Search

Long-acting injectable (LAI) drug products enable the controlled release of a drug over an extended duration of time to improve the therapeutic effect, safety profile, or administration of an injectable product. The development of generic [505(j)] and differentiated [505(b)(2)] LAI products helps to provide patients and healthcare providers with more treatment options and to reduce overall healthcare costs, including those associated with drug product administration and patient compliance. In this review, we analyze the landscape of LAI products and identify the most common technical challenges that potential generic product entrants face. We focus on five formulation technologies that account for ~90% of approved LAI products, including those eligible for generic product registration over the next five years, to illustrate technology-specific challenges. We then review efforts from the U.S. Food and Drug Administration (FDA) to promote more generic product competition and emphasize the importance of collaboration among government, industry, and academia to advance the knowledge and capabilities of the scientific community. Regulatory bodies, industry, and academia are encouraged to anticipate challenges with emerging innovative LAI technologies and to leverage the experiences built on established technologies to foster generic product development.

Complex iron nanoparticle-based drugs are one of the oldest and most frequently administered classes of nanomedicines. In the US, there are seven FDA-approved iron nanoparticle reference drug products, of which one also has an approved generic drug product (i.e., sodium ferric gluconate (SFG)). These products are indicated for the treatment of iron deficiency anemia and are administered intravenously. On the molecular level, iron nanomedicines are colloids composed of an iron oxide core with a carbohydrate coating. This formulation makes nanomedicines more complex than conventional small molecule drugs. As such, these products are often referred to as nonbiological complex drugs (e.g., by the nonbiological complex drugs (NBCD) working group) or complex drug products (e.g., by the FDA). Herein, we report a comprehensive study of the physiochemical properties of the iron nanoparticle product SFG. SFG is the single drug for which both an innovator (Ferrlecit) and generic product are available in the US, allowing for comparative studies to be performed. Measurements focused on the iron core of SFG included optical spectroscopy, inductively coupled plasma mass spectrometry (ICP-MS), X-ray powder diffraction (XRPD), 57Fe Mossbauer spectroscopy, and X-ray absorbance spectroscopy (XAS). The analysis revealed similar ferric-iron-oxide structures. Measurements focused on the carbohydrate shell comprised of the gluconate ligands included forced acid degradation, dynamic light scattering (DLS), analytical ultracentrifugation (AUC), and gel permeation chromatography (GPC). Such analysis revealed differences in composition for the innovator versus the generic SFG. These studies have the potential to contribute to future quality assessment of iron complex products and will inform on a pharmacokinetic study of two therapeutically equivalent iron gluconate products.

In contrast to nifedipine matrix-based extended-release dosage forms, the osmotic pump drug delivery systems have a zero-order drug release independent of external variables such as pH, agitation rate, and dissolution media. The objective of this study focuses on the in vitro evaluation of the mechanical properties of osmotic pump and polymer matrix-based formulations in dissolution media, and the potential impacts that media pH and simulated gastrointestinal contraction have on drug release. Two strengths of osmotic pump product A and polymer matrix-based product B were used in this study. An in-house system was developed with the capability of applying mechanical compression and monitoring mechanical properties of sample during dissolution testing. A United States Pharmacopeia or an in-house apparatus was used for dissolution testing under various conditions. Compared to the product A, the mechanical properties of the product B change significantly at various pHs and mechanical compressions. The results suggest that polymer matrix-based products bear a risk of formulation-related interactions with the gastrointestinal tract during in vivo drug dissolution, especially in the case of concomitant pH and gastric contractile changes. Modified dissolution testing devices may help formulation scientists in product development and provide regulatory agencies with an additional metric for quality assurance of drug products.

Nanomedicines are nanoparticle-based therapeutic or diagnostic agents designed for targeted delivery or enhanced stability. Nanotechnology has been successfully employed to develop various drug formulations with improved pharmacokinetic characteristics, and current research efforts are focused on the development of new innovator and generic nanomedicines. Nanomedicines, which are often denoted as complex or nonbiological complex drugs, have inherently different physicochemical and pharmacokinetic properties than conventional small molecule drugs. The tools necessary to fully evaluate nanomedicines in clinical settings are limited, which can hamper their development. One of the most successful families of nanomedicines are iron-carbohydrate nanoparticles, which are administered intravenously (IV) to treat iron-deficiency anemia. In the U.S., the FDA has approved six distinct iron-carbohydrate nanoparticles but only one generic version (sodium ferric gluconate for Ferrlecit). There is significant interest in approving additional generic iron-carbohydrate drugs; however, the lack of a direct method to monitor the fate of the iron nanoparticles in clinical samples has impeded this approval. Herein we report a novel liquid chromatography–inductively coupled plasma–mass spectrometry (LC–ICP–MS) method that allows for the direct quantification of the iron-carbohydrate drugs in clinical samples, while simultaneously measuring the speciation of the iron released from the nanoparticles in biological samples. To our knowledge, this is the first time that iron nanoparticles have been observed in clinical samples, opening the door for direct pharmacokinetic studies of this family of drugs. This method has potential applications not only for iron-nanoparticle drugs but also for any nanomedicine with an inorganic component.

BACKGROUND: Generic versions of a drug can vary in appearance, which can impact adherence. OBJECTIVE: To assess the preferences, perceptions, and responses of patients who experienced a change in the appearance of a generic medication. DESIGN: Cross-sectional survey of patients from a large commercial health plan. PARTICIPANTS: Adults receiving generic versions of lisinopril, fluoxetine, lamotrigine, or simvastatin who experienced a change in the color or shape of their pills between March 2014 and November 2015. MAIN MEASURES: Likert-scale responses to questions concerning perceptions of generic drug safety and effectiveness, reliance on and preferences for pill appearance, and responses to pill appearance changes. Multivariable logistic regression-modeled predictors of seeking advice and adjusting use following a pill appearance change. KEY RESULTS: Of 814 respondents (response rate = 41%), 72% relied on pill appearance to ensure they took the correct medication. A similar percentage wanted their pills to remain the same color (72%), shape (71%), and size (75%) upon refill, but 58% would not have paid a $1 premium on a $5 co-pay to ensure such consistency. Most respondents (86%) wanted their pharmacists to notify them about pill appearance changes, but only 37% recalled such notification; 21% thought they received the wrong medication, and 8% adjusted medication use. Younger respondents (18–33 vs. 50–57 years) were more likely to seek advice (odds ratio [OR] = 1.91; 95% confidence interval [CI],1.02–3.59), and respondents with lower household income ( $100,000) were more likely to adjust medication use (OR = 3.40; 95% CI,1.09–10.67). CONCLUSIONS: Requiring uniform pill appearance may help increase adherence but presents challenges. Standardized pharmacy notification and education policies may be a more feasible short-term solution. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11606-018-4791-1) contains supplementary material, which is available to authorized users.

