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U.S. Department of Health and Human Services

About FDA

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Division of Product Quality Research Programs

Federal Research Center Life Sciences
Life Sciences Building 64, 1st Floor
10903 New Hampshire Avenue
Silver Spring, MD 20993
Phone: (301) 796-0012 Fax: (301) 796-9818

Mansoor Khan, Ph.D., Director


Research Programs

  • FDA-Track FY2010 Completed Key Project: Quality Assessment of Repackaged Products (PDF - 22KB)
  • Preformulation and Analytical Development
    • Chromatographic Methods
      • Development and Applications of Validated HPLC Methods
    • Spectroscopic Methods
      • Enabling Molecular Analysis with Laser-Induced Breakdown Spectroscopy (LIBS) using Chemometrics
      • Process Analytical Technology (PAT) Tools: Chemometric, Spectroscopic and Chemical Imaging Techniques to Assess Pharmaceutical Quality
      • Terahertz Spectroscopy: Pharmaceutical PAT Application and its Regulatory Considerations
  • Drug Delivery and Formulations
    • Lab-Scale Pharmaceutical Manufacturing
      • Characterization and Functionality of Magnesium Stearate Derived from Bovine and Vegetable Sources
      • A Quality by Design Approach for Predicting the Impact of Manufacturing Changes on In Vivo Product Performance
    • On-line Process Monitoring: Lab-Scale
      • Quality by Design and Process Understanding by PAT
      • Integrating Design of Experiment and Multivariate Statistical Approach for FDA’s Process Analytical Technology (PAT) Regulatory Utility
    • On-line Process Monitoring: Pilot-Scale
      • FDA-Pfizer CRADA: Quality by Design and Process Monitoring of Pharmaceutical Manufacturing at Pilot-Scale
      • FDA-Novartis Quality by Design CRADA
    • Nanoparticles: Preparation, Characterization, and Permeability
  • Biopharmaceutics
    • Dose Dumping of Extended Release Drug Products in Alcohol
    • Biopharmaceutical Evaluation of Drug Substances and Products
    • In Vitro Cellular Uptake of Stressed Liposomal Drug Products Permeability Studies
    • Gastric Stability of Venlafaxine
    • Quality Research for Therapeutic Botanicals
    • Prussian Blue Binding and Characterization Studies
    • Prussian Blue and Antimicrobials: In vitro drug-drug interactions and in vivo bioavailability studies
    • Thermodynamic and Kinetic Stability of Colloidal Iron Drug Products
  • Drug Stability
    • Shelf Life Extension Program
    • Comparison of the Stability of Whole versus Split Tablets
    • Repackaging Product Stability

PREFORMULATION and ANALYTICAL DEVELOPMENT

Chromatographic Methods 

Development and Applications of Validated HPLC Methods

Principal Investigator: Patrick J. Faustino

 Public Health Issue: The accurate evaluation of active pharmaceutical ingredients (API) and formulation excipients is essential for preformulation assessment and optimization. Development and validation of analytical methods in the preformulation phase provides the basis for analytical assessment of specific regulatory endpoints such as identity, strength, quality, purity, and potency to ensure the safety and efficacy of pharmaceuticals throughout the regulatory timeline.

 Regulatory Contribution: The development of validated analytical methods has contributed to recent regulatory projects such as the split tablet stability study (gabapentin) the repackaging study (furosemide, metoprolol, gabapentin), the colloidal iron thermodynamic stability study (Ferrlecit and Venofer) and in vitro gastric and intestinal stability (venlafaxine) and product solubility (vancomycin). This program has developed over 50 analytical methods that have additionally contributed to a wide variety of in vitro and in vivo pharmacology, pharmacokinetic, toxicology as well as product quality regulatory issues.  This program provided scientific support for the FDA Analytical Procedures and Method Validation and FDA Bioanalytical Method Validation guidance’s as well as the BCS, Food Effect and SUPAC guidance’s. 

Research Approach: The development of analytical and chromatographic procedures requires the successful implementation of appropriate system qualification, system suitability, and method validation protocols. Implementation of these protocols ensures the development of robust methodology that can effectively address preformulation issues and be successfully transferred for addressing regulatory issues (i.e., product quality) in each succeeding regulatory phases including post market assessment. The program focuses on the use of validated methodology including QbD approaches for API and product characterization, formulation processing, product stability and pharmaceutical equilivalence.

Mission Relevance and Outcomes: Validated analytical methodology is the basis for most regulatory approval (i.e. pre-clinical, CMC, BA, BE, PK), post-market assessment and scientific research at the Agency. The scientific information and understanding obtained from validated analytical methodology ensures the safety and efficacy of pharmaceuticals and other FDA regulated medical products for the American Public.  
Spectroscopic Methods

Enabling Molecular Analysis with Laser-Induced Breakdown Spectroscopy (LIBS) using Chemometrics

Principal Investigator: Patrick J. Faustino

Public Health Issue: Quality assurance of drug substances and drug products depends on sophisticated analytical and spectroscopic tools. New technologies such as Laser-Induced Breakdown Spectroscopy (LIBS) can provide powerful methods of detection and quantitation not previously available.

Regulatory Contribution: The scientific assessment of LIBS evolved out of the novel technologies program whose mission was to identify cutting edge technologies that could be utilized as effective “critical path” tools. The research and development of this technology (atomic and molecular spectroscopy) will provide the Agency with critical path tools that will significantly impact the Agency’s scientific and regulatory understanding and oversight of chemistry, manufacturing and controls (CMC) quality issues. 

Research Approach: Chemometric analysis is a novel approach to evaluating the molecular emission signal from LIBS. Traditionally LIBS requires elements such as Br, Cl, F, and S or to be present in compound of interest and these elements are present only in some active pharmaceutical ingredient (API) and not in excipients.  However, using the emission signal originating from small diatomic fragments like C2, CN, CH, Hb, Hg, C, and Mg, we have successfully developed a multivariate calibration capable of monitoring the API and other ingredients in a formulation including Avicel, lactose and magnesium stearate. Partial Least Squares analysis provided an accurate prediction of the concentrations of API and formulation excipients.  Coupled with the 3D chemical mapping capabilities of LIBS this molecular spectroscopic approach can provide the first comprehensive quantitative map of API and excipients globally in pharmaceutical formulations.

Mission Relevance and Outcomes: Our recent collaborative studies with the National Research Council of Canada, combining LIBS and chemometrics have enabled the quantitative analysis of several molecules that was not technically possible with the traditional approach using a target’s specific element. This work suggests the potential for LIBS to be more widely applied to process monitoring and quality control of pharmaceuticals. LIBS when coupled with standoff detection approaches may revolutionize the way pharmaceuticals are evaluated, providing highly efficient minimally invasive approaches to assess pharmaceuticals to better ensure the quality of pharmaceuticals for the American public. 

Spectroscopic Methods

Process Analytical Technology (PAT) Tools: Chemometric, Spectroscopic and Chemical Imaging Techniques to Assess Pharmaceutical Quality 

Principal Investigator: Robbe C. Lyon

Public Health Issue: Efficient pharmaceutical manufacturing is a critical part of an effective U.S. health care system. Significant opportunities exist for improving product and process development, process analysis, and process control through quality by design and PAT approaches. Development and understanding the capabilities of new technologies is the foundation leading to the implementation of PAT tools for process monitoring. 

Regulatory Contribution: There are many tools available that enable process understanding for scientific, risk-managed pharmaceutical development, manufacture, and quality assurance. When used appropriately, these tools enable the identification and evaluation of product and process variables that may be critical to product quality and performance.  The tools may also identify potential failure modes and mechanisms and quantify their effects on product quality. There is an ongoing need to assess the capabilities of promising technologies.

Research Approach: This research explores applications of vibrational spectroscopy and chemical imaging as rapid, noninvasive, nondestructive techniques for assessing the quality of pharmaceutical materials and products. The technologies that have been evaluated include near-infrared (NIR) spectroscopy, Raman spectroscopy, attenuated total reflectance mid-infrared spectroscopy and NIR chemical imaging. Each technology was assessed based on the ability to directly or indirectly measure chemical and physical attributes that may impact product performance. The chemical attributes that have been measured include drug content, impurities, ingredient identification and the physical attributes that have been measured include blend uniformity, hardness, density, hydration state, polymorphic state, particle coating. One project compared the ability of each of the above techniques to noninvasively predict the active drug content of acetaminophen tablets as confirmed by HPLC analysis. Chemical imaging was used to determine the minimum spot size required for accurately sampling the tablet surface. In addition, chemical imaging has been effective in determining blend uniformity in powders and tablets, the structure of complex dosage forms, density gradients in tablets, and localized regions of hydration and degradation in tablets and capsules. NIR spectroscopy was used to noninvasively determine the hydration state of Prussian blue capsules and consequently predicting the cesium binding activity. For proper data evaluation, expertise has been developed in the selection, development and implementation of relevant chemometric analysis tools.

Mission Relevance and Outcomes: The CDER Office of Pharmaceutical Sciences has launched a comprehensive program, the PAT Initiative, to evaluate the technologies, the methods of data analysis and the regulatory impact associated with the implementation of PAT. The goal of this initiative is to ensure optimal regulatory applications of PAT and concurrently to acquire, utilize and disseminate knowledge related to PAT applications. It is anticipated that understanding the capabilities of PAT sensors and data analysis tools will increase product quality and advance the scientific basis and efficiencies of product/process development, manufacturing, review assessment, and inspection activities.

Spectroscopic Methods

TeraHertz Spectroscopy: Pharmaceutical PAT Application and its Regulatory Considerations

Principal Investigator: Huiquan Wu 

Public Health Issues: Recent publications and public debate have highlighted the importance of excipients in the final dosage form in terms of product quality and safety. THz spectroscopy as emerging technology holds promise for characterizing both API and excipients simultaneously. From the public health perspective, this is critical as in the case of narrow therapeutic index (NTI) drugs and high potency drugs, knowing the precise concentrations of all of the components in the final dosage form is critical to ensure product quality and safety.

Regulatory Contributions: To enable scientists to extract critical information for product/process design and process control, a few critical scientific questions must be answered for THz pharmaceutical PAT applications:

(1) What measurement factors impact the quality, precision, accuracy, and repeatability of acquired THz spectra?

(2) How does one optimize these measurement factors for quantification purpose?

(3) How can process and product knowledge be brought into the spectral data analysis domain such that THz spectra can be better explained and interpreted?  And

(4) Can spectroscopic techniques and chemometric modeling methods be integrated to understand product and process interactions for PAT implementation?

An interagency agreement (IAG) was established between FDA and NIST in August 2004 to address the above regulatory and technical challenges. It will provide a case study to the Agency as how to integrate THz spectroscopy, multivariate chemometric approaches, PAT tools, and QbD principles to explore the scientific merits and regulatory challenges associated with adapting THz spectroscopy for pharmaceutical applications.

Research Approach: Two consecutive research phases were planned and executed:

(1) Systematically examining the effects of instrumental and compositional variables on the THz spectral data quality and their impact on quantitative interpretation of THz spectral data;

(2) Creatively developing quantification approaches to THz pharmaceutical applications in the PAT and QbD regulatory domain.

Mission Relevance and Outcomes: This study is highly relevant to the FDA regulatory mission by providing case studies for PAT/QbD applications using THz spectroscopy. It focuses on critical aspects of CