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.
dermatologic product; generic; semi-solid; topical product; quality by design
attention deficit hyperactivity disorder; bioequivalence; generic drugs; methylphenidate; pAUC
Highly variable (HV) drugs are defined as those for which within-subject variability (%CV) in bioequivalence (BE) measures is 30% or greater. Because of this high variability, studies designed to show whether generic HV drugs are bioequivalent to their corresponding HV reference drugs may need to enroll large numbers of subjects even when the products have no significant mean differences. To avoid unnecessary human testing, the US Food and Drug Administration’s Office of Generic Drugs developed a reference-scaled average bioequivalence (RSABE) approach, whereby the BE acceptance limits are scaled to the variability of the reference product. For an acceptable RSABE study, an HV generic drug product must meet the scaled BE limit and a point estimate constraint. The approach has been implemented successfully. To date, the RSABE approach has supported four full approvals and one tentative approval of HV generic drug products.
bioequivalence; generic drugs; highly variable drugs; reference-scaled average bioequivalence; US Food and Drug Administration
The Biopharmaceutics Classification system (BCS) classifies drug substances based on aqueous solubility and intestinal permeability. The objective of this study was to use the World Health Organization Model List of Essential Medicines to determine the distribution of BCS Class 1, 2, 3, and 4 drugs in Abbreviated New drug Applications (ANDA) submissions. To categorize solubility and intestinal permeability properties of generic drugs under development, we used a list of 61 drugs which were classified as BCS 1, 2, 3, and 4 drugs with certainty in the World Health Organization Model List of Essential Medicines. Applying this list to evaluation of 263 ANDA approvals of BCS drugs during the period of 2000 to 2011 indicated 110 approvals (41.8%) for Class 1 drugs (based on both biowaiver and in vivo bioequivalence studies), 55 (20.9%) approvals for Class 2 drugs, 98 (37.3%) approvals for Class 3 drugs, and no (0%) approvals for Class 4 drugs. The present data indicated a trend of more ANDA approvals of BCS Class 1 drugs than Class 3 or Class 2 drugs. Antiallergic drugs in Class 1, drugs for pain relief in Class 2 and antidiabetic drugs in Class 3 have received the largest number of approvals during this period.
ANDA; BCS biowaiver; bioequivalence; Biopharmaceutics Classification System; generic drug product
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 β-sheet conformation (~12%). Circular dichroism spectropolarimetry confirmed the FTIR results with prominent minima at 206 nm observed for all five sources. Finally, proton (1H) 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 β-sheet present.
circular dichroism; differential scanning calorimetry; Fourier-transform infrared spectroscopy; nuclear magnetic resonance; peptide; protamine sulfate; thermogravimetric analysis
The development of mucosal-associated invariant T (MAIT) cells is dependent upon the class Ib molecule MHC-related protein 1 (MR1), commensal bacteria, and a thymus. Furthermore, recent studies have implicated MR1 presentation to MAIT cells in bacteria recognition, although the mechanism remains undefined. Surprisingly, however, surface expression of MR1 has been difficult to detect serologically, despite ubiquitous detection of MR1 transcripts and intracellular protein. In this article, we define a unique mAb capable of stabilizing endogenous mouse MR1 at the cell surface, resulting in enhanced mouse MAIT cell activation. Our results demonstrated that under basal conditions, endogenous MR1 transiently visits the cell surface, thus reconciling the aforementioned serologic and functional studies. Furthermore, using this approach, double-positive thymocytes, macrophages, and dendritic cells were identified as potential APCs for MAIT cell development and activation. Based on this pattern of MR1 expression, it is intriguing to speculate that constitutive expression of MR1 may be detrimental for maintenance of immune homeostasis in the gut and/or detection of pathogenic bacteria in mucosal tissues.
