Effect of Antioxidants in Medicinal Products on Intestinal Drug Transporters.

The presence of mutagenic and carcinogenic N-nitrosamine impurities in medicinal products poses a safety risk. While incorporating antioxidants in formulations is a potential mitigation strategy, concerns arise regarding their interference with drug absorption by inhibiting intestinal drug transporters. Our study screened thirty antioxidants for inhibitory effects on key intestinal transporters-OATP2B1, P-gp, and BCRP in HEK-293 cells (OATP2B1) or membrane vesicles (P-gp, BCRP) using 3H-estrone sulfate, 3H-N-methyl quinidine, and 3H-CCK8 as substrates, respectively. The screen identified that butylated hydroxyanisole (BHA) and carnosic acid inhibited all three transporters (OATP2B1, P-gp, and BCRP), while ascorbyl palmitate (AP) inhibited OATP2B1 by more than 50%. BHA had IC50 values of 71 ± 20 µM, 206 ± 14 µM, and 182 ± 49 µM for OATP2B1, BCRP, and P-gp, respectively. AP exhibited IC50 values of 23 ± 10 µM for OATP2B1. The potency of AP and BHA was tested with valsartan, an OATP2B1 substrate, and revealed IC50 values of 26 ± 17 µM and 19 ± 11 µM, respectively, in HEK-293-OATP2B1 cells. Comparing IC50 values of AP and BHA with estimated intestinal concentrations suggests an unlikely inhibition of intestinal transporters at clinical concentrations of drugs formulated with antioxidants.

Bumetanide as a Model NDSRI Substrate: N-nitrosobumetanide Impurity Formation and its Inhibition in Bumetanide Tablets.

Nitrosamine compounds are classified as potential human carcinogens, the origin of these impurities can be broadly classified in two categories, nitrosamine impurity found in drug products that are not associated with the Active Pharmaceutical Ingredient (API), such as N-nitrosodimethylamine (NDMA) or nitrosamine impurities associated with the API, such as nitrosamine drug substance-related impurities (NDSRIs). The mechanistic pathway for the formation of these two classes of impurities can be different and the approach to mitigate the risk should be tailored to address the specific concern. In the last couple of years number of NDSRIs have been reported for different drug products. Though, not the only contributing factor for the formation of NDSIRs, it is widely accepted that the presence of residual a nitrites/nitrates in the components used in the manufacturing of the drug products can be the primary contributor to the formation of NDSRIs. Approaches to mitigate the formation of NDSRIs in drug products include the use of antioxidants or pH modifiers in the formulation. The primary objective of this work was to evaluate the role of different inhibitors (antioxidants) and pH modifiers in tablet formulations prepared in-house using bumetanide (BMT) as a model drug to mitigate the formation of N-nitrosobumetanide (NBMT). A multi-factor study design was created, and several bumetanide formulations were prepared by wet granulation with and without sodium nitrite spike (100 ppm) and different antioxidants (ascorbic acid, ferulic acid or caffeic acid) at three concentrations (0.1%, 0.5% or 1% of the total tablet weight). Formulations with acidic and basic pH were also prepared using 0.1 N hydrochloric acid and 0.1 N sodium bicarbonate, respectively. The formulations were subjected to different storage (temperature and humidity) conditions over 6 months and stability data was collected. The rank order of N-nitrosobumetanide inhibition was highest with alkaline pH formulations, followed by formulations with ascorbic acid, caffeic acid or ferulic acid present. In summary, we hypothesize that maintaining a basic pH or the addition of an antioxidant in the drug product can mitigate the conversion of nitrite to nitrosating agent and thus reduce the formation of bumetanide nitrosamines.

FDA's new pharmaceutical quality initiative: Knowledge-aided assessment & structured applications.

This paper describes a new FDA's pharmaceutical quality assessment system: Knowledge-aided Assessment & Structured Application (KASA). The KASA system is designed to: 1) capture and manage knowledge during the lifecycle of a drug product; 2) establish rules and algorithms for risk assessment, control, and communication; 3) perform computer-aided analyses of applications to compare regulatory standards and quality risks across applications and facilities; and 4) provide a structured assessment that minimizes text-based narratives and summarization of provided information. When fully developed and implemented, KASA will enrich the effectiveness, efficiency, and consistency of regulatory quality oversight through lifecycle management of products and facilities, and information sharing in a standardized and structured format. Ultimately, KASA will advance FDA's focus on pharmaceutical quality, the foundation for ensuring the safety and efficacy of drugs.

Physicochemical Characterization of Iron Carbohydrate Colloid Drug Products.

Iron carbohydrate colloid drug products are intravenously administered to patients with chronic kidney disease for the treatment of iron deficiency anemia. Physicochemical characterization of iron colloids is critical to establish pharmaceutical equivalence between an innovator iron colloid product and generic version. The purpose of this review is to summarize literature-reported techniques for physicochemical characterization of iron carbohydrate colloid drug products. The mechanisms, reported testing results, and common technical pitfalls for individual characterization test are discussed. A better understanding of the physicochemical characterization techniques will facilitate generic iron carbohydrate colloid product development, accelerate products to market, and ensure iron carbohydrate colloid product quality.

Building parity between brand and generic peptide products: Regulatory and scientific considerations for quality of synthetic peptides.

Peptides are a fast growing segment in the pharmaceutical industry. Consequently, the industry and regulatory agencies are increasing their focus on the regulatory path and quality considerations for peptide development and manufacturing. Although most peptides are synthetic, manufactured by solid phase synthesis, nevertheless they are complex molecules with challenging quality and regulatory aspects. This paper provides a structured overview of relevant quality issues for chemically synthesized peptides used as active pharmaceutical ingredients (API) in drug products. It addresses the unique characteristics of peptides pertaining to structural and physicochemical characterization, manufacturing and in process controls, impurities and aggregates arising from manufacturing and storage, along with their potential impact on safety (including immunogenicity) and efficacy of the peptide drug products.

Advancing Product Quality: a Summary of the Inaugural FDA/PQRI Conference.

On September 16 and 17, 2014, the Food and Drug Administration (FDA) and Product Quality Research Institute (PQRI) inaugurated their Conference on Evolving Product Quality. The Conference is conceived as an annual forum in which scientists from regulatory agencies, industry, and academia may exchange viewpoints and work together to advance pharmaceutical quality. This Conference Summary Report highlights key topics of this conference, including (1) risk-based approaches to pharmaceutical development, manufacturing, regulatory assessment, and post-approval changes; (2) FDA-proposed quality metrics for products, facilities, and quality management systems; (3) performance-based quality assessment and clinically relevant specifications; (4) recent developments and implementation of continuous manufacturing processes, question-based review, and European Medicines Agency (EMA)-FDA pilot for Quality-by-Design (QbD) applications; and (5) breakthrough therapies, biosimilars, and international harmonization, focusing on ICH M7 and Q3D guidelines. The second FDA/PQRI conference on advancing product quality is planned for October 5-7, 2015.

Current challenges in bioequivalence, quality, and novel assessment technologies for topical products.

This paper summarises the proceedings of a recent workshop which brought together pharmaceutical scientists and dermatologists from academia, industry and regulatory agencies to discuss current regulatory issues and industry practices for establishing therapeutic bioequivalence (BE) of dermatologic topical products. The methods currently available for assessment of BE were reviewed as well as alternatives and the advantages and disadvantages of each method were considered. Guidance on quality and performance of topical products was reviewed and a framework to categorise existing and alternative methods for evaluation of BE was discussed. The outcome of the workshop emphasized both a need for greater attention to quality, possibly, via a Quality-By-Design (QBD) approach and a need to develop a "whole toolkit" approach towards the problem of determination of rate and extent in the assessment of topical bioavailability. The discussion on the BE and clinical equivalence of topical products revealed considerable concerns about the variability present in the current methodologies utilized by the industry and regulatory agencies. It was proposed that academicians, researchers, the pharmaceutical industry and regulators work together to evaluate and validate alternative methods that are based on both the underlying science and are adapted to the drug product itself instead of single "universal" method.

Pharmaceutical characterization and thermodynamic stability assessment of a colloidal iron drug product: iron sucrose.

The study objective was to evaluate the thermodynamic stability of iron sucrose complexes as determined by molecular weight (m.w.) changes. The first part of the study focused on the effect of thermal stress, pH, electrolyte or excipient dilution on the stability of a colloidal iron drug product. Part two focused on the physical and chemical evaluation of the colloidal nature of iron sucrose using a series of characterization experiments: ultracentrifugation, dialysis, particle size, zeta potential, and osmotic pressure analysis. A validated Taguchi-optimized high performance gel permeation chromatography method was used for m.w. determinations. Results indicate m.w. of the iron sucrose complex remained unchanged after excipient dilution, ultracentrifugation, dialysis, and electrolyte dilution. Electrolyte dilution studies indicated the lyophilic nature of the iron sucrose colloid with a particle size of 10nm and zeta potential of 0 mV. The complex deformed at low pH and reformed back at the formulation pH. The complex is stable under mild-to-moderate temperature <50°C but aggregates following prolonged exposure to high temperatures >70°C. In conclusion, the resistance of the complex to breakdown by electrolytic conditions, excipient dilution, ultracentrifugation and the reversible complexation after alteration of formulation pH suggest iron sucrose is a lyophilic colloid in nature and lyophilic colloidals are thermodynamically stable.

Generic development of topical dermatologic products, Part II: quality by design for topical semisolid products.

The emergence of quality by design as a relatively new systematic science and risk-based approach has added a new dimension to pharmaceutical development and manufacturing. This review attempts to discuss the quality by design elements and concepts applied for topical semisolid products. Quality by design begins with defining a quality target product profile as well as critical quality attributes. Subsequently, this is followed by risk identification/risk analysis/risk evaluation to recognize critical material attributes and critical process parameters, in conjunction with design of experiments or other appropriate methods to establish control strategies for the drug product. Several design-of-experiment examples are included as practical strategies for the development and optimization of formulation and process for topical drug products.

Scientific considerations in the review and approval of generic enoxaparin in the United States.

In 2010, the US Food and Drug Administration (FDA) approved a generic low-molecular-weight heparin without clinical safety or efficacy data under the Abbreviated New Drug Application (ANDA) pathway. To enable a determination of active ingredient sameness of generic and innovator enoxaparin products, the FDA developed a scientifically rigorous approach based on five criteria: first, equivalence of physicochemical properties; second, equivalence of heparin source material and mode of depolymerization; third, equivalence in disaccharide building blocks, fragment mapping and sequence of oligosaccharide species; fourth, equivalence in biological and biochemical assays; and finally, equivalence of in vivo pharmacodynamic profile. In addition to fulfillment of these criteria, FDA also used in vitro, ex vivo and model animal data to ensure there was no increased immunogenicity risk of the generic enoxaparin product relative to the brand name product. The approval of the highly complex enoxaparin product using this framework under the ANDA pathway represents a major development. It also suggests that analytical and scientific advancements may in certain cases allow the elimination of unnecessary in vivo testing in animals and humans.

Generic development of topical dermatologic products: formulation development, process development, and testing of topical dermatologic products.

This review presents considerations which can be employed during the development of a semi-solid topical generic product. This includes a discussion on the implementation of quality by design concepts during development to ensure the generic drug product has similar desired quality attributes to the reference-listed drug (RLD) and ensure batch to batch consistency through commercial production. This encompasses the concept of reverse-engineering to copy the RLD as a strategy during product development to ensure qualitative (Q1) and quantitative (Q2) formulation similarity, as well as similarity in formulation microstructure (Q3). The concept of utilizing in vitro skin permeation studies as a tool to justify formulation differences between the test generic product and the RLD to ensure a successful pharmacodynamic or clinical endpoint bioequivalence study is discussed. The review concludes with a discussion on drug product evaluation and quality tests as well as in vivo bioequivalence studies.

Physicochemical characterization of complex drug substances: evaluation of structural similarities and differences of protamine sulfate from various sources.

