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The IQ Consortium Uniformity Testing Working Group reviewed the current BU and CU testing practices among ten member companies. All ten companies presented their current approach to BU and CU testing at the three stages of Product Lifecycle Management: the Process Design Stage, the Process Qualification Stage, and the Continuous Verification Stage. With this information on hand, the Uniformity Testing Working Group members developed a risk-based approach to BU and CU testing, and proposed innovative methods to reduce or eliminate blend sampling based on risk to Uniformity of Dosage Unit (UDU) testing. This approach uses prior knowledge, mechanistic understanding, and structured risk assessment tools to classify formulations as low-risk or high-risk, thus guiding the testing strategy. A decision tree was outlined on this basis for low-risk and high-risk formulations. The Working Group aims to influence health authorities on the matter, enabling streamlined testing expectations., Competing Interests: Declarations. Conflict of Interest: The authors declare having no personal or financial conflicts of interest pertaining to the topics discussed herein., (© 2025. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

At the Product Quality Research Institute (PQRI) Workshop held last January 14-15, 2014, participants from academia, industry, and governmental agencies involved in the development and regulation of nanomedicines discussed the current state of characterization, formulation development, manufacturing, and nonclinical safety evaluation of nanomaterial-containing drug products for human use. The workshop discussions identified areas where additional understanding of material attributes, absorption, biodistribution, cellular and tissue uptake, and disposition of nanosized particles would continue to inform their safe use in drug products. Analytical techniques and methods used for in vitro characterization and stability testing of formulations containing nanomaterials were discussed, along with their advantages and limitations. Areas where additional regulatory guidance and material characterization standards would help in the development and approval of nanomedicines were explored. Representatives from the US Food and Drug Administration (USFDA), Health Canada, and European Medicines Agency (EMA) presented information about the diversity of nanomaterials in approved and newly developed drug products. USFDA, Health Canada, and EMA regulators discussed the applicability of current regulatory policies in presentations and open discussion. Information contained in several of the recent EMA reflection papers was discussed in detail, along with their scope and intent to enhance scientific understanding about disposition, efficacy, and safety of nanomaterials introduced in vivo and regulatory requirements for testing and market authorization. Opportunities for interaction with regulatory agencies during the lifecycle of nanomedicines were also addressed at the meeting. This is a summary of the workshop presentations and discussions, including considerations for future regulatory guidance on drug products containing nanomaterials.

In this whitepaper, the Manufacturing Technical Committee of the Product Quality Research Institute provides information on the common, best practices in use today in the development of high-quality chemistry, manufacturing and controls documentation. Important topics reviewed include International Conference on Harmonization, in vitro-in vivo correlation considerations, quality-by-design approaches, process analytical technologies and current scale-up, and process control and validation practices. It is the hope and intent that this whitepaper will engender expanded dialog on this important subject by the pharmaceutical industry and its regulatory bodies.

Human leukocyte elastase (HLE) has been proposed as a primary mediator of pulmonary emphysema and other inflammatory airway diseases. HLE is capable of cleaving many proteins, including elastin, other components of connective tissue, certain complement proteins, and receptors. Under normal conditions an appropriate balance exists in the lung between HLE and endogenous inhibitors, which scavenge the released enzyme before it exerts deleterious effects in the lung. Emphysema is thought to result from an imbalance in the lung between HLE and endogenous inhibitor (elevated elastase or insufficient inhibitor) that leads to the destruction of alveoli. We have identified WIN 64733 (2) and WIN 63759 (3) as potent (Ki* = 14 and 13 pM, respectively), selective, mechanism-based inhibitors of HLE which are orally bioavailable in the dog (absolute bioavailability 46% and 21%, respectively). In this series the in vitro stabilities of the inhibitors in blood, jejunal homogenates, and liver S9 homogenates are useful predictors of oral bioavailability. After being administered orally (30 mg/kg) to dogs, compounds 2 and 3 are found in the lung, being detected in the epithelial lining fluid obtained by bronchoalveolar lavage (Cmax of 2.5 and 0.47 microgram/mL, respectively).

A liquid chromatographic (LC) method for determination of etoposide in dog blood is described. The technique includes solvent extraction of etoposide using a dichloroethane-hexane mixture and reconstitution of the drug in an aqueous reconstitution solution. The samples are analyzed by reversed-phase LC with electrochemical detection. Validation of the method demonstrated good sensitivity, precision and reproducibility. The method is useful for the study of etoposide pharmacokinetics in the dog.

