PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (41)
 

Clipboard (0)
None
Journals
Year of Publication
Document Types
1.  Micro-Flow Imaging: Flow Microscopy Applied to Sub-visible Particulate Analysis in Protein Formulations 
The AAPS Journal  2010;12(3):455-464.
ABSTRACT
The need to monitor, measure, and control sub-visible proteinaceous particulates in biopharmaceutical formulations has been emphasized in recent publications and commentaries. Some of these particulates can be highly transparent, fragile, and unstable. In addition, for much of the size range of concern, no practical measurement method with adequate sensitivity and repeatability has been available. A complication in measuring protein particulates in many formulations is the simultaneous presence of other particle types such as silicone micro-droplets, air bubbles, and extrinsic contaminants. The need has therefore been identified for new analytical methods which can accurately measure and characterize sub-visible particulates in formulations. Micro-flow imaging has been shown to provide high sensitivity in detecting and imaging transparent protein particles and a unique capability to independently analyze such populations even when other particle types are present.
doi:10.1208/s12248-010-9205-1
PMCID: PMC2895433  PMID: 20517661
light obscuration; micro-flow imaging; particle sizing; protein aggregation; protein formulation
2.  Assessment of a Spectrophotometric Assay for Monoacylglycerol Lipase Activity 
The AAPS journal  2010;12(2):197-201.
doi:10.1208/s12248-010-9180-6
PMCID: PMC2844520  PMID: 20186507
monoacylglycerol lipase; spectrophotometric assay
3.  Assessment of a Spectrophotometric Assay for Monoacylglycerol Lipase Activity 
The AAPS Journal  2010;12(2):197-201.
doi:10.1208/s12248-010-9180-6
PMCID: PMC2844520  PMID: 20186507
monoacylglycerol lipase; spectrophotometric assay
4.  Micro-Flow Imaging: Flow Microscopy Applied to Sub-visible Particulate Analysis in Protein Formulations 
The AAPS Journal  2010;12(3):455-464.
ABSTRACT
The need to monitor, measure, and control sub-visible proteinaceous particulates in biopharmaceutical formulations has been emphasized in recent publications and commentaries. Some of these particulates can be highly transparent, fragile, and unstable. In addition, for much of the size range of concern, no practical measurement method with adequate sensitivity and repeatability has been available. A complication in measuring protein particulates in many formulations is the simultaneous presence of other particle types such as silicone micro-droplets, air bubbles, and extrinsic contaminants. The need has therefore been identified for new analytical methods which can accurately measure and characterize sub-visible particulates in formulations. Micro-flow imaging has been shown to provide high sensitivity in detecting and imaging transparent protein particles and a unique capability to independently analyze such populations even when other particle types are present.
doi:10.1208/s12248-010-9205-1
PMCID: PMC2895433  PMID: 20517661
light obscuration; micro-flow imaging; particle sizing; protein aggregation; protein formulation
7.  [No title available] 
PMCID: PMC3933585  PMID: 24493374
8.  Recommendations from the Global Bioanalysis Consortium Team A8: Documentation 
The AAPS Journal  2014;16(2):240-245.
The A8 Global Harmonization Team focused on the documentation needed to support both small and large molecule bioanalysis. Current regulatory requirements were compiled and compared. The scope of the team’s discussions included the validation report, the bioanalytical report, study plans, raw data, and bioanalytical summaries for the common technical document (CTD). A common high-level table of contents for method validation and sample analysis reports is proposed. Suggestions have been made as to how the CTD can be standardized to improve usability and review. Additional comments have been made on reports of failure investigations, study plans, and raw data documentation. The recommendation is that no prescriptive guidelines are required in these areas but should be led by good scientific practices subject to particular circumstances.
doi:10.1208/s12248-013-9556-5
PMCID: PMC3933576  PMID: 24408787
A8; documentation; GBC; reports
9.  Automation Practices in Large Molecule Bioanalysis: Recommendations from Group L5 of the Global Bioanalytical Consortium 
The AAPS Journal  2013;16(1):164-171.