The purpose of this study was to characterize and evaluate differences of protamine sulfate, a highly basic peptide drug, obtained from five different sources, using orthogonal thermal and spectroscopic analytical methods. Thermogravimetric analysis and modulated differential scanning calorimetry showed that all five protamine sulfate samples had different moisture contents and glass transition and melting temperatures when temperature was modulated from 25 to 270°C. Protamine sulfate from source III had the highest residual moisture content (4.7 ± 0.2%) at 105°C, resulting in the lowest glass transition (109.7°C) and melting (184.2°C) temperatures compared with the other four sources. By Fourier-transform infrared (FTIR) spectroscopy, the five sources of protamine sulfate had indistinguishable spectra, and the spectra were consistent with a predominantly random coil conformation in solution and a minor population in a ß-sheet conformation (~12%). Circular dichroism spectropolarimetry confirmed the FTIR results with prominent minima at 206 nm observed for all five sources. Finally, proton ((1)H) nuclear magnetic resonance spectroscopy showed that all five protamine sulfate sources had identical spectra with backbone amide chemical shifts between 8.20 and 8.80 ppm, consistent with proteins with predominantly random coil conformation. In conclusion, thermal analyses showed differences in the thermal behavior of the five sources of protamine sulfate, while spectroscopic analyses showed the samples had a predominantly random coil conformation with a small amount of ß-sheet present.

Use of partial AUC to demonstrate bioequivalence of Zolpidem Tartrate Extended Release formulations.

PURPOSE: FDA's bioequivalence recommendation for Zolpidem Tartrate Extended Release Tablets is the first to use partial AUC (pAUC) metrics for determining bioequivalence of modified-release dosage forms. Modeling and simulation studies were performed to aid in understanding the need for pAUC measures and also the proper pAUC truncation times. METHODS: Deconvolution techniques, In Vitro/In Vivo Correlations, and the CAT (Compartmental Absorption and Transit) model were used to predict the PK profiles for zolpidem. Models were validated using in-house data submitted to the FDA. Using dissolution profiles expressed by the Weibull model as input for the CAT model, dissolution spaces were derived for simulated test formulations. RESULTS: The AUC(0-1.5) parameter was indicative of IR characteristics of early exposure and effectively distinguished among formulations that produced different pharmacodynamic effects. The AUC(1.5-t) parameter ensured equivalence with respect to the sustained release phase of Ambien CR. The variability of AUC(0-1.5) is higher than other PK parameters, but is reasonable for use in an equivalence test. CONCLUSIONS: In addition to the traditional PK parameters of AUCinf and Cmax, AUC(0-1.5) and AUC(1.5-t) are recommended to provide bioequivalence measures with respect to label indications for Ambien CR: onset of sleep and sleep maintenance.

Crystallinity evaluation of tacrolimus solid dispersions by chemometric analysis.

Different destructive and nondestructive analytical methods, namely powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), Raman and near-infrared (NIR) spectroscopy and imaging, to detect and characterize tacrolimus trace crystallinity in an amorphous solid dispersion (SD) using chemometric analysis were developed. The SD was spiked with different percentages of the crystalline drug to construct an array of SDs with different crystallinity percentages. Partial least square (PLS) regression analysis was employed to compare the performance of the calibration models created using these analytical methods. The obtained results indicated a significant interaction between tacrolimus and the employed polymer and a drug dissolution dependency on the crystalline fraction within the SDs. Using two PLS factors, these analytical methods were ranked according to its specificity to detect the trace crystallinity of SDs as NIR>PXRD>Raman>DSC. Through the application of PLS, root-mean-squared error of calibration values of 2.91%, 5.36%, 7.07% and 11.58% were calculated for the calibration models constructed by NIR, PXRD, Raman and DSC, respectively. Having a prediction error of 2.1% and a correlation coefficient of 0.99, it is demonstrated that combined NIR imaging and chemometric analysis outperformed the other methods in detecting trace crystallinity in tacrolimus amorphous systems. The spatial distributions of amorphous and crystalline drug were also obtained in order to allow for studying the crystallization dissemination in the solid dispersions. Consequently, NIR and NIR imaging coupled with chemometry was shown to be a powerful tool for the prediction of drug crystallinity within SDs.

Pharmaceutical equivalence by design for generic drugs: modified-release products.

The Office of Generic Drugs has ensured the high quality of generic products based upon two requirements: pharmaceutical equivalence and bioequivalence to the reference listed drug (RLD). This paradigm has been used with success toward ensuring quality generic drug products that provide the same therapeutic benefit as the RLD. Drug products have increased in design complexity; as a result, approaches to ensure therapeutic equivalence must evolve to provide assurance of quality generic drug products. The Food and Drug Administration quality by design initiative (QbD) provides an enhanced evaluation approach by introducing the concept of a quality target product profile (QTPP). The QTPP introduces, within the context of the current regulatory framework, the quality concept of "pharmaceutical equivalence by design." This article illustrates through several examples how this QbD element in the evaluation of modified-release drug products enhances the current framework to ensure generic drug product equivalence. It achieves this by complementing the traditional paradigm, "equivalence by testing," where product equivalence is based upon inferences from a limited bioequivalence study, to one that also considers whether the drug product was developed to be an equivalent to the RLD, using appropriate quality surrogates that target "pharmaceutical equivalence by design."