Purpose The purpose of this study was to provide an algorithm for generic brittleness and to elucidate the demographic factors that anticipate generic brittleness for patients with epilepsy. Methods This exploratory, observational, and nontherapeutic study was conducted in patients with epilepsy who were routinely followed at the University of Maryland epilepsy outpatient clinic in Baltimore, Maryland. Patients were taking at least one antiepileptic drug (AED) for treatment of epilepsy. Based on patient interview and medical history, 12 demographic factors were collected. Each patient was assessed to be either generic brittle (GB) or not GB. Demographic factors were subjected to binary logistical regression and other statistical tests, to elucidate determinants of GB status. Results N = 148 patients completed the study. An algorithm to define whether a patient was GB or not GB was devised. The two elements that defined GB status are as follows: patient opinion about generics and (if needed) whether patients were currently taking brand or generic of their most problematic AED. About 40% of patients were GB. From binary logistical regression, two demographic factors that contributed to patients being GB were whether a patient was currently taking a problem AED and total number of current medications for a patient, with odds ratios of 4.06 (95% confidence interval [CI] from 1.53 to 10.81) and 1.10 (95% CI from 1.003 to 1.21), respectively. Of the patients on a problem AED, 46.9% were GB, while only 18.2% of patients not currently on a problem AED were GB. The total number of current medications ranged from 1 to 22, with mode of four medications. From regression, for each additional medication that a patient took, the odds of being GB increased 1.10-fold. Although patient seizure and adverse event history was not employed to define GB status, being GB was associated with less seizure control and greater adverse events. Conclusions An algorithm for generic brittleness was derived, and about 40% of patients were GB, usually due to prior history of a switch problem. Two demographic factors favored patients being GB: whether the patient was currently taking a problem AED and the total number of current medications.

We demonstrate the use of modeling and simulation to investigate bioequivalence (BE) concerns raised about generic warfarin products. To test the hypothesis that the loss of isopropyl alcohol and slow dissolution in acidic pH has significant impact on the pharmacokinetics of warfarin sodium tablets, we conducted physiologically based pharmacokinetic absorption modeling and simulation using formulation factors or in vitro dissolution profiles as input parameters. Sensitivity analyses indicated that warfarin pharmacokinetics was not sensitive to solubility, particle size, density, or dissolution rate in pH 4.5, but was affected by dissolution rate in pH 6.8 and potency. Virtual BE studies suggested that stressed warfarin sodium tablets with slow dissolution rate in pH 4.5 but having similar dissolution rate in pH 6.8 would be bioequivalent to the unstressed warfarin sodium tablets. A four-way, crossover, single-dose BE study in healthy subjects was conducted to test the same hypothesis and confirmed the simulation conclusion.

Enteral feeding tubes are used to deliver food or drugs to patients that cannot swallow. To deliver delayed-release drugs that are formulated as enteric coated granules to these patients via feeding tubes requires that they be suspended in water prior to administration. Importantly, the suspension of enteric granules in water of varying pH can cause damage to the enteric coating and affect the bioavailability of the drug. Here, analytical methods for testing acid resistance stability and particle size distribution (PSD) of esomeprazole granules were utilized to monitor the integrity of the granule enteric coating after water pretreatment and delivery through an oral syringe and nasogastric (NG) tube. Granules from esomeprazole magnesium delayed-release capsules were transferred to an oral syringe, suspended in water, and delivered on the bench through a NG tube. Subsequently, acid resistance stability, (i.e., the amount of drug released after 2-hour acid dissolution) was determined via HPLC and the particle size distributions (PSD) were measured with a laser diffraction system. All of the granules demonstrated acid resistance stability when the granules were delivered immediately (0 min incubation) through the oral syringe and NG tube. By contrast, some granules demonstrated significant drug release during acid exposure after a 15-min incubation period which mimics a possible delay in delivery of the drug from the syringe by the caregiver. A bimodal PSD was observed with these granules, which was attributed to debris from damaged enteric coating and particle agglomeration. The methods developed in this study could be used to distinguish batches with suboptimal product quality for delivery using NG tubes and to confirm the substitutability of generic drug products for this alternative route of administration.

From 2005 to 2014, 370 data entries of dissolution failures of solid oral drug products were assessed with respect to the solubility of drug substances, dosage forms [immediate release (IR) vs. modified release (MR)], and manufacturers (brand name vs. generic). The study results show that the solubility of drug substances does not play a significant role in dissolution failures; however, MR drug products fail dissolution tests more frequently than IR drug products. When multiple variables were analyzed simultaneously, poorly water-soluble IR drug products failed the most dissolution tests, followed by poorly soluble MR drug products and very soluble MR drug products. Interestingly, the generic drug products fail dissolution tests at an earlier time point during a stability study than the brand name drug products. Whether the dissolution failure of these solid oral drug products has any in vivo implication will require further pharmacokinetic, pharmacodynamic, clinical, and drug safety evaluation. Food and Drug Administration is currently conducting risk-based assessment using in-house dissolution testing, physiologically based pharmacokinetic modeling and simulation, and post-market surveillance tools. At the meantime, this interim report will outline a general scheme of monitoring dissolution failures of solid oral dosage forms as a pharmaceutical quality indicator.

Biotechnology and nanotechnology provide a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron-carbohydrate complexes, drug-carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1-day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the World Health Organization) to approve these complex drug products and their follow-on versions. One of the key questions remains how to assess equivalence of these complex products. We identify a number of points for which consensus was found among the stakeholders who were present: scientists from innovator and generic/follow-on companies, academia, and regulatory bodies from different parts of the world. A number of topics requiring follow-up were identified: (1) assessment of critical attributes to establish equivalence for follow-on versions, (2) the need to publish scientific findings in the public domain to further progress in the field, (3) the necessity to develop worldwide consensus regarding nomenclature and labeling of these complex products, and (4) regulatory actions when substandard complex drug products are identified.

We sought to examine rates of clinical outcomes among patients before and after market introduction of generic versions of five drugs approved using product-specific equivalence determinations. We used data from a large national insurer to identify patients who initiated a study (acarbose tablets, salmon calcitonin nasal spray, enoxaparin injection, vancomycin capsules, venlafaxine extended-release tablets) or control drug (nateglinide, glimepiride, alendronate, fondaparinux, metronidazole, sertraline, paroxetine) in each calendar month between 2003 and 2012 and to determine rates of claims-based proxies for lack of effectiveness outcomes following initiation. We used segmented time-series analyses to evaluate level (short-term) and slope (longer-term) changes in outcomes upon introduction of a generic study or control drug. Among study drugs, we observed three increases (one with p

The development of curative glioblastoma treatments and tumour-specific contrast agents that can overcome the blood–brain barrier (BBB) and infiltrative tumour morphology remains a challenge. Apolipoprotein E3 (apoE3) is a high density lipoprotein apolipoprotein that chaperones the transcytosis of nanoparticles across the BBB, and displays high-affinity binding with the low density lipoprotein receptor (LDLR), a cell-surface receptor overexpressed by glioblastoma cells. This LDLR overexpression and apoE3 binding capacity was exploited for the development of glioblastoma-targeted porphyrin-lipid apoE3 lipid nanoparticles (pyE-LNs) with intrinsic theranostic properties. Size-controlled discoidal and cholesteryl oleate (CO)-loaded spherical pyE-LNs were synthesized through the systematic variation of particle composition, which dictated nanoparticle size and morphology. Composition optimization yielded 30 nm pyE-LNs with stable loading of apoE3 and porphyrin-lipid that simultaneously conferred the nanoparticles with glioblastoma targeting and activatable near-infrared fluorescence imaging functionalities. A 4-fold higher uptake of pyE-LNs by LDLR-expressing U87 glioblastomas cells relative to minimally expressing ldlA7 cells was observed in vitro. This uptake was a result of receptor-mediated endocytosis, which could be inhibited through LDL competition and acetylation of particle apoE3 moieties. ApoE3-dependent delivery of pyE-LN to glioblastomas was also demonstrated in orthotopic U87-GFP tumour-bearing animals. Quantification of CO-loaded pyE-LN biodistribution demonstrated successful selective uptake of porphyrin by malignant tissue, with a 4 : 1 tumour : healthy tissue particle specificity. This allowed for the detection of strong, tumour-localized porphyrin fluorescence, which was diminished when apoE3-devoid py-LN particles were administered. Furthermore, this selective uptake yielded cell-specific potent PDT sensitization in vitro, resulting in an 83% reduction in glioblastoma cell viability. These results highlight the promising capacity of pyE-LNs to target porphyrin delivery to glioblastoma tumours for theranostic applications.

