Office Of Generic Drugs Research Articles

Evaluation of Physico-Chemical Properties Influence on Drug Product in vitro Profiles and Solubility Profile of Fourth Generation Antibacterial Drug

Moxifloxacin hydrochloride drug substance used to treat bacterial infections in many different parts of the body and most widely used worldwide. In this study, various high-end physico-chemical techniques are used like PXRD, DSC, TGA, BET SSA and PSD analysis to check the relative differences on the product behaviour. The present work reports an impact of alteration in particle size due to compaction process where increase in particle size has been observed from 15.912 μm to 751.001 μm, decrease in specific surface area from 1.89 m2/g to 0.861 m2/g, decrease in crystallinity from 91.65% to 59.15% and impact of dehydration or loss of water from 3.776% to 1.866%, which were observed during study. All the alterations in the physico-chemical properties impacting the drug manufacturing process and on the bioperformance of the finished product. This research attempt aims to investigate the effects of these modifications on in vitro experiments conducted in the office of generic drugs (OGD) media and the equilibrium solubility profile. The in vitro studies resulted about 35% release difference observed in the initial time points, whereas solubility in water observed about 17 mg/mL difference. This research work helps to demonstrate the optimization of finished product development process to meet the biofriendly formulation.

Increasing impact of quantitative methods and modeling in establishment of bioequivalence and characterization of drug delivery.

Increasing impact of quantitative methods and modeling in establishment of bioequivalence and characterization of drug delivery.

Development of bio-relevant dissolution method for prognosis of In-vivo performance of Dipyridamole from modified release capsules

In-vitro biorelevant dissolution test method was developed for Dipyridamole in modified release multi-particulate dosage form, to simulate the product drug release after oral administration to human. The Dipyridamole concentration in blood plasma achieved after oral administration under pre-prandial (fasting) condition were used for deriving the target dissolution profile deconvoluting the plasma concentration using numerical deconvolution technique. The fraction of drug absorbed was considered as the target dissolution profile. The drug product was tested by using the dissolution method recommended by office of generic drugs, and the dissolution results observed are not comparable with the target dissolution profile. Dissolution method was developed using reciprocating cylinder, Bio-Dis (apparatus -3 as per USP), by simulating the pre-prandial conditions. A full factorial design of experiment was carried out to achieve the target dissolution profile. Media volume and dips per minute (DPM) are considered as main factors, in design of experiment. The dissolution results achieved with media volume 250ml and 10DPM were found to be comparable with target dissolution profile and observed with the F2 value (similarity factor) of 92%. The developed dissolution method demonstrates a very good in-vitro/in-vivo correlation under pre-prandial condition, and shall be used as a predictive in-vitro tool for evaluation Dipyridamole extended release capsules.

An Integrated Bioinformatics and Quantitative Modeling Approach to Investigate Potential Claims of Oral Generic Drug Product Bioinequivalence: Introduction.

An Integrated Bioinformatics and Quantitative Modeling Approach to Investigate Potential Claims of Oral Generic Drug Product Bioinequivalence: Introduction.

In vitro Approaches to Support Bioequivalence and Substitutability of Generic Proton Pump Inhibitors via Nasogastric Tube Administration

Administration of proton pump inhibitors (PPIs) through nasogastric tubes may present risks. If the PPI drug products are not prepared properly, clogging or obstruction of nasogastric tubes can pose a safety concern. In addition, the integrity of the enteric coating of the drug product may be damaged resulting in reduced bioavailability of the active moiety. From the perspective of administration of generic PPIs when compared to the reference drug product, differences in formulation can potentially result in a greater relative risk for the generic drug product. As part of the assessment of bioequivalence, the Office of Generic Drugs (OGD) has developed a suite of in vitro testing to compare the delivery of the generic and reference products via nasogastric tubes. These in vitro tests assess essential attributes associated with the likelihood of clogging and maintenance of the enteric coating. These in vitro tests include studies evaluating sedimentation, granule size distribution, drug recovery, and acid resistance. One of the challenges is that while the administration of PPIs through nasogastric tubes is common in clinical practice, this issue is not uniformly addressed in the FDA approved label of the reference drug products. This paper discusses the design and rationale for in vitro testing of PPI formulations with respect to bioequivalence via nasogastric tube administration and in addition, it summarizes commonly occurring deficiencies in the in vitro nasogastric tube testing of 14 recent Abbreviated New Drug Applications (ANDA) submitted for five generic PPI drug products.

Pharmacokinetic studies for proving bioequivalence of orally inhaled drug products-critical issues and concepts.

OPINION article Front. Pharmacol., 03 June 2015Sec. Experimental Pharmacology and Drug Discovery https://doi.org/10.3389/fphar.2015.00117

Modeling and simulation of biopharmaceutical performance.

Biopharmaceutical performance refers to the influence of pharmaceutical formulation variables on in vivo performance. New drug product success depends on formulation design for sufficient bioavailability for clinically desired dosing. Regulatory interest in biopharmaceutical performance includes batch-to-batch consistency, acceptability of postapproval changes, and evaluation of bioequivalence (BE) for generic drug products. This Commentary summarizes biopharmaceutical modeling and simulation in the US Food and Drug Administration (FDA) Office of Generic Drugs (OGD) for orally administered generic drugs.

Establishment and Significance of Bioequivalence Recommendations for Individual Products-Drugs Acting on Circulatory System and Others

Along with the enactment of a law separating the prescribing and dispensing of drugs in Korea in 2000, attempts at reducing medical expenses by generic substitution have been allowed since August 2001 so long as generic products are bioequivalent to the original products. In the pharmaceutical industry, the required development and investment to make generic products are much less in terms of time and money. Thus, the number of bioequivalence studies in Korea has increased. This has resulted in the need for bioequivalence recommendations (guidelines), taking into account the circumstances of the Korean pharmaceutical industry. In this paper, we provide procedures for making bioequivalence determinations for individual products acting on the circulatory system (30 drugs, 2011), the components of which are widely accepted for the development of generic products in Korea. These recommendations correspond with international guidelines, such as those of the US FDA and EMEA. For the 30 drugs that act on the circulatory system, we examined each in terms of subject selection (healthy volunteers vs. patients), dosage strength, dosage route, analytes to measure, and evaluation parameters, and prepared bioequivalence recommendations for individual products through an analysis of many published papers, US FDA and EMEA guidelines, and clinical trial websites. Based on the bioequivalence recommendations for individual products, we had several meetings in which KFDA officers (members of the New Drug Research team and the Office of Generic Drugs), three pharmacy professors with expertise in drug analysis and pharmacokinetics, and three professors of medicine with extensive experience in clinical trials participated to confirm and discuss the contents. Finally, the bioequivalence recommendations for individual products were provided on the KFDA website. The individual bioequivalence recommendations have been used by KFDA officers in drug evaluations and bioequivalency testing to improve consistency, clarity, and professionalism in the drug evaluation process. These recommendations will be useful for domestic pharmaceutical companies by shortening the time and cost associated with bioequivalence studies, especially in terms of standardized trial designs, dosage forms, and analytical methods.

Use of Partial Area under the Curve Metrics to Assess Bioequivalence of Methylphenidate Multiphasic Modified Release Formulations

Use of Partial Area under the Curve Metrics to Assess Bioequivalence of Methylphenidate Multiphasic Modified Release Formulations

Pharmaceutical Equivalence by Design for Generic Drugs: Modified-Release Products

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

Variability and Impact on Design of Bioequivalence Studies

In 2008, the European Agency for the Evaluation of Medicinal Products released a draft guidance on the investigation of bioequivalence for immediate release dosage forms with systemic action to replace the former guidance of a decade ago. Revisions of the regulatory guidance are based upon many questions over the past years and sometimes continuing scientific discussions on the use of the most suitable statistical analysis methods and study designs, particularly for drugs and drug products with high within-subject variability. Although high within-subject variability is usually associated with a coefficient of variation of 30% or more, new approaches are available in the literature to allow a gradual increase and a levelling off of the bioequivalence limits to some maximum wider values (e.g. 75-133%), dependent on the increase in the within-subject variability. The two-way, cross-over single dose study measuring parent drug is still the design of first choice. A partial replicate design with repeating the reference product and scaling the bioequivalence for the reference variability are proposed for drugs with high within-subject variability. In case of high variability, more regulatory authorities may accept a two-stage or group-sequential bioequivalence design using appropriately adjusted statistical analysis. This review also considers the mechanisms why drugs and drug products may exhibit large variability. The physiological complexity of the gastrointestinal tract and the interaction with the physicochemical properties of drug substances may contribute to the variation in plasma drug concentration-time profiles of drugs and drug products and to variability between and within subjects. A review of submitted bioequivalence studies at the Food and Drug Administration's Office of Generic Drugs over the period 2003-2005 indicated that extensive pre-systemic metabolism of the drug substance was the most important explanation for consistently high variability drugs, rather than a formulation factor. These scientific efforts are expected to further lead to revisions of earlier regulatory guidance in other regions as is the current situation in Europe.

Highly Variable Drugs: Observations from Bioequivalence Data Submitted to the FDA for New Generic Drug Applications

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. 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 C (max) and/or AUC was > or =0.3. To identify factors contributing to high variability, we evaluated drug substance pharmacokinetic characteristics and drug product dissolution performance. 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.

US FDA Question-Based Review for Generic Drugs: A New Pharmaceutical Quality Assessment System

The US Food and Drug Administration Office of Generic Drugs has developed a question-based review (QbR) for the Chemistry, Manufacturing, and Controls (CMC) evaluation of an abbreviated new drug application (ANDA). This new QbR system incorporates quality by design and implements risk-based assessment. It recommends that ANDAs be submitted using the Common Technical Document and include the Quality Overall Summary (QOS) that addresses all the QbR questions. The main benefits of this QbR system are to (1) assure product quality through design and performance-based specifications, (2) facilitate continuous improvement and reduce CMC supplements through risk assessment, (3) enhance the quality of reviews through standardised review questions, and (4) reduce CMC review time when applicants submit a QOS that addresses the QbR questions. The QbR was partially implemented in 2006 and is being fully implemented in 2007.

Physicians Question FDA's Confidence in Generic Drugs' Safety, Efficacy

Physicians Question FDA's Confidence in Generic Drugs' Safety, Efficacy

Drug Master file Review Issues at the Office of Generic Drugs

The Office of Generic Drugs (OGD) in the US Food and Drug Adminstration's (FDA) Center for Drug Evaluation and Research (CDER) has recently been receiving unprecedented numbers of abbreviated new drug applications (ANDAs); currently, more than 700 per year. Each ANDA is supported by drug master files (DMFs), which are separate proprietary documents describing the chemistry, manufacture and associated controls for the active pharmaceutical ingredients (APIs). Usually, the firm submitting the ANDA purchases the API from a fine chemicals producer who has filed a DMF with the FDA. A Letter of Authorisation (LOA) from the DMF holder allows the FDA staff to review the DMF in conjunction with review of the ANDA. An adequate DMF is one requirement for approval of an ANDA. To date, over 18,000 DMFs have been submitted to the FDA. Very few of these are found to be adequate in an initial review and, consequently, approvals of ANDAs are delayed as additional information and data are needed from the DMF holder to ensure consistent production of high-quality APIs. Illustrative examples of typical DMF deficiencies are presented in this paper and suggestions for improved DMF submissions are given.

RSD Requirement for Different Sample Size for Blend Sampling

A formula for calculating the equivalent relative standard deviation (RSD) for different sample sizes other than the Office of Generic Drugs (OGD) draft guidance was derived. These critical values vary with the population RSD and the sample size and guarantee the same confidence of passing a batch similar to the OGD blend uniformity test. Simulation results showed that the normal approximations give very close results to the simulation results. An assessment of the proposed OGD blend uniformity criteria against the first-stage USP content uniformity (CU) criteria for tablets was also made.

Albuterol MDI in Vivo Bioequivalence: FDA's Office of Generic Drugs' Dose-Response Studies

Bioequivalence studies based on pharmacodynamic response must be sensitive to differences in dose of drug. Pilot dose-response studies in asthmatic subjects were conducted under agency contract to evaluate the suitability of three study designs for use in the documentation of in vivo bioequivalence of multisource albuterol inhalation aerosols (metered dose inhalers [MDI]). Differences between study designs were observed in the ability to fit individual subject dose-response curves to an Emax model, in the estimates of ED50, and in the response to two actuations relative to one actuation of albuterol MDI. One of the three study designs appeared preferable as a basis for development of an in vivo bioequivalence guidance. Subsequent to review of study data by an advisory committee, an interim guidance based upon this study design was issued by the Division of Bioequivalence in the Food and Drug Administration's (FDA) Office of Generic Drugs in January 1994.

Bioequivalence of racemic drugs.

Although pharmacokinetic and pharmacodynamic differences between the enantiomers of a chiral drug have been known or suspected for many years, racemate drugs have frequently been developed and approved without clinical pharmacologic consideration of their chiral components. In the late 1970s, the technology to isolate, manufacture, and detect pure enantiomers of racemate drugs became generally available. This availability has created new demands on both pharmaceutical firms and regulatory agencies. To prepare for this new technology, the Center for Drug Evaluation and Research at the Food and Drug Administration is formulating a policy statement to guide evaluation of new chiral drugs. At this time, it appears that whatever new policies are developed will not necessarily be applied retroactively to previously approved racemate drugs. Additional policies to guide the development and approval of generic and OTC chiral drugs may be required. In the Office of Generic Drugs in the Center, abbreviated new drug or antibiotic applications are approved on the basis of adequate chemistry, manufacturing, and control procedures and comparative pharmacokinetics (bioequivalence). The generic drug must be a racemate or single enantiomer if the corresponding innovator drug is a racemate or single enantiomer respectively. Whether a generic firm will be required to provide bioequivalence information on enantiomers of a racemate is determined on a case-by-case basis. Although it might be claimed that a generic drug product should be required only to undergo the same general kind of pharmaceutical evaluation as did the innovator, there may be instances when the approval of a generic drug or antibiotic will require measurement of specific enantiomers of a chiral drug.