A new, practical method called microdialysis has been developed for the estimation of free, unbound drug concentrations in the interstitial fluid. This method is based on the use of urea as an endogenous recovery marker. Urea freely distributes throughout the body water compartment, and its plasma concentration can be used as an accurate measure of its interstitial levels. Microdialysis exploits the relationship between the relative recoveries of urea and the recoveries of an analyte that are established during calibration. The calibration is carried out using different probes, varying perfusion rates, membrane surface areas, temperatures, and tissue models. After obtaining a broad range of recoveries, an empirical mathematical model of the relationship between the recovery of the respective analyte and that of urea is formed. During in vivo experiments, a microdialysis probe is placed into a tissue or fluid of interest, and the urea recovery is monitored by comparing the corresponding dialysate and plasma urea levels. From the calculated urea recoveries, correlation equation, and analyte dialysate concentrations, the extracellular concentration of the unbound analyte in the tissue or fluid can be estimated at any given time point. The purpose of this study is to describe the method of microdialysis and demonstrate its applicability in vitro using two model compounds, theophylline and 3'-azido-3'-deoxythymidine (AZT), in the rat plasma.

A novel technique for in vivo intrabronchial pharmacokinetic measurements using microdialysis is described. The technique was applied to the measurement of tobramycin and gentamicin in the anesthetized rat. The concentration versus time profiles of the drugs in the lung epithelial lining fluid (ELF) following intravenous bolus administration were determined. The mean penetration ratios into the ELF were determined and found to be 0.36 +/- 0.06 (mean +/- SEM, n = 5) for gentamicin and 0.56 +/- 0.09 (mean +/- SEM, n = 5) for tobramycin. The findings suggest that the technique can be used for intrabronchial pharmacokinetic measurement of drugs in the lung, either as an extension of the bronchoalveolar lavage technique or as a practical alternative to it.

A novel water-soluble polymer, poly[(chloromethoxytrialanine methyl ester)phosphazene] (poly-Tame), was characterized and evaluated using high-performance size-exclusion chromatography, gradient reversed-phase high-performance liquid chromatography and ion chromatography. These novel liquid chromatographic methods were validated for application to in vitro biodegradation experiments of poly-Tame in aqueous solutions. Results from method validation experiments are presented.

Indomethacin is a potent and efficacious antiinflammatory agent. However, a limiting side effect is its ability to cause gastric ulceration. This study was designed to investigate the effects of an amphoteric gel on the gastric ulcerogenicity and pharmacokinetics of indomethacin. Oral administration (5 mg/kg) in a suspension and a gel formulation were compared to an intravenous (iv) formulation of indomethacin in rats. The iv formulation administered to rats produced large severe ulcers in some rats but not in others. In contrast, the oral suspension produced small ulcers in all rats. The difference in toxicities is attributed to a centrally mediated action as a result of high plasma levels of indomethacin following iv administration, compared to locally mediated action with the suspension, resulting from local high concentrations of indomethacin on the apical epithelial surface because of the presence of indomethacin crystals. Oral administration of the gel formulation did not result in any gastric ulceration and improved the bioavailability of indomethacin to 115.5%, compared with 68.2% for the suspension. The reduced gastrointestinal toxicity of indomethacin in the gel was attributed to the gel's ability to dissolve indomethacin, preventing the localized high concentration observed with the suspension and possibly providing a gastric protectant phospholipid. The gel formulation doubled the oral bioavailability and the tmax of indomethacin compared to the suspension but did not affect the half-life. The results indicate that the local irritant effect of indomethacin, in rats, can be reduced by appropriate formulation design and suggest that the ulcerogenicity index for indomethacin can be improved by the use of an amphoteric gel formulation.

An automated high-performance liquid chromatography (HPLC) assay for ethinyl estradiol and norgestrel or levonorgestrel in oral contraceptive tablets was developed. Tablets were prepared for on-line injection using a solid sampler and segmented continuous flow techniques. The active components were separated from tablet excipients, impurities, and degradation products on reversed-phase C8 and C18 columns by elution with water-acetonitrile-methanol (45:35:15). A UV detector connected in series with a fluorometric detector measured the UV absorbance of levonorgestrel and norgestrel at 240 nm and the fluorescence of ethinyl estradiol at 310 nm (excitation at 210 nm). The method employed computer control of the injection system and solid sampler for synchronization of the chromatographic and segmented flow streams. The method is applicable for content uniformity and stability testing at a rate of eight samples per hour.