A patient was denoted to be generic brittle (GB) if they had a negative opinion about generics (e.g. prior history of a switch problem) or took the innovator brand of their most problematic anti-epileptic drug (AED) when generic was available. The aim of this hypothesis-generating study was to assess possible genetic and physiologic differences between GB and not GB patients with epilepsy. Patients (n = 148) with epilepsy were previously characterized as being either GB or not GB. Blood was collected from each subject for genotyping and physiologic testing. Genotyping for 24 single nucleotide polymorphisms (SNPs) and two copy number variants (CNVs) was performed across 12 genes in each patient. Forty-four physiologic tests were conducted in each patient. Chi square analysis was performed to assess for associations between genotyping results and GB status, as well as between physiologic test results and GB status. No SNP or CNV discriminated GB status in genetic analysis (genotype or allele frequency). Physiologic test results in this study were not associated with GB status. Questions from neurologists and patients about generics is frequently based on applicability of generic drug standards to individual subjects. However, findings here in patients with epilepsy did not uncover genetic or physiologic reasons that explained which patients were GB and which were not GB.

Identification and quantification of excipient related degradation products in the liposomal formulation is important, as they may impact the safety and efficacy of the drug. Phospholipids are one of the major excipients in liposome drugs composing the lipid bilayer, and they are vulnerable to oxidation and hydrolysis reactions. Since phospholipids with saturated fatty acid chain were preferred in most of liposome drug products, the major degradation pathway of phospholipids in liposome formulations are limited to hydrolysis of phospholipids into free fatty acids and lysophospholipids. These hydrolyzed degradation products may form during manufacturing and/or long-term storage of liposomal formulations. Herein, we report development and application of accurate and sensitive methods that can be utilized for the quantitation of saturated free fatty acids (FFA 18:0 and FFA 16:0), lysophosphocholines (LPC 18:0 and LPC 16:0), and lysophosphoglycerol (LPG 18:0) in liposomal formulations. The free fatty acids were separated using a C8 column whereas the LPCs and LPGs were separated using a C18 stationary phase upon direct injection without the need of lipid extraction process. Each analyte was quantified by Q-TOF mass spectrometry. This method was validated according to USP compendial procedures and has been applied to the analysis of four commercial liposomal pharmaceutical formulations. The limit of quantitation (LOQs) of FFA 16:0, FFA 18:0, LPC 16:0, LPC 18:0 and LPG 18:0 are 5 ng/mL, 5 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 10 ng/mL respectively. Compared to CAD (Charge Aerosol Detector) and ELSD (Evaporative Light Scattering Detector) detection methods in ppm levels, this ultra-performance liquid chromatography (UPLC)-Mass Spectroscopy (MS) method displays precise determination of lysophospholipids in the liposomal formulations with higher accuracy and sensitivity.

The European Federation of Pharmaceutical Sciences (EUFEPS) and American Association of Pharmaceutical Scientists (AAPS) have collaborated since 2015 to organize international conferences to support global harmonization of regulatory requirements for bioequivalence (BE) assessment. This collaboration has resulted in three Global Bioequivalence Harmonization Initiative (GBHI) workshops which provided a unique opportunity for scientists from academia, industry, and regulatory agencies to discuss current, complex BE issues. The 3rd GBHI workshop was held in April 2018 in Amsterdam/The Netherlands and covered the following topics: (a) the necessity of multiple-dose studies in BE testing; (b) BE of transdermal delivery systems, and (c) liposomal parenteral preparations. This report summarizes the extensive discussions that led to better understanding of the similarities and differences across the major regulatory agencies on these topics and paved the way for future international harmonization.

Cholesterol is one of the major structural constituents in a liposomal bilayer. Cholesterol is susceptible to various reactions in the presence of oxygen, heat, light, certain metals, and radicals during manufacturing or storage, which may cause to generate cholesterol oxidation products (COPs). Herein, we report the development of a liquid chromatography-mass spectrometry based analytical method for screening and quantitating COPs present in liposomal parenteral pharmaceutical formulations (LPFs) from four different vendors. We detected and quantitated six COPs and desmosterol in LPFs, and desmosterol is an intermediate of cholesterol biosynthesis. 7α-hydroxycholesterol, 7β-hydroxycholesterol, 7-keto-cholesterol, and desmosterol were the major cholesterol-related impurities in LPFs. COPs were not detected in any of USP/NF grade cholesterol raw materials, implying that COPs were generated during liposome manufacturing and/or storage. This validated method presented here can be used to quantify cholesterol-related impurities present in liposomal pharmaceutical formulations to ensure the quality and the safety of liposomal pharmaceutical formulations.

To guide developers of innovative and generic drug products that contain nanomaterials, the U.S. Food and Drug Administration issued the draft guidance for industry titled: "Drug Products, Including Biological Products, that Contain Nanomaterials" in December 2017. During the AAPS Guidance Forum on September 11, 2018, participants from industry, academia, and regulatory bodies discussed this draft guidance in an open setting. Two questions raised by the AAPS membership were discussed in more detail: what is the appropriate regulatory pathway for approval of drug products containing nanomaterials, and how to determine critical quality attributes (CQAs) for nanomaterials? During the meeting, clarification was provided on how the new FDA center-led guidance relates to older, specific nanomaterial class, or specific product-related guidances. The lively discussions concluded with some clear observations and recommendations: (I) Important lessons can be learned from how CQAs were determined for, e.g., biologics. (II) Publication of ongoing scientific discussions on strategies and studies determining CQAs of drug products containing nanomaterials will significantly strengthen the science base on this topic. Furthermore, (III) alignment on a global level on how to address new questions regarding nanomedicine development protocols will add to efficient development and approval of these much needed candidate nanomedicines (innovative and generic). Public meetings such as the AAPS Guidance Forum may serve as the place to have these discussions.

The introduction of prescription opioids with abuse-deterrent (AD) properties to the marketplace has created a need for new testing methodologies to evaluate the performance of potentially abuse-deterrent opioid products. Drug abusers may attempt to chew solid oral extended-release (ER) opioids prior to ingestion to bypass the ER mechanism of the formulation to achieve euphoria. In the present study, a chewing apparatus was utilized to develop an in vitro chewing method for Hysingla ER tablets, a prescription opioid with labeling describing abuse deterrence via the oral route when chewed. Simulated chewing of Hysingla resulted in initially faster drug release during chewing while subsequent dissolution testing demonstrated that the masticated tablets still maintained ER properties. The degree of mastication and corresponding drug release were influenced by the compression gap and the resulting chewing forces. Simulated chewing followed by dissolution testing with different strengths of Hysingla indicated similar AD performance across strengths. By contrast, an opioid product with labeling that does not describe abuse-deterrent properties showed lower resistance to chewing resulting in higher drug release. The results of the present study suggest that the chewing methodology evaluated in this work may provide a useful in vitro tool for the comparative evaluation of AD properties.