Quantitative estimations of first-in-human (FIH) doses are critical for phase I clinical trials in drug development. Human pharmacokinetic (PK) prediction methods have been developed to project the human clearance (CL) and bioavailability with reasonable accuracy, which facilitates estimation of a safe yet efficacious FIH dose. However, the FIH dose estimation is still very challenging and complex. The aim of this article is to review the common approaches for FIH dose estimation with an emphasis on PK-guided estimation. We discuss 5 methods for FIH dose estimation, 17 approaches for the prediction of human CL, 6 methods for the prediction of bioavailability, and 3 tools for the prediction of PK profiles. This review may serve as a practical protocol for PK- or pharmacokinetic/pharmacodynamic-guided estimation of the FIH dose.
allometric scaling; FIH dose; in vitro–in vivo correlations; pharmacokinetics; prediction
We recommend that regulatory agencies add the extent of drug metabolism (i.e., ≥90% metabolized) as an alternate method in defining Class 1 marketed drugs suitable for a waiver of in vivo studies of bioequivalence. That is, ≥90% metabolized is an additional methodology that may be substituted for ≥90% absorbed. We propose that the following criteria be used to define ≥ 90% metabolized for marketed drugs: Following a single oral dose to humans, administered at the highest dose strength, mass balance of the Phase 1 oxidative and Phase 2 conjugative drug metabolites in the urine and feces, measured either as unlabeled, radioactive labeled or nonradioactive labeled substances, account for ≥ 90% of the drug dosed. This is the strictest definition for a waiver based on metabolism. For an orally administered drug to be ≥ 90% metabolized by Phase 1 oxidative and Phase 2 conjugative processes, it is obvious that the drug must be absorbed. This proposal, which strictly conforms to the present ≥90% criteria, is a suggested modification to facilitate a number of marketed drugs being appropriately assigned to Class 1.
Regulatory approaches for evaluating therapeutic equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo bioequivalence studies and avoid unnecessary drug exposure to humans. Global harmonization for regulatory requirements may be promoted by a better understanding of factors underlying product performance and expectations from different regulatory authorities. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on current regulatory issues and industry practices, facilitating harmonization of regulatory approaches for establishing therapeutic equivalence and interchangeability of multisource drug products.
bioequivalence; harmonization; interchangeability; regulatory standards; therapeutic equivalence
In vitro dissolution testing is an important tool used for development and approval of generic dosage forms. The objective of this article is to summarize how dissolution testing is used for the approval of safe and effective generic drug products in the United States (US). Dissolution testing is routinely used for stability and quality control purposes for both oral and non-oral dosage forms. The dissolution method should be developed using an appropriate validated method depending on the dosage form. There are several ways in which dissolution testing plays a pivotal role in regulatory decision-making. It may be used to waive in vivo bioequivalence (BE) study requirements, as BE documentation for Scale Up and Post Approval Changes (SUPAC), and to predict the potential for a modified-release (MR) drug product to dose-dump if co-administered with alcoholic beverages. Thus, in vitro dissolution testing plays a major role in FDA’s efforts to reduce the regulatory burden and unnecessary human studies in generic drug development without sacrificing the quality of the drug products.
bioequivalence; biopharmaceutics; generic drugs; in vitro dissolution; quality by design
To implement Quality by Design (QbD) in drug development, scientists need tools that link drug products properties to in vivo performance. Physiologically based absorption models are potentially useful tools; yet, their utility of QbD implementation has not been discussed or explored much in the literature. We simulated pharmacokinetics (PK) of carbamazepine (CBZ) after administration of four oral formulations, immediate-release (IR) suspension, IR tablet, extended-release (XR) tablet and capsule, under fasted and fed conditions and presented a general diagram of a modeling and simulation strategy integrated with pharmaceutical development. We obtained PK parameters and absorption scale factors (ASFs) by deconvolution of the PK data for IR suspension under fasted condition. The model was validated for other PK profiles of IR formulations and used to predict PK for XR formulations. We explored three key areas where a modeling and simulation approach impacts QbD. First, the model was used to help identify optimal in vitro dissolution conditions for XR formulations. Second, identification of critical formulations variables was illustrated by a parameter sensitivity analysis of mean particle radius for the IR tablet that showed a PK shift with decreased particle radius, Cmax was increased and Tmax was decreased. Finally, virtual trial simulations allowed incorporation of inter-subject variability in the model. Virtual bioequivalence studies performed for two test formulations suggested that an in vitro dissolution test may be a more sensitive discriminative method than in vivo PK studies. In summary, a well-validated predictive model is a potentially useful tool for QbD implementation in drug development.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-010-9250-9) contains supplementary material, which is available to authorized users.
advanced compartmental absorption and transit (ACAT) model; gastroplus™; modified release (MR); quality by design (QbD)
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.
bioequivalence; generic; immunogenicity; nasal spray; pharmaceutical equivalence; salmon calcitonin
The bead sizes used in approved modified release capsules labeled for sprinkling on food was investigated to generate bead size guidelines for generic products labeled for sprinkling. The conclusions from a survey of FDA databases were corroborated with experimental data obtained by measuring the bead sizes of several reference-listed drugs on the market labeled for administration by sprinkling on food. The experimental data show that majority of the marketed products were found to have bead sizes of less than 1,500 μm (1.5 mm). Based on this information, a bead size of less than 1,500 μm should generally be considered acceptable for use in generic products labeled for sprinkling.
bead size; generic drugs; modified-release capsules; quality target product profile; sprinkle
Modified release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current industry practices and regulatory expectations for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.
bioequivalence; interchangeability; modified release; pharmaceutical equivalence; therapeutic equivalence
Dry powder inhalers (DPIs) are used to deliver locally acting drugs (e.g., bronchodilators and corticosteroids) for treatment of lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). Demonstrating bioequivalence (BE) for DPI products is challenging, primarily due to an incomplete understanding of the relevance of drug concentrations in blood or plasma to equivalence in drug delivery to the local site(s) of action. Thus, BE of these drug/device combination products is established based on an aggregate weight of evidence, which utilizes in vitro studies to demonstrate equivalence of in vitro performance, pharmacokinetic or pharmacodynamic studies to demonstrate equivalence of systemic exposure, and pharmacodynamic and clinical endpoint studies to demonstrate equivalence in local action. This review discusses key aspects of in vitro studies in supporting the establishment of BE for generic locally acting DPI products. These aspects include comparability in device resistance and equivalence in in vitro testing for single inhalation (actuation) content and aerodynamic particle size distribution.
bioequivalence (BE); dry powder inhaler (DPI); locally acting drugs; particle size distribution; single inhalation (actuation) content
Modeling and simulation of oral drug absorption have been widely used in drug discovery, development, and regulation. Predictive absorption models are used to determine the rate and extent of oral drug absorption, facilitate lead drug candidate selection, establish formulation development strategy, and support the development of regulatory policies. This review highlights the development of recent drug absorption models including dispersion and compartmental models. The compartmental models include the compartmental absorption and transit model; Grass model; gastrointestinal transit absorption model; advanced compartmental absorption and transit model; and advanced dissolution, absorption, and metabolism model. Compared to the early absorption models, the above models developed or extended since the mid-1990s have demonstrated greatly improved predictive performance by accounting for multiple factors such as drug degradation, gastric emptying, intestinal transit, first-pass metabolism, and intestinal transport. For future model development, more heterogeneous features of the gastrointestinal tract (villous blood flow, metabolizing enzymes, and transporters), food effects, and drug–drug interactions should be fully characterized and taken into consideration. Moreover, predicting population inter- and intravariability in oral drug absorption can be useful and important for the evaluation of clinical safety and efficacy of drugs. Establishing databases and libraries that contain accurate pharmaceutical and pharmacokinetic information for commercialized and uncommercialized drugs may also be helpful for model development and validation.