Scientific considerations for generic synthetic salmon calcitonin nasal spray products.

Under the Abbreviated New Drug Application pathway, a proposed generic salmon calcitonin nasal spray is required to demonstrate pharmaceutical equivalence and bioequivalence to the brand-name counterpart or the reference listed drug. This review discusses two important aspects of pharmaceutical equivalence for this synthetic peptide nasal spray product. The first aspect is drug substance sameness, in which a proposed generic salmon calcitonin product is required to demonstrate that it contains the same active ingredient as that in the brand-name counterpart. The second aspect is comparability in product- and process-related factors that may influence immunogenicity (i.e., peptide-related impurities, aggregates, formulation, and leachates from the container/closure system). The comparability of these factors helps to ensure the product safety, particularly with respect to immunogenicity. This review also highlights the key features of in vitro and/or in vivo studies for establishing bioequivalence for a solution nasal spray containing a systemically acting salmon calcitonin.

Thermodynamic stability assessment of a colloidal iron drug product: sodium ferric gluconate.

A high performance gel permeation chromatography (HP-GPC) method was developed, validated and used to determine the molecular weight (MW) of sodium ferric gluconate following various stress conditions. The intra-day accuracy (90-103%), intra-day precision (1.5-2.7%), inter-day accuracy (91-105%), inter-day precision (1.3-3.2%) were within acceptable range stated in FDA guidance. The MW of sodium ferric gluconate remained unchanged after: (1) autoclaving (121 degrees C), (2) moderate thermal stress (30 days at 50 degrees C or 7 days at 70 and 90 degrees C), (3) excipient dilution, (4) basic buffer dilution (pH of 8 and 9), (5) ultracentrifugation, (6) dialysis, and (7) electrolyte dilution. However sodium ferric gluconate showed signs of instability at higher temperatures (>90 degrees C) after 30 days and at pH of 10-11. Sodium ferric gluconate was found to be a lypophilic colloidal solution with an average particle size of 10 nm and a zeta potential of -13 mV. The colloid osmotic pressure was 3.5 mmHg and remained unchanged after moderate thermal stress. Additionally, in-house drug products with similar MW to sodium ferric gluconate were produced by three different synthetic procedures, suggesting that this colloidal iron drug product might be thermodynamically stable.

Generic omeprazole delayed-release capsules: in vitro performance evaluations.

BACKGROUND: After the patent on omeprazole delayed-release capsules expired, Food and Drug Administration (FDA) approved several generic omeprazole delayed-release capsule applications. FDA has received some complaints concerning a lack of therapeutic effect of the generic omeprazole delayed-release capsules. AIM: To investigate the quality of five different marketed generic omeprazole delayed-release capsules. METHOD: The dissolution characteristics of these generic omeprazole delayed-release capsules were determined according to the United States Pharmacopeia (USP). Additional dissolution studies under simulated in vivo physiological conditions were also conducted to determine whether generic omeprazole capsules would perform similarly under these conditions. RESULTS: The experimental data show that all the generic omeprazole delayed-release capsules met the USP standards. The in vitro dissolution of generic drugs is similar to that of the brand omeprazole product. CONCLUSIONS: There is no scientific evidence to support the claims that the generic omeprazole delayed-release capsules perform differently from the brand omeprazole product in vitro.

Quality by design: concepts for ANDAs.

Quality by design is an essential part of the modern approach to pharmaceutical quality. There is much confusion among pharmaceutical scientists in generic drug industry about the appropriate element and terminology of quality by design. This paper discusses quality by design for generic drugs and presents a summary of the key terminology. The elements of quality by design are examined and a consistent nomenclature for quality by design, critical quality attribute, critical process parameter, critical material attribute, and control strategy is proposed. Agreement on these key concepts will allow discussion of the application of these concepts to abbreviated new drug applications to progress.