Sirolimus, an immunosuppressive agent used in renal transplantation, can prevent allograft rejection. Identification of the therapeutic index (the ratio of minimum toxic concentration to minimum therapeutic concentration) for immunosuppresants is necessary to optimize the care of patients and set standards for bioequivalence evaluation of sirolimus products. However, the therapeutic index for sirolimus has been inconsistently defined, potentially because of inconsistencies in sirolimus exposure-response relationships.The authors used retrospective therapeutic drug monitoring data from the electronic health records of patients treated in a tertiary health care system from 2008 to 2014 to (1) develop a population pharmacokinetic (PK) model, (2) use the model to simulate sirolimus concentrations, and (3) characterize the exposure-response relationship. Using Wilcoxon rank-sum and Fisher exact tests, the authors determined relationships between sirolimus exposure and adverse events (AEs) (anemia, leukopenia, thrombocytopenia, hyperlipidemia, and decline in renal function) and the composite efficacy end point of graft loss or rejection.The developed 2-compartment population PK model showed appropriate goodness of fit. In a late-phase (12 months), postrenal transplant population of 27 inpatients, the authors identified statistically significant relationships between 83 simulated peak and trough sirolimus concentrations and outcomes: graft loss or rejection (P = 0.018) and decline in renal function (P = 0.006), respectively.Use of therapeutic drug monitoring results and PK modeling permitted correlation of sirolimus concentrations with graft loss or rejection and decline in renal function. However, the method was limited in its assessment of other AEs. To better evaluate sirolimus exposure-response relationships, the method should be applied to a larger sample of newly transplanted patients with a higher propensity toward AEs or efficacy failure.

Objective We sought to examine rates of clinical outcomes among patients before and after market introduction of generic versions of five drugs approved using product-specific equivalence determinations.

The objective was to assess the impact of larger than conventional amounts of 14 commonly used excipients on Biopharmaceutics Classification System (BCS) class 3 drug absorption in humans. Cimetidine and acyclovir were used as model class 3 drugs across three separate four-way crossover bioequivalence (BE) studies (n = 24 each) in healthy human volunteers, denoted as study 1A, 1B, and 2. In study 1A and 1B, three capsule formulations of each drug were manufactured, collectively involving 14 common excipients. Capsule formulations that incorporated hydroxypropyl methylcellulose (HPMC) or magnesium stearate exhibited lower absorption. The cimetidine commercial solution contained sorbitol and also resulted in lower absorption. Hence, in study 2, two capsule formulations with lower amounts of HPMC and magnesium stearate, the sorbitol-containing commercial solution, and a sorbitol-free solution were assessed for BE. Overall, 12 common excipients were found in large amounts to not impact BCS class 3 drug absorption in humans, such that these excipients need not be qualitatively the same nor quantitatively very similar to reference, but rather simply be not more than the quantities studied here. Meanwhile, for each HPMC and microcrystalline cellulose, BCS class 3 biowaivers require these two excipients to be qualitatively the same and quantitatively very similar to the reference.

Purpose The purpose of the study was to assess if any antiepileptic drug (AED) was associated with patients being generic brittle (GB) and if any specific AED caused – and was not merely associated with – more frequent switch problems. Methods Chi square and binary logistical regression analysis were performed, using a previously described study in patients with epilepsy who were routinely followed at the University of Maryland epilepsy outpatient clinic in Baltimore, Maryland. Determination of generic brittleness mirrored clinical practice and included patient opinion about generic formulations, usually based on a history of worsened seizures or side effects with prior AED formulation switching. The dataset included a total of 148 patients, who took 30 different AED formulations. Patients collectively took 530 AED formulation products. Results Taking lamotrigine immediate release (IR) tablets was associated with a greater probability of being GB and tended to cause more frequent switch problems. Interestingly, six AEDs – Vimpat tablet, carbamazepine IR tablet, phenobarbital (any formulation), gabapentin capsule, Lyrica capsules, and phenytoin (any formulation) – were associated with a reduced probability of being GB, although perhaps not through greater efficacy and tolerability, or better formulation quality. Since tablet and capsule appearance may influence patient perceptions and clinical outcomes, it was observed that the six AEDs less associated with being GB also tended to have fewer generics, and hence possibly lessen treatment uncertainties from the patient perspective. A patient taking more AEDs had significantly increased odds of having a switch problem. An additional observation was that, when a generic was available for their most problematic AED, GB patients took a generic AED only 50% of the time, while not GB patients took a generic AED all the time. Conclusions Taking lamotrigine IR tablets was associated with a greater probability of being GB and tended to cause more frequent switch problems than other AEDs in this cohort of patients. Six AEDs were associated with a reduced probability of being GB. The lower number of different generics for these six drugs may result in greater patient certainty in medication identity, due to greater consistency in medication color, shape, and size, and hence less generic skepticism or generic brittleness. Also, patients taking more AEDs showed increased odds of a switch problem.

The purpose of this study was to determine the intrapatient (within the same patient) variability of tacrolimus in adherent patients. Daily tacrolimus trough levels were obtained at home using dried blood spot technology in kidney and liver transplant recipients. Patients were randomized to receive 3 formulations of tacrolimus, each for two 1-week periods. Adherence was monitored by patient diary, pill counts, and use of the Medication Event Monitoring System (MEMS). Variability was quantified as the coefficient of variation (CV). Comparison of CV between groups was by independent t test or one-way ANOVA as appropriate. The population was found to be adherent with a rate of 99.9% with a mean interval between the evening and morning dose of tacrolimus of 11.86 hours. The median CV for the entire population was 15.2% (range 4.8%-110%). There were no differences in CV by allograft type or tacrolimus formulation. The multivariate analysis did not identify any demographic characteristics associated with a CV > 30%. In a highly adherent population, tacrolimus did not display high intrapatient variability. Given the association between IPV and poor allograft outcomes, future studies are needed to quantitate the influence of adherence and establish target IPV goals.

Nearly 90% of drugs dispensed in the US are generic products. The aim of this study was to develop and implement a tool for analyzing manufacturer-level drug utilization and switching patterns within the US Food and Drug Administration’s Sentinel system. A descriptive tool was designed to analyze data in the Sentinel common data model and was tested with two case studies—metoprolol extended release (ER) and lamotrigine ER—using claims data from four Sentinel data partners. We plotted initiators of each brand and generic product over time. For metoprolol ER, we evaluated rates of switching from generics around the time of manufacturing issues. For lamotrigine ER, we examined rates of switching back to the brand among those who switched from brand to generic. We identified 1,651,285 initiators of metoprolol ER products between July 2008 and September 2015. We observed a large decrease in monthly metoprolol ER initiators (from 25,465 in December 2008 to 13,128 in February 2009), corresponding to recalls by generic manufacturers. We observed simultaneous increases in utilization of the authorized generic and brand products. We identified 4266 initiators of lamotrigine ER with an epilepsy diagnosis between January 2012 and September 2015. Among those who switched from brand to generic, the cumulative incidence of switching back was close to 20% at 2 years. Switchback rates were higher for the first available generic products. This developed tool was able to elucidate novel utilization and switching patterns in two case studies. Such information can be used to support surveillance of generic drugs and biosimilars.