advanced compartmental absorption and transit (ACAT) model; advanced dissolution, absorption, and metabolism (ADAM) model; compartmental model; dispersion model; oral drug absorption
Various approaches for evaluating the bioequivalence (BE) of highly variable drugs (CV ≥ 30%) have been debated for many years. More recently, the FDA conducted research to evaluate one such approach: scaled average BE. A main objective of this study was to determine the impact of scaled average BE on study power, and compare it to the method commonly applied currently (average BE). Three-sequence, three period, two treatment partially replicated cross-over BE studies were simulated in S-Plus. Average BE criteria, using 80–125% limits on the 90% confidence intervals for Cmax and AUC geometric mean ratios, as well as scaled average BE were applied to the results. The percent of studies passing BE was determined under different conditions. Variables tested included within subject variability, point estimate constraint, and different values for σw0, which is a constant set by the regulatory agency. The simulation results demonstrated higher study power with scaled average BE, compared to average BE, as within subject variability increased. At 60% CV, study power was more than 90% for scaled average BE, compared with about 22% for average BE. A σw0 value of 0.25 appears to work best. The results of this research project suggest that scaled average BE, using a partial replicate design, is a good approach for the evaluation of BE of highly variable drugs.
bioequivalence; highly variable drugs; scaled bioequivalence; simulations
The workshop “Bioequivalence, Biopharmaceutics Classification System, and Beyond” was held May 21–23, 2007 in North Bethesda, MD, USA. This workshop provided an opportunity for pharmaceutical scientists to discuss the FDA guidance on the Biopharmaceutics Classification System (BCS), bioequivalence of oral products, and related FDA initiatives such as the FDA Critical Path Initiative. The objective of this Summary Workshop Report is to document the main points from this workshop. Key highlights of the workshop were (a) the described granting of over a dozen BCS-based biowaivers by the FDA for Class I drugs whose formulations exhibit rapid dissolution, (b) continued scientific support for biowaivers for Class III compounds whose formulations exhibit very rapid dissolution, (c) scientific support for a number of permeability methodologies to assess BCS permeability class, (d) utilization of BCS in pharmaceutical research and development, and (e) scientific progress in in vitro dissolution methods to predict dosage form performance.
bioavailability; bioequivalence; biopharmaceutics classification system (BCS); oral absorption; permeability; regulatory science; solubility
It is widely believed that acceptable bioequivalence studies of drugs with high within-subject pharmacokinetic variability must enroll higher numbers of subjects than studies of drugs with lower variability. We studied the scope of this issue within US generic drug regulatory submissions.
Materials and Methods
We collected data from all in vivo bioequivalence studies reviewed at FDA’s Office of Generic Drugs (OGD) from 2003–2005. We used the ANOVA root mean square error (RMSE) from bioequivalence statistical analyses to estimate within-subject variability. A drug was considered highly variable if its RMSE for Cmax and/or AUC was ≥0.3. To identify factors contributing to high variability, we evaluated drug substance pharmacokinetic characteristics and drug product dissolution performance.
Results and Discussion
In 2003–2005, the OGD reviewed 1,010 acceptable bioequivalence studies of 180 different drugs, of which 31% (57/180) were highly variable. Of these highly variable drugs, 51%, 10%, and 39% were either consistently, borderline, or inconsistently highly variable, respectively. We observed that most of the consistent and borderline highly variable drugs underwent extensive first pass metabolism. Drug product dissolution variability was high for about half of the inconsistently highly variable drugs. We could not identify factors causing variability for the other half. Studies of highly variable drugs generally used more subjects than studies of lower variability drugs.
About 60% of the highly variable drugs we surveyed were highly variable due to drug substance pharmacokinetic characteristics. For about 20% of the highly variable drugs, it appeared that formulation performance contributed to the high variability.
bioequivalence; generic drugs; highly variable drugs; presystemic drug metabolism; variable drug product dissolution
Q3 equivalence rheology; spreadability; topical formulations; vane method
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.