In recent years, the use of automated sample handling instrumentation has come to the forefront of bioanalytical analysis in order to ensure greater assay consistency and throughput. Since robotic systems are becoming part of everyday analytical procedures, the need for consistent guidance across the pharmaceutical industry has become increasingly important. Pre-existing regulations do not go into sufficient detail in regard to how to handle the use of robotic systems for use with analytical methods, especially large molecule bioanalysis. As a result, Global Bioanalytical Consortium (GBC) Group L5 has put forth specific recommendations for the validation, qualification, and use of robotic systems as part of large molecule bioanalytical analyses in the present white paper. The guidelines presented can be followed to ensure that there is a consistent, transparent methodology that will ensure that robotic systems can be effectively used and documented in a regulated bioanalytical laboratory setting. This will allow for consistent use of robotic sample handling instrumentation as part of large molecule bioanalysis across the globe.
doi:10.1208/s12248-013-9551-x
PMCID: PMC3889521  PMID: 24311307
automation; documentation; large molecule bioanalysis; robotic system
10.  A Novel Approach to Evaluate the Pharmacokinetic Biocomparability of a Monoclonal Antibody Derived from Two Different Cell Lines Using Simultaneous Crossover Design 
The AAPS Journal  2013;16(1):125-128.
A parallel study design with a large number of subjects has been a typical path for pharmacokinetic (PK) biocomparability assessment of biotherapeutics with long half-lives and immunogenic propensity, for example, monoclonal antibodies (mAb). A recently published innovative bioanalytical method that can quantify mAb produced from two different cell lines in the same sample opened an avenue to exploring a simultaneous crossover study design for PK biocomparability assessment of biotherapeutics. Siltuximab, a chimeric IgG1 mAb-targeting interleukin-6, was studied as an example. The pharmacokinetic biocomparability of siltuximab derived from mouse myeloma (Sp2/0) cells and Chinese hamster ovary cells was previously assessed and demonstrated in a clinical PK biocomparability study that enrolled more than 140 healthy subjects using a parallel trial design. The biocomparability was successfully shown in six cynomolgus monkeys in a preclinical proof-of-concept study using the new crossover study design supported by the analytical method. The impact of antidrug antibodies on the assessment of biocomparability was minimal. This novel approach opened up a new arena for the evaluation of PK biocomparability of biotherapeutics with unique molecular signatures such as a mAb derived from different cell lines.
doi:10.1208/s12248-013-9547-6
PMCID: PMC3889524  PMID: 24281691
liquid chromatography-mass spectrometry (LC/MS); monoclonal antibody; pharmacokinetic biocomparability; siltuximab; simultaneous crossover
11.  Is Extrapolation of the Safety and Efficacy Data in One Indication to Another Appropriate for Biosimilars? 
The AAPS Journal  2013;16(1):22-26.
CT-P13, the world’s first biosimilar monoclonal antibody to infliximab, was approved for marketing in South Korea for all the six indications of infliximab, which Europe may follow, although the product was tested only in rheumatoid arthritis (RA) with a limited pharmacokinetic comparison in ankylosing spondylitis. However, the extrapolation of the efficacy and safety findings of CT-P13 in RA to the other indications appears scientifically challenging when assessed by the current regulatory requirements. RA is not a sensitive clinical model to detect potential differences between CT-P13 and infliximab, and other mechanisms of action than antagonizing tumor necrosis factor α appear to be also important, which could be different by the approved indications. Furthermore, the immunogenicity and safety profiles of CT-P13 were not sufficiently characterized in that immunogenicity potential was lowest in RA, which was even further suppressed by the concomitant use of methotrexate. Extrapolation of the safety and efficacy data in one indication to another may be inappropriate for biosimilars unless backed up by strong scientific justification, which may include the mechanistic exposure–relationship approach. Therefore, regulatory agencies need to exercise caution before granting extrapolated indications to biosimilars.
doi:10.1208/s12248-013-9534-y
PMCID: PMC3889539  PMID: 24114449
biosimilars; CT-P13; extrapolation of indication; infliximab; regulatory agency
12.  Impact of Osmotically Active Excipients on Bioavailability and Bioequivalence of BCS Class III Drugs 
The AAPS Journal  2013;15(4):1043-1050.
doi:10.1208/s12248-013-9509-z
PMCID: PMC3787221  PMID: 23868749
BCS; bioavailability/bioequivalence; drug absorption; excipient; osmotic potential
13.  Evaluation of Pre-existing Antibody Presence as a Risk Factor for Posttreatment Anti-drug Antibody Induction: Analysis of Human Clinical Study Data for Multiple Biotherapeutics 
The AAPS Journal  2013;15(3):893-896.
Biotherapeutic-reactive antibodies in treatment-naïve subjects (i.e., pre-existing antibodies) have been commonly detected during clinical immunogenicity assessments; however information on pre-existing antibody prevalence, physiological effects, and impact on posttreatment anti-drug antibody (ADA) induction remains limited. In this analysis, pre-existing antibody prevalence and impact on posttreatment ADA induction were determined using ADA data from 12 biotherapeutics analyzed in 32 clinical studies. Approximately half (58%) of the biotherapeutics were associated with some level of pre-existing antibodies and 67% of those were associated with posttreatment ADA induction. Across all studies, 5.6% of study subjects demonstrated presence of pre-existing antibodies, among which, 17% of the individual subjects had posttreatment increases in their ADA titers while 16% had decreased titers and 67% had no change in titers. However, in studies conducted in the rheumatoid arthritis (RA) population, 14.8% of RA patients were associated with pre-existing antibodies and 30% of those had posttreatment titer increases. The results suggest that in most study subjects, pre-existing antibodies pose a low risk for posttreatment ADA induction. That said, the high risk of induction implicated for RA patients, primarily observed in treatments evaluating novel antibody-based constructs, indicates that further understanding of the contribution of product and disease-specific factors is needed. Cross-industry efforts to collect and analyze a larger data set would enhance understanding of the prevalence, nature, and physiological consequences of pre-existing antibodies, better inform the immunogenicity risk profiles of products associated with these antibodies and lead to better fit-for-purpose immunogenicity management and mitigation strategies.
doi:10.1208/s12248-013-9497-z
PMCID: PMC3691441  PMID: 23761225
anti-drug antibodies; immunogenicity risk; pre-existing antibodies
14.  Bioequivalence for Locally Acting Nasal Spray and Nasal Aerosol Products: Standard Development and Generic Approval 
The AAPS Journal  2013;15(3):875-883.
Demonstrating bioequivalence (BE) for nasal spray/aerosol products for local action has been very challenging because the relationship between the drug in systemic circulation and the drug reaching the nasal site of action has not been well established. Thus, the current BE standard for these drug/device combination products is based on a weight-of-evidence approach, which contains three major elements: equivalent in vitro performance, equivalent systemic exposure, and equivalent local delivery. In addition, formulation sameness and device similarity are evidences to support BE. This paper presents a comprehensive review of the scientific rationale of the current BE standard and their development history for nasal spray/aerosol products, as well as the Food and Drug Administration’s review and approval status of generic nasal sprays/aerosols with the application of these BE standard.
doi:10.1208/s12248-013-9494-2
PMCID: PMC3691440  PMID: 23686396
bioequivalence; generic; locally acting drug; nasal aerosol; nasal spray
15.  Pre-Existing Biotherapeutic-Reactive Antibodies: Survey Results Within the American Association of Pharmaceutical Scientists 
The AAPS Journal  2013;15(3):852-855.
The immunogenicity profile of a biotherapeutic is determined by a multitude of product and patient-related risk factors that can influence the observed incidence and clinical consequences of immunogenicity. Pre-existing antibodies, i.e., biotherapeutic-reactive antibodies present in samples from treatment-naïve subjects, have been commonly observed during immunogenicity assessments; however their relevance in terms of the safety and efficacy of a biotherapeutic is poorly understood. An American Association of Pharmaceutical Scientists-sponsored survey was conducted to gather information about the prevalence, nature, and consequences of pre-existing antibodies in clinical and nonclinical studies. The survey results indicate that pre-existing antibodies against a variety of biotherapeutics (e.g., mAbs, fusion proteins) are frequently encountered, especially in the context of autoimmune diseases, but that the methods and approaches used to detect, characterize, and report these antibodies vary. In most cases, pre-existing antibodies did not appear to have clinical consequences; however, a few of the respondents reported having observed an effect on pharmacokinetic, pharmacodynamic, safety, and/or efficacy parameters. The findings from this survey are an important first step in evaluating the potential risks associated with the presence of pre-existing antibodies and highlight the importance of standardizing the approaches for detection and characterization of these antibodies. Cross-industry sharing of case studies and relevant data collection will help better inform biotherapeutic risk/benefit profiles and provide deeper understanding of the biological consequences of pre-existing antibodies.
doi:10.1208/s12248-013-9492-4
PMCID: PMC3691423  PMID: 23620231
immunogenicity risk; pre-existing antibodies; standardization
16.  Generic Development of Topical Dermatologic Products, Part II: Quality by Design for Topical Semisolid Products 
The AAPS Journal  2013;15(3):674-683.
The emergence of quality by design as a relatively new systematic science and risk-based approach has added a new dimension to pharmaceutical development and manufacturing. This review attempts to discuss the quality by design elements and concepts applied for topical semisolid products. Quality by design begins with defining a quality target product profile as well as critical quality attributes. Subsequently, this is followed by risk identification/risk analysis/risk evaluation to recognize critical material attributes and critical process parameters, in conjunction with design of experiments or other appropriate methods to establish control strategies for the drug product. Several design-of-experiment examples are included as practical strategies for the development and optimization of formulation and process for topical drug products.
doi:10.1208/s12248-013-9472-8
PMCID: PMC3691439  PMID: 23572241
dermatologic product; generic; quality by design; semisolid; topical product
17.  Sequential Bioequivalence Trial Designs with Increased Power and Controlled Type I Error Rates 
The AAPS Journal  2013;15(3):659-661.
Methods to implement two-stage designs in two-treatment, two-sequence, and two-period crossover bioequivalence studies have only recently been developed. The two-stage methods have so far only been described for a targeted study power of 80%. Since it is sometimes desirable to increase the targeted power to 90%, this study identifies sets of alphas that work for the recently developed two-stage methods while controlling type I error rates around 5% for assumed geometric mean test/reference ratios of 0.90 and 0.95 at targeted power of 90%, and provides a characterization of the methods in terms of the resulting sample sizes and power. Depending on the actual variability and the chosen sample size at stage 1, the actual power will be between 83% and 100%. The previously characterised methods at target power 80% as well as 90% result in trivial inflation of type 1 error, but the type 1 error inflation at 90% target powers with decreased alpha at the second stage result in slightly less inflation. These results may be useful for applicant wishing to achieve increased power in bioequivalence trials without a penalty for type I error rates.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-013-9475-5) contains supplementary material, which is available to authorized users.
doi:10.1208/s12248-013-9475-5
PMCID: PMC3691437  PMID: 23543603
bioequivalence; dry powder inhalers; power; sequential designs; type I errors
18.  CDER Risk Assessment Exercise to Evaluate Potential Risks from the Use of Nanomaterials in Drug Products 
The AAPS Journal  2013;15(3):623-628.
The Nanotechnology Risk Assessment Working Group in the Center for Drug Evaluation and Research (CDER) within the United States Food and Drug Administration was established to assess the possible impact of nanotechnology on drug products. The group is in the process of performing risk assessment and management exercises. The task of the working group is to identify areas where CDER may need to optimize its review practices and to develop standards to ensure review consistency for drug applications that may involve the application of nanotechnology. The working group already performed risk management exercises evaluating the potential risks from administering nanomaterial active pharmaceutical ingredients (API) or nanomaterial excipients by various routes of administration. This publication outlines the risk assessment and management process used by the working group, using nanomaterial API by the oral route of administration as an example.
doi:10.1208/s12248-013-9466-6
PMCID: PMC3691428  PMID: 23512727
CDER; nanomaterial; nanotechnology; risk assessment; risk management
19.  Direct and Rapid Genotyping of SLCO1B1 388A>G and 521T>C in Human Blood Specimens Using the SmartAmp-2 Method 
The AAPS Journal  2013;15(2):618-622.
Organic anion-transporting polypeptide (OATP) 1B1, encoded by the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene, mediates the active uptake of various organic anions into hepatocytes and determines their hepatic clearances as the first step in the detoxification pathway. Previous reports indicated that alterations in its function by drug–drug interactions or genetic polymorphisms affect the pharmacokinetics of the substrate drugs. In the present study, we developed a method to genotype SLCO1B1 388A>G (rs2306283) and 521>C (rs4149056), which significantly affect the clinical pharmacokinetics and subsequent side effects such as myopathy caused by statins, OATP1B1 substrates in humans. We used a small aliquot of blood and the isothermal Smart Amplification Process version 2 (SmartAmp-2), which could complete the genotyping of 388A>G and 521T>C within 60 min. The genotypes of 101 genomic DNA samples and blood samples assessed by SmartAmp-2 matched perfectly to those determined previously by the conventional PCR-SSCP method. The SmartAmp-2 method enables the rapid identification of the 388A>G and 521T>C genotypes, saving time and effort in the genomic DNA preparation in clinical practice. This method will be useful for evaluating and predicting altered pharmacological and toxicological effects of substrate drugs caused by SLCO1B1 polymorphisms.
doi:10.1208/s12248-013-9471-9
PMCID: PMC3675730  PMID: 23471819
membrane transporters; pharmacogenetics; single nucleotide polymorphisms
20.  Generic Development of Topical Dermatologic Products: Formulation Development, Process Development, and Testing of Topical Dermatologic Products 
The AAPS Journal  2012;15(1):41-52.
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.
doi:10.1208/s12248-012-9411-0
PMCID: PMC3535108  PMID: 23054971
dermatologic product; generic; semi-solid; topical product; quality by design
21.  Common Reasons for “For-Cause” Inspections in Bioequivalence Studies Submitted to the Food and Drug Administration 
The AAPS Journal  2012;15(1):10-14.
“For-cause” inspections are initiated during the review of bioequivalence (BE) data submitted to Abbreviated New Drug Applications when possible scientific misconduct and study irregularities are discovered. We investigated the common reasons for initiating “for-cause” inspections related to the clinical, analytical, and dissolution study sites associated with BE studies. This information may help the pharmaceutical industry to understand the root causes of compliance failures in BE studies and help them to improve compliance with FDA’s regulations, thereby facilitating more rapid approval of safe and effective generic drugs.
doi:10.1208/s12248-012-9415-9
PMCID: PMC3535114  PMID: 23054974
bioequivalence; FDA; inspection
22.  Use of Partial Area under the Curve Metrics to Assess Bioequivalence of Methylphenidate Multiphasic Modified Release Formulations 
The AAPS Journal  2012;14(4):925-926.
doi:10.1208/s12248-012-9397-7
PMCID: PMC3475859  PMID: 22976173
attention deficit hyperactivity disorder; bioequivalence; generic drugs; methylphenidate; pAUC
23.  Statistics on BCS Classification of Generic Drug Products Approved Between 2000 and 2011 in the USA 
The AAPS Journal  2012;14(4):664-666.
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.
doi:10.1208/s12248-012-9384-z
PMCID: PMC3475853  PMID: 22718306
ANDA; BCS biowaiver; bioequivalence; Biopharmaceutics Classification System; generic drug product
24.  Biopharmaceutic Planning in Pediatric Drug Development 
The AAPS Journal  2012;14(3):519-522.
Pediatric drug development is a required consideration for all drug development programs. Age-appropriate formulations such as suspensions, chewable tablets, oral disintegrating tablets, etc., are typically developed and used in the pediatric clinical studies. However, it is not uncommon to use enabling formulations in the pivotal pediatric clinical study followed by bridging bioavailability and/or bioequivalence studies. Development of age-appropriate formulations is an essential part of pediatric drug development and adds additional biopharmaceutical considerations to an already complex problem. Careful planning of biopharmaceutic data collection during the adult and pediatric development program can contribute significantly to the biopharmaceutic risk assessment and planning of appropriate clinical studies leading to successful development of pediatric formulations.
doi:10.1208/s12248-012-9364-3
PMCID: PMC3385835  PMID: 22562590
bioavailability; bioequivalence; biopharmaceutics; formulations; pediatric
25.  Common Deficiencies with Bioequivalence Submissions in Abbreviated New Drug Applications Assessed by FDA 
The AAPS Journal  2011;14(1):19-22.
ABSTRACT
Purpose
A generic product must meet the standards established by the Food and Drug Administration (FDA) to be approved for marketing in the USA. FDA approves a generic product for marketing if it is proved to be therapeutically equivalent to the reference product. Bioequivalence (BE) between a proposed generic product and its corresponding reference product is one of the major components of therapeutic equivalence. These approvals may be delayed if the BE portion of the submission is determined to be deficient. Many of these BE deficiencies recur commonly and can be avoided.
Method
We conducted a survey of the BE submissions to abbreviated new drug applications (ANDAs) over years 2001 to 2008 to identify the most commonly occurring BE deficiencies.
Results
Recurring deficiencies are found in a majority of the ANDAs reviewed by FDA’s Division of Bioequivalence. The most common deficiencies were the two deficiencies related to dissolution (method and specifications) found in 23.3% of the applications and analytical method validation and/or report found in 16.5% of the applications. The approval of generic drugs would be greatly accelerated if these deficiencies could be avoided.
doi:10.1208/s12248-011-9312-7
PMCID: PMC3291193  PMID: 22130775
ANDA; bioequivalence; common deficiency; FDA

Results 1-25 (41)