AmBisome® is a liposomal formulation of amphotericin B (Amp B), a complex parenteral antifungal product with no US FDA approved generic version available to date. For generic Amp B liposomal product development, examination of the drug release profile is important for product quality control and analytical comparability evaluation with the reference listed drug. Yet, there is no standardized in vitro drug release (IVR) assay currently available for Amp B liposomes. In this study, we describe the development of a USP-4 apparatus-based IVR assay capable of discriminating liposomal Amp B formulations based on the drug release profile. The goal of the IVR assay development was to identify release media compositions and assay temperatures capable of facilitating 70–100% of drug release from AmBisome® in 24 h without Amp B precipitation or disruption of liposome structure. We found that an addition of 5% w/v of γ-cyclodextrin to the release media of 5% sucrose, 10 mM HEPES, and 0.01% NaN3 (pH = 7.4) prevented Amp B precipitation and facilitated drug release. Increased IVR assay temperature led to increased drug release rate, and 55 °C was selected as the highest temperature that induced drug release close to our target without causing product precipitation. The developed IVR assay was used to discriminate between drug release rates from AmBisome® and micellar Amp B products like Fungizone® and Fungcosome. The IVR assay was also capable of discriminating between Amp B liposomes with the same composition as AmBisome® but prepared by either extrusion or homogenization processes, both of which resulted in measurable liposomal particle size heterogeneity and Amp B concentration differences. Finally, the USP-4 IVR assay was used to compare Amp B release profiles between AmBisome® and two generic products approved in India, Amphonex® (Bharat Serums and Vaccines Ltd.) (f2 = 66.3) and Phosome® (Cipla Ltd.) (f2 = 55.4). Taken together, the developed USP-4 IVR assay can be a useful tool for drug release profile characterization in generic liposomal Amp B formulation development.

The objective of this study was to evaluate physicochemical equivalence between brand (i.e., Ferrlecit) and generic sodium ferric gluconate (SFG) in sucrose injection by conducting a series of comparative in vitro characterizations using advanced analytical techniques. The elemental iron and carbon content, thermal properties, viscosity, particle size, zeta potential, sedimentation coefficient, and molecular weight were determined. There was no noticeable difference between brand and generic SFG in sucrose injection for the above physical parameters evaluated, except for the sedimentation coefficient determined by sedimentation velocity analytical ultracentrifugation (SV-AUC) and molecular weight by asymmetric field flow fractionation-multi-angle light scattering (AFFF-MALS). In addition, brand and generic SFG complex products showed comparable molecular weight distributions when determined by gel permeation chromatography (GPC). The observed minor differences between brand and generic SFG, such as sedimentation coefficient, do not impact their biological activities in separate studies of in vitro cellular uptake and rat biodistribution. Coupled with the ongoing clinical study comparing the labile iron level in healthy volunteers, the FDA-funded post-market studies intended to illustrate comprehensive surveillance efforts ensuring safety and efficacy profiles of generic SFG complex in sucrose injection, and also to shed new light on the approval standards on generic parenteral iron colloidal products.

Head and neck cancer is the fifth most common type of cancer worldwide and remains challenging for effective treatment due to the proximity to critical anatomical structures in the head and neck region, which increases the probability of toxicity from surgery and radiotherapy, and therefore emphasizes the importance of maximizing the targeted ablation. We have assessed the effectiveness of porphysome nanoparticles to enhance fluorescence and photoacoustic imaging of head and neck tumors in rabbit and hamster models. In addition, we evaluated the effectiveness of this agent for localized photothermal ablative therapy of head and neck tumors. We have demonstrated that porphysomes not only enabled fluorescence and photoacoustic imaging of buccal and tongue carcinomas, but also allowed for complete targeted ablation of these tumors. The supremacy of porphysome-enabled photothermal therapy over surgery to completely eradicate primary tumors and metastatic regional lymph node while sparing the adjacent critical structures' function has been demonstrated for the first time. This study represents a novel breakthrough that has the potential to revolutionize our approach to tumor diagnosis and treatment in head and neck cancer and beyond.

Purpose Currently, the FDA allows biowaivers for Class I (high solubility and high permeability) and Class III (high solubility and low permeability) compounds of the Biopharmaceutics Classification System (BCS). Scientific evidence should be provided to support biowaivers for BCS Class I and Class III (high solubility and low permeability) compounds. Methods Data on the effects of excipients on drug permeability are needed to demonstrate that commonly used excipients do not affect the permeability of BCS Class III compounds, which would support the application of biowaivers to Class III compounds. This study was designed to generate such data by assessing the permeability of four BCS Class III compounds and one Class I compound in the presence and absence of five commonly used excipients. Results The permeability of each of the compounds was assessed, at three to five concentrations, with each excipient in two different models: Caco-2 cell monolayers, and in situ rat intestinal perfusion. No substantial increases in the permeability of any of the compounds were observed in the presence of any of the tested excipients in either of the models, with the exception of disruption of Caco-2 cell monolayer integrity by sodium lauryl sulfate at 0.1 mg/ml and higher. Conclusion The results suggest that the absorption of these four BCS Class III compounds would not be greatly affected by the tested excipients. This may have implications in supporting biowaivers for BCS Class III compounds in general.

• Release of levetiracetam from extended-release tablets that appear intact in patient stool.

We previously concluded that 12 common excipients need not be qualitatively the same and quantitatively very similar to reference for Biopharmaceutics Classification System-based biowaivers. This conclusion for regulatory relief is based upon a series of bioequivalence studies in humans involving cimetidine and acyclovir. Limitations were also discussed. We understand the major concern of García-Arieta et al. is that "results obtained by Vaithianathan et al. should not be extrapolated to other drugs." We understand that individuals conducting their own risk/benefit analysis may reach that conclusion, and we reply to the concerns of García-Arieta et al. We continue to conclude that the 12 common excipients need not be qualitatively the same nor quantitatively very similar to reference, but rather, simply be not more than the quantities studied in our manuscript for cimetidine and acyclovir, and potentially other class 3 drugs with similar properties.

Iron deficiency anemia is a common clinical consequence for people who suffer from chronic kidney disease, especially those requiring dialysis. Intravenous (IV) iron therapy is a widely accepted safe and efficacious treatment for iron deficiency anemia. Numerous IV iron drugs have been approved by U.S. Food and Drug Administration (FDA), including a single generic product, sodium ferric gluconate complex in sucrose. In this study, we compared the cellular iron uptake profiles of the brand (Ferrlecit®) and generic sodium ferric gluconate (SFG) products. We used a colorimetric assay to examine the amount of iron uptake by three human macrophage cell lines. This is the first published study to provide a parallel evaluation of the cellular uptake of a brand and a generic IV iron drug in a mononuclear phagocyte system. The results showed no difference in iron uptake across all cell lines, tested doses, and time points. The matching iron uptake profiles of Ferrlecit® and its generic product support the FDA’s present position detailed in the draft guidance on development of SFG complex products that bioequivalence can be based on qualitative (Q1) and quantitative (Q2) formulation sameness, similar physiochemical characterization, and pharmacokinetic bioequivalence studies.

Background: Social media offer a novel avenue to engage with and recruit research participants. Facebook in particular is a promising option given its popularity and widespread use. Objective: To explore the feasibility of using Facebook to recruit physicians and patients to participate in a survey to assess their perceptions about generic venlafaxine extended release (ER) tablet indicated for depression. Methods: Web-based surveys were developed to gauge physicians’ prescribing experiences with and patients’ perceptions of generic venlafaxine ER tablet. The surveys included questions specific to venlafaxine ER tablets, such as perceived safety and efficacy of the drug and overall comfort level with either prescribing or taking the drug. Survey links were then posted and advertised on Facebook to recruit physicians and patients. Results: Advertisement for physicians reached 1898 Facebook users and advertisement for patients reached 1144 users during a 10-day advertising period. However, only 14 and 35 users clicked on the survey for physicians and patients, respectively. No physician completed the physician survey while 3 patients completed the patient survey. Conclusions: The findings of this study suggest that Facebook may not be an effective method to recruit physicians. Facebook holds promise to recruit patients, but additional recruitment efforts, such as incentives, are needed.

Intravenous (IV) iron formulations are complex colloidal suspensions of iron oxide nanoparticles. Small changes in formulation can allow more labile iron to be released after injection causing toxicity. Thus, bioequivalence (BE) evaluation of generic IV iron formulations remains challenging. We evaluated labile iron release in vitro and in vivo using a high performance liquid chromatography chelatable iron assay to develop a relational model to support BE. In vitro labile iron release and in vivo labile iron pharmacokinetics were evaluated for Venofer®, Ferrlecit®, generic sodium ferric gluconate complex, InFeD®, Feraheme® and a pre-clinical formulation GE121333. Labile iron release profiles were studied in vitro in 150mM saline and a biorelevant matrix (rat serum) at 0.952 mgFe/mL. In vivo plasma labile iron concentration-time profiles (t0-240 min) were studied in rats after a 40 mgFe/kg IV dose. In vitro labile iron release in saline was significantly higher compared to rat serum, especially with InFeD®. An in vitro release constant (iKr) was calculated which correlated well with maximal plasma concentrations in the in vivo rat PK model (R(2) = 0.711). These data suggest an in vitro to in vivo correlation model of labile iron release kinetics could be applied to BE. Other generic IV iron formulations need to be studied to validate this model.

Background Although the generic drug approval process has a long-term successful track record, concerns remain for approval of narrow therapeutic index generic immunosuppressants, such as tacrolimus, in transplant recipients. Several professional transplant societies and publications have generated skepticism of the generic approval process. Three major areas of concern are that the pharmacokinetic properties of generic products and the innovator (that is, “brand”) product in healthy volunteers may not reflect those in transplant recipients, bioequivalence between generic and innovator may not ensure bioequivalence between generics, and high-risk patients may have specific bioequivalence concerns. Such concerns have been fueled by anecdotal observations and retrospective and uncontrolled published studies, while well-designed, controlled prospective studies testing the validity of the regulatory bioequivalence testing approach for narrow therapeutic index immunosuppressants in transplant recipients have been lacking. Thus, the present study prospectively assesses bioequivalence between innovator tacrolimus and 2 generics in individuals with a kidney or liver transplant. Methods and findings From December 2013 through October 2014, a prospective, replicate dosing, partially blinded, randomized, 3-treatment, 6-period crossover bioequivalence study was conducted at the University of Cincinnati in individuals with a kidney (n = 35) or liver transplant (n = 36). Abbreviated New Drug Applications (ANDA) data that included manufacturing and healthy individual pharmacokinetic data for all generics were evaluated to select the 2 most disparate generics from innovator, and these were named Generic Hi and Generic Lo. During the 8-week study period, pharmacokinetic studies assessed the bioequivalence of Generic Hi and Generic Lo with the Innovator tacrolimus and with each other. Bioequivalence of the major tacrolimus metabolite was also assessed. All products fell within the US Food and Drug Administration (FDA) average bioequivalence (ABE) acceptance criteria of a 90% confidence interval contained within the confidence limits of 80.00% and 125.00%. Within-subject variability was similar for the area under the curve (AUC) (range 12.11–15.81) and the concentration maximum (Cmax) (range 17.96–24.72) for all products. The within-subject variability was utilized to calculate the scaled average bioequivalence (SCABE) 90% confidence interval. The calculated SCABE 90% confidence interval was 84.65%–118.13% and 80.00%–125.00% for AUC and Cmax, respectively. The more stringent SCABE acceptance criteria were met for all product comparisons for AUC and Cmax in both individuals with a kidney transplant and those with a liver transplant. European Medicines Agency (EMA) acceptance criteria for narrow therapeutic index drugs were also met, with the only exception being in the case of Brand versus Generic Lo, in which the upper limits of the 90% confidence intervals were 111.30% (kidney) and 112.12% (liver). These were only slightly above the upper EMA acceptance criteria limit for an AUC of 111.11%. SCABE criteria were also met for the major tacrolimus metabolite 13-O-desmethyl tacrolimus for AUC, but it failed the EMA criterion. No acute rejections, no differences in renal function in all individuals, and no differences in liver function were observed in individuals with a liver transplant using the Tukey honest significant difference (HSD) test for multiple comparisons. Fifty-two percent and 65% of all individuals with a kidney or liver transplant, respectively, reported an adverse event. The Exact McNemar test for paired categorical data with adjustments for multiple comparisons was used to compare adverse event rates among the products. No statistically significant differences among any pairs of products were found for any adverse event code or for adverse events overall. Limitations of this study include that the observations were made under strictly controlled conditions that did not allow for the impact of nonadherence or feeding on the possible pharmacokinetic differences. Generic Hi and Lo were selected based upon bioequivalence data in healthy volunteers because no pharmacokinetic data in recipients were available for all products. The safety data should be interpreted in light of the small number of participants and the short observation periods. Lastly, only the 1 mg tacrolimus strength was utilized in this study. Conclusions Using an innovative, controlled bioequivalence study design, we observed equivalence between tacrolimus innovator and 2 generic products as well as between 2 generic products in individuals after kidney or liver transplantation following current FDA bioequivalence metrics. These results support the position that bioequivalence for the narrow therapeutic index drug tacrolimus translates from healthy volunteers to individuals receiving a kidney or liver transplant and provides evidence that generic products that are bioequivalent with the innovator product are also bioequivalent to each other. Trial registration ClinicalTrials.gov NCT01889758., In a randomized 3-treatment crossover clinical trial, Rita Alloway of the University of Cincinnati and colleagues establish bioequivalence between 3 versions of the drug tracolimus (a brand name and 2 disparate generics) in kidney and liver transplant recipients., Author summary Why was this study done? Consensus documents developed by professional transplantation societies worldwide have cautioned the use of generic immunosuppressants such as tacrolimus in individuals with a solid organ transplant. Reasons have included repeated switching between innovator (that is, “brand” products) and generics and among different generics, especially when not controlled by physicians. There was uncertainty in the transplant community as to whether tacrolimus generics that are bioequivalent to the innovator are also bioequivalent to each other. For market approval, generic drug products of the narrow therapeutic index drug tacrolimus had to be studied only in healthy individuals and not in the much more complex organ transplant population. What did the researchers do and find? We performed a randomized, prospective, 3-treatment, 6-period, crossover, replicate dose study in individuals with a kidney or liver transplant. Thirty-five individuals with a kidney transplant and 36 individuals with a liver transplant receiving tacrolimus were studied to compare the tacrolimus time concentration profiles of 3 different products in their blood: namely, Innovator (Prograf), Generic Hi (Sandoz), and Generic Lo (Dr. Reddy) 1.0 mg tacrolimus capsules. Generic products were selected based upon pharmacokinetic data from healthy volunteer studies since bioequivalence data were not available in individuals with an organ transplant. We observed bioequivalence based on average bioequivalence and scaled average bioequivalence criteria in individuals after kidney or liver transplant between tacrolimus innovator and the 2 generics on the US market as well as between the 2 generics. What do these findings mean? Similar tacrolimus exposure is expected in individuals with a kidney or liver transplant when receiving Prograf, Sandoz generic, or Dr. Reddy’s generic tacrolimus.

This review summarizes the current FDA practice in developing risk- and evidence-based product-specific bioequivalence guidances for antiepileptic drugs (AEDs). FDA’s product-specific guidance (PSG) for AEDs takes into account the therapeutic index of each AED product. Several PSGs for AEDs recommend fully replicated studies and a reference-scaled average bioequivalence (RS-ABE) approach that permit the simultaneous equivalence comparison of the mean and within-subject variability of the test and reference products. The PSGs for AEDs published by FDA reflect the agency’s current thinking on the bioequivalence studies and approval standards for generics of AEDs. Bioequivalence between brand and generic AED products demonstrated in controlled studies with epilepsy patients provides strong scientific support for the soundness of FDA bioequivalence standards.