control strategy; critical material attributes; critical process parameters; design space; quality by design
We examined the activity of human T cells engineered to express variants of a single TCR (1G4) specific for the cancer/testis Ag NY-ESO-1, generated by bacteriophage display with a wide range of affinities (from 4 μM to 26 pM). CD8+ T cells expressing intermediate- and high-affinity 1G4 TCR variants bound NY-ESO-1/HLA-A2 tetramers with high avidity and Ag specificity, but increased affinity was associated with a loss of target cell specificity of the TCR gene-modified cells. T cells expressing the highest affinity TCR (KD value of 26 pM) completely lost Ag specificity. The TCRs with affinities in the midrange, KD 5 and 85 nM, showed specificity only when CD8 was absent or blocked, while the variant TCRs with affinities in the intermediate range—with KD values of 450 nM and 4 μM— demonstrated Ag-specific recognition. Although the biological activity of these two relatively low-affinity TCRs was comparable to wild-type reactivity in CD8+ T cells, introduction of these TCR dramatically increased the reactivity of CD4+ T cells to tumor cell lines.
The objective of this study was to evaluate near-infrared (NIR) spectroscopic imaging as a tool to assess a pharmaceutical quality assurance problem—blend uniformity in the final dosage product. A system based on array detector technology was used to rapidly collect high-contrast NIR images of furosemide tablets. By varying the mixing, 5 grades of experimental tablets containing the same amount of furosemide and microcrystalline cellulose were produced, ranging from well blended to unblended. For comparison, these tablets were also analyzed by traditional NIR spectroscopy, and both approaches were used to evaluate drug product homogeneity. NIR spectral imaging was capable of clearly differentiating between each grade of blending, both qualitatively and quantitatively. The spatial distribution of the components was based on the variation or contrast in pixel intensity, which is due to the NIR spectral contribution to each pixel. The chemical nature of each pixel could be identified by the localized spectrum associated with each pixel. Both univariate and partial least squares (PLS) images were evaluated. In the suboptimal blends, the regions of heterogeneity were obvious by visual inspection of the images. A quantitative measure of blending was determined by calculating the standard deviation of the distribution of pixel intensities in the PLS score images. The percent standard deviation increased progressively from 11% to 240% from well blended to unblended tablets. The NIR spectral imaging system provides a rapid approach for acquiring spatial and spectral information on pharmaceuticals. The technique has potential for a variety of applications in product quality assurance and could affect the control of manufacturing processes.
NIR imaging; chemical imaging; NIR spectroscopy; blend uniformity; quality assurance
We sought to evaluate whether U.S. Pharmacopeia (USP) apparatus 3 can be used as an alternative to USP apparatus 2 for dissolution testing of immediate-release (IR) dosage forms. Highly soluble drugs, metoprolol and ranitidine, and poorly soluble drugs, acyclovir and furosemide, were chosen as model drugs. The dissolution profiles of both innovator and generic IR products were determined using USP apparatus 2 at 50 rpm and apparatus 3 at 5, 15, and 25 dips per minute (dpm). The dissolution profiles from USP apparatus 3 were compared to those from USP apparatus 2 using the f2 similarity test. The dissolution profile from USP apparatus 3 generally depends on the agitation rate, with a faster agitation rate producing a faster dissolution rate. It was found that USP apparatus 3 at the extreme low end of the possible agitation range, such as 5 dpm, gave hydrodynamic conditions equivalent to USP apparatus 2 at 50 rpm. With appropriate agitation rate, USP apparatus 3 can produce similar dissolution profiles to USP apparatus 2 or distinguish dissolution characteristics for the IR products of metoprolol, ranitidine, and acyclovir. Incomplete dissolution was observed for the furosemide tablets using USP apparatus 3. Although it is primarily designed for the release testing of extended-release products, USP apparatus 3 may be used for the dissolution testing of IR products of highly soluble drugs, such as metoprolol and ranitidine, and some IR products of poorly soluble drugs, such as acyclovir. USP apparatus 3 offers the advantages of avoiding cone formation and mimicking the changes in physiochemical conditions and mechanical forces experienced by products in the gastrointestinal tract.
Dissolution; USP apparatus 2; USP apparatus 3; Immediate-Release; and Product