation of Bias in Extra-Fine Mass Fraction with AIM-HRT Impactor

The purpose of this study was to resolve an anomalously high measure of extra-fine particle fraction (EPF) determined by the abbreviated cascade impactor possibly relevant for human respiratory tract (AIM-HRT) in the experiment described in Part 1 of this two-part series, in which the relative precision of abbreviated impactors was evaluated in comparison with a full resolution Andersen eight-stage cascade impactor (ACI). Evidence that the surface coating used to mitigate particle bounce was laterally displaced by the flow emerging from the jets of the lower stage was apparent upon microscopic examination of the associated collection plate of the AIM-HRT impactor whose cut point size defines EPF. A filter soaked in surfactant was floated on top of this collection plate, and further measurements were made using the same pressurized metered-dose inhaler-based formulation and following the same procedure as in Part 1. Measures of EPF, fine particle, and coarse particle fractions were comparable with those obtained with the ACI, indicating that the cause of the bias had been identified and removed. When working with abbreviated impactors, this precaution is advised whenever there is evidence that surface coating displacement has occurred, a task that can be readily accomplished by microscopic inspection of all collection plates after allowing the impactor to sample ambient air for a few minutes.

Confidence Intervals in a Gauge R&R Study with Fixed Operators

The objective of this paper is to develop a method for constructing confidence intervals in a two-factor gauge repeatability and reproducibility (R&R) study with fixed operators. A previously proposed method is compared with a generalized confidence interval method using computer simulation. Simulation results suggest that, although the two methods are comparable in most cases, there are situations where the generalized confidence interval is a better choice.

Statistical analysis of data from limiting dilution cloning to assess monoclonality in generating manufacturing cell lines

Assurance of monoclonality of recombinant cell lines is a critical issue to gain regulatory approval in biological license application (BLA). Some of the requirements of regulatory agencies are the use of proper documentations and appropriate statistical analysis to demonstrate monoclonality. In some cases, one round may be sufficient to demonstrate monoclonality. In this article, we propose the use of confidence intervals for assessing monoclonality for limiting dilution cloning in the generation of recombinant manufacturing cell lines based on a single round. The use of confidence intervals instead of point estimates allow practitioners to account for the uncertainty present in the data when assessing whether an estimated level of monoclonality is consistent with regulatory requirements. In other cases, one round may not be sufficient and two consecutive rounds are required to assess monoclonality. When two consecutive subclonings are required, we improved the present methodology by reducing the infinite series proposed by Coller and Coller (Hybridoma 1983;2:91–96) to a simpler series. The proposed simpler series provides more accurate and reliable results. It also reduces the level of computation and can be easily implemented in any spreadsheet program like Microsoft Excel.

Statistical analysis of data from dilution assays with censored correlated counts

Frequently, count data obtained from dilution assays are subject to an upper detection limit, and as such, data obtained from these assays are usually censored. Also, counts from the same subject at different dilution levels are correlated. Ignoring the censoring and the correlation may provide unreliable and misleading results. Therefore, any meaningful data modeling requires that the censoring and the correlation be simultaneously addressed. Such comprehensive approaches of modeling censoring and correlation are not widely used in the analysis of dilution assays data. Traditionally, these data are analyzed using a general linear model on a logarithmic-transformed average count per subject. However, this traditional approach ignores the between-subject variability and risks, providing inconsistent results and unreliable conclusions. In this paper, we propose the use of a censored negative binomial model with normal random effects to analyze such data. This model addresses, in addition to the censoring and the correlation, any overdispersion that may be present in count data. The model is shown to be widely accessible through the use of several modern statistical software.

Process Design: Stage 1 of the FDA Process Validation Guidance

This is the first of three chapters that describe statistical approaches related to the three stages of process validation described in the FDA Process Validation Guidance for Industry (2011). The three stages are

GMP Monitoring and Continuous Process Verification: Stage 3 of the FDA Process Validation Guidance

The FDA Process Validation Guidance (2011) advocates Continued process verification Procedure validation a life cycle approach to product manufacturing which ensures the process can reliably and consistently produce quality product that meets the therapy’s desired efficacy and safety profile. This life cycle approach emphasizes collection and evaluation of appropriate data as evidence to demonstrate that the process is in a controlled state to deliver quality product. It has three stages: Process design, process qualification, and continued process verification (CPV). In CPV stage, data are continuously collected and evaluated to verify the process remains in the desired controlled state. This chapter discusses the key components of CPV and statistical tools that are useful for this purpose.

Statistical Methods for CMC Applications

In this chapter, we provide statistical methods that are useful in CMC applications. Our goal is to provide a description of these methods without delving deeply into the theoretical aspects. References are provided for the reader who desires a more in depth understanding of the material.

Analytical Comparability and Similarity

In all manufacturing settings, there is an inherent drive to improve product through the reduction in process variation, implementing new technology, increasing efficiency, optimizing resources, and improving customer experience through innovation. In the pharmaceutical industry, these improvements come with added responsibility to the patient such that product made under the post-improvement or post-change condition maintains the safety and efficacy of the pre-change product. As described in FDA comparability guidance (1996) and ICH Q5E (2004), regulatory agencies also recognize the importance in providing manufacturers the flexibility to improve their manufacturing processes. Agencies also acknowledge that some changes may not require additional clinical studies to demonstrate safety and efficacy so that implementation may be more efficient and expeditious to benefit patients. Activities performed when changes are made to the process include demonstration of comparability in product parameters. The actual timing of each activity and the statistical rigor required for the evaluation of pre- and post-change product is linked to the stage of the product development (e.g., clinical versus commercial material) and the scope of the change (e.g., process transfer with similar scale versus a new cell line or formulation).