Importance Switching between generic antiepileptic drugs is a highly debated issue that affects both clinical care and overall health care costs. Objective To evaluate the single-dose pharmacokinetic bioequivalence of 3 (1 branded and 2 generic drugs) on-market, immediate-release lamotrigine drug products. Design, Setting, and Participants The Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy (EQUIGEN) single-dose study is a crossover, prospective, sequence-randomized, replicate pharmacokinetic study conducted at 5 US academic epilepsy centers. Fifty adults (≥18 years) with epilepsy who were taking concomitant antiepileptic drugs and not currently receiving lamotrigine were enrolled between July 18, 2013, and January 19, 2015. Every participant was randomly assigned to 1 of 3 equivalent sequences, each comprising 6 study periods, during which they had blood draws before and after medication administration. Forty-nine participants were included in intention-to-treat analyses. Interventions Participants received a single 25-mg dose of immediate-release lamotrigine at the start of each period, with the branded and the 2 most disparate generic products each studied twice. Lamotrigine was selected as the antiepileptic drug of interest because of its wide use, publications indicating problems with generic switches, and complaints to the US Food and Drug Administration regarding generic products. Both participants and study personnel were blinded to the specific generic products selected. Main Outcomes and Measures The primary outcome was bioequivalence between products. Maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC) were compared, and average bioequivalence (ABE) was established if the 90% CIs of the ratios of the 2 products were within equivalence limits (80%-125%). Results Of the 50 randomized participants, 49 (98%) received all 3 lamotrigine products and completed at least 3 pharmacokinetic assessments and 46 (92%) completed all 6 pharmacokinetic assessments. Among the 49 participants, 28 (57%) were men and 21 (43%) were women, 42 (86%) self-identified as white, and 46 (16) years was the mean (SD) age. The 3 drug products were considered bioequivalent because the 90% CIs were within equivalence limits (lowest and highest CI limits for Cmax, 92.6% and 110.4%; for AUC 0-96 , 96.9% and 101.9%). Replicate testing demonstrated no significant differences in within-subject variability across the 3 products (likelihood ratios, χ 2 2 for log-transformed variables: AUC 0-96 , 2.58; Cmax, 0.64; and AUC 0-∞ , 4.05; P ≥ .13) and that the 3 products were also bioequivalent according to scaled ABE and individual bioequivalence criteria with no subject × formulation interaction (Cmax, 0.00; AUC 0-96 , 0.54; and AUC 0-∞ , 0.36; P ≥ .76). Conclusions and Relevance This study provides evidence that the disparate lamotrigine products studied are bioequivalent when tested in people with epilepsy taking concomitant antiepileptic drugs. Trial Registration clinicaltrials.gov Identifier:NCT01733394

Small changes in bioavailability of narrow therapeutic index (NTI) drugs can alter clinical outcomes, raising concern over generic NTI substitution. We surveyed pharmacists to identify their perceptions of generic NTI drugs, their frequency of performing generic NTI substitution, and predictors of this behavior. Of 710 respondents (33% response rate), 87% perceived generic NTI drugs as effective as their brand-name versions and 94% as safe. Whereas 82% almost always performed generic NTI substitution for initial prescriptions, only 60% did for refills. Pharmacists in non-chain settings (odds ratio (OR) = 2.37; 95% confidence interval (CI) = 1.40-4.02), in practice longer (per year OR = 1.04; 95% CI = 1.02-1.06), in states with affirmative patient consent laws (OR = 1.88; 95% CI = 1.06-3.32), and in states with NTI-specific substitution requirements (OR = 1.95; 95% CI = 1.16-3.26) were more likely not to substitute initial prescriptions. Education of non-chain and veteran pharmacists and elimination of affirmative patient consent and NTI-specific substitution requirements could increase generic NTI substitution.

The Nanotechnology Risk Assessment Working Group in the Center for Drug Evaluation and Research (CDER) within the United States Food and Drug Administration (FDA) was established to assess the potential impact of nanotechnology on drug products. One of the working group’s major initiatives has been to conduct a comprehensive risk management exercise regarding the potential impact of nanomaterial pharmaceutical ingredients and excipients on drug product quality, safety, and efficacy. This exercise concluded that current review practices and regulatory guidance are capable of detecting and managing the potential risks to quality, safety, and efficacy when a drug product incorporates a nanomaterial. However, three risk management areas were identified for continued focus during the review of drug products containing nanomaterials: (1) the understanding of how to perform the characterization of nanomaterial properties and the analytical methods used for this characterization, (2) the adequacy of in vitro tests to evaluate drug product performance for drug products containing nanomaterials, and (3) the understanding of properties arising from nanomaterials that may result in different toxicity and biodistribution profiles for drug products containing nanomaterials. CDER continues to actively track the incorporation of nanomaterials in drug products and the methodologies used to characterize them, in order to continuously improve the readiness of our science- and risk-based review approaches. In parallel to the risk management exercise, CDER has also been supporting regulatory research in the area of nanotechnology, specifically focused on characterization, safety, and equivalence (between reference and new product) considerations. This article provides a comprehensive summary of regulatory and research efforts supported by CDER in the area of drug products containing nanomaterials and other activities supporting the development of this emerging technology.

Conventional quantitation of drug content in the liposome formulation involves the breakdown of bulk liposomes, which ignores details on the distribution of the active pharmaceutical ingredient (API) and excipients in liposomes of different sizes. The objective of this study is to develop an analytical method which can separate the liposomes into different sizes and obtain information of the drug and excipient distribution in the different sized liposomes. We developed an asymmetric flow field-flow fractionation (AF4) method for size-based separation of AmBisome, an amphotericin B liposomal formulation, and a high-performance liquid chromatography ultraviolet-visible and charged aerosol detection (HPLC-UV-CAD) method for simultaneous quantitation of the API (Amphotericin B) and the lipid excipients [1,2-Distearoyl-sn-glycero-3-phosphoglycerol (DSPG), hydrogenated soy phosphatidylcholine (HSPC), and cholesterol]. The measured drug content in the bulk liposome formulation was consistent with the drug product labeling. Liposomes were separated using AF4 into eleven size fractions and the liposomes particles sizes of each fraction were measured with nanoparticle tracking analysis. The drug to total lipid ratios in fractionated liposomes increased from 0.1 to 0.45 when the liposome size increased from 75 nm to 124 nm, while the lipid composition remained constant throughout the fractioned size range (cholesterol:DSPG, 0.7 and HSPC:DSPG, 0.3). These study results suggest that, for liposomal formulations of Amphotericin B in liposomes, the drug to lipid ratio increases with the size of the liposomes. This new analytical method provided a more in-depth characterization of liposomes, i.e., determining drug and excipient distributions in different sizes of liposomes, in a more efficient manner with more specific size-based composition information.

In the past few decades, the development of medicine at the nanoscale has been applied to oral and parenteral dosage forms in a wide range of therapeutic areas to enhance drug delivery and reduce toxicity. An obvious response to these benefits is reflected in higher market shares of complex drug products containing nanomaterials than that of conventional formulations containing the same active ingredient. The surging market interest has encouraged the pharmaceutical industry to develop cost-effective generic versions of complex drug products based on nanotechnology when the associated patent and exclusivity on the reference products have expired. Due to their complex nature, nanotechnology-based drugs present unique challenges in determining equivalence standards between generic and innovator products. This manuscript attempts to provide the scientific rationales and regulatory considerations of key equivalence standards (e.g., in vivo studies and in vitro physicochemical characterization) for oral drugs containing nanomaterials, iron-carbohydrate complexes, liposomes, protein-bound drugs, nanotube-forming drugs, and nano emulsions. It also presents active research studies in bridging regulatory and scientific gaps for establishing equivalence of complex products containing nanomaterials. We hope that open communication among industry, academia, and regulatory agencies will accelerate the development and approval processes of generic complex products based on nanotechnology.

Orally administered medications in extended-release (ER) dosage forms continue to play a pivotal role in the treatment of various central nervous system disorders. For certain ER dosage forms, pharmaceutical scientists have been familiar with the passage of intact tablet-like objects in patients’ feces after administration of ER tablets or capsules based on water-insoluble or slowly dissolving excipients. Nevertheless, because of lack of awareness of the “ghost pill” phenomenon, anxiety has ensued among some patients and clinicians, who have less understanding of how drugs are released from these tablets once ingested. It has been brought to the attention of the US Food and Drug Administration (FDA) that epilepsy patients administered with Teva’s levetiracetam ER tablets have noticed intact tablets in their stools and been concerned that they were not getting the needed dose of the drug. In response to neurologists’ clinical reporting, the FDA has conducted investigations to confirm a minimal risk of incomplete drug release of Teva’s drug product. The objective of this study was to evaluate the risks of incomplete drug release associated with the passing of intact levetiracetam ER tablets, by conducting in vitro dissolution testing. Dissolution testing of Teva’s drug product was performed in accordance with the US Pharmacopeia monograph for levetiracetam ER tablets in phosphate buffer and bio-relevant buffers at different pH values. In addition, dissolution testing was conducted with split and crushed tablets. At the end of the dissolution testing, all samples were visually inspected for any undissolved pieces. Approximately 90 % of levetiracetam had been released in all dissolution media after 8 h of dissolution. The levetiracetam ER tablets after dissolution testing remained fully intact in all dissolution media. The rates of drug release were significantly faster from split and crushed tablets than that from whole tablets. On the basis of these findings, Teva’s levetiracetam ER tablets may appear intact in the stools but have released the drug successfully. The FDA has requested Teva to revise its product labeling to include remarks regarding the potential passing of intact tablets. Since patients who notice ghost pills in their stools may impetuously crush or split the tablets of subsequent doses on their own, healthcare providers should instruct patients to swallow whole tablets throughout the treatment, in accordance with the drug label.

Summary Background Patients and clinicians share concerns that generic drug substitution might lead to loss of efficacy or emergence of adverse events. In this trial, we assessed US Food and Drug Administration (FDA) bioequivalence standards by studying the effects of switching between two disparate generic immediate-release lamotrigine products in patients with epilepsy. Methods The Equivalence among Generic Antiepileptic Drugs (EQUIGEN) chronic-dose study was a randomised, double-blind, crossover study that enrolled adults (aged ≥18 years) with epilepsy from six epilepsy centres at academic institutions across the USA who were receiving immediate-release lamotrigine dosed at 100 mg, 200 mg, 300 mg, or 400 mg twice daily. Eligible patients were randomly allocated (1:1) to one of two treatment sequences (sequence 1 or sequence 2), comprising four study periods of 14 days each. During each 14-day treatment period, patients received balanced doses of an oral generic lamotrigine product every 12 h (200–800 mg total, identical to lamotrigine dose prior to study enrolment); after each 14-day period, patients were crossed over to receive the other generic product. Computer-based randomisation was done using random permuted blocks of size two or four for each site to prevent sequence predictability. Both patients and study personnel were masked to the generic products selected, their predicted exposure (ie, "high" vs "low"), and their group allocation. The primary outcome of this trial was bioequivalence between the generic products, which was assessed at the end of the study through a comparison of maximum plasma concentration (C max ) and area under the concentration–time curve (AUC) for each product in the analysis population (all patients who completed all four treatment periods). Bioequivalence was established if the 90% CIs of the ratios of these two parameters for the two products were within equivalence limits (80–125%) in the analysis population. This study is registered with ClinicalTrials.gov\, number NCT01713777. Findings Between April 25, 2013, and Aug 12, 2014, 35 eligible patients were enrolled and randomly assigned to treatment sequence 1 (n=15) or treatment sequence 2 (n=20). 33 patients completed all four treatment periods and were included in the primary outcome analysis. The 90% CIs of the ratios of both C max and AUC were within equivalence limits (AUC 90% CI 98–103, C max 90% CI 99–105), showing that lamotrigine exposures were equivalent between the generic products. No significant changes in seizure frequency or adverse events were recorded. No deaths, study-related serious adverse events, or changes in clinical laboratory values or vital signs occurred during this study. Interpretation Disparate generic lamotrigine products in patients with epilepsy showed bioequivalence with no detectable difference in clinical effects, confirming that US Food and Drug Administration bioequivalence standards are appropriate. Funding American Epilepsy Society, Epilepsy Foundation, and US Food and Drug Administration.

Doxil® is a complex parenteral doxorubicin (DOX) liposome formulation approved by the FDA. For generic doxorubicin liposomes, analyzing the release profile of DOX is important for quality control and comparability studies. However, there is no robust standard drug release assay available for doxorubicin liposomes. In this study, we describe a USP-4 apparatus assay capable of discriminating DOX liposomal formulations based on release profile. Establishment of the assay was hindered by limited DOX release from liposomes in physiological conditions at 37°C. The addition of NH4HCO3 to the release media facilitated DOX release proportionally to the salt concentration added but caused precipitation of released drug in USP-4 apparatus. Precipitation of DOX was avoided by adding hydroxypropyl-cyclodextrin (HP-CD) to the release medium. We optimized conditions for DOX release by varying a number of parameters such as: concentration of HP-CD, testing temperature, and concentration of tested samples. The optimized release medium contained: 100 mM NH4HCO3, 75 mM 2-(N-morpholino) ethanesulfonic acid (MES) and 5% w/v HP-CD, 5% w/v sucrose, 0.02% w/v NaN3 (pH 6). The drug release assay was performed at 45°C. The optimized release assay can discriminate between DOX liposomal formulations of different compositions, physicochemical properties, and prepared by different manufacturing methods. This indicates that the assay could be used to compare DOX release from generic DOX formulations to the innovator product Doxil®.

The development of curative glioblastoma treatments and tumour-specific contrast agents that can overcome the blood-brain barrier (BBB) and infiltrative tumour morphology remains a challenge. Apolipoprotein E3 (apoE3) is a high density lipoprotein apolipoprotein that chaperones the transcytosis of nanoparticles across the BBB, and displays high-affinity binding with the low density lipoprotein receptor (LDLR), a cell-surface receptor overexpressed by glioblastoma cells. This LDLR overexpression and apoE3 binding capacity was exploited for the development of glioblastoma-targeted porphyrin-lipid apoE3 lipid nanoparticles (pyE-LNs) with intrinsic theranostic properties. Size-controlled discoidal and cholesteryl oleate (CO)-loaded spherical pyE-LNs were synthesized through the systematic variation of particle composition, which dictated nanoparticle size and morphology. Composition optimization yielded 30 nm pyE-LNs with stable loading of apoE3 and porphyrin-lipid that simultaneously conferred the nanoparticles with glioblastoma targeting and activatable near-infrared fluorescence imaging functionalities. A 4-fold higher uptake of pyE-LNs by LDLR-expressing U87 glioblastomas cells relative to minimally expressing ldlA7 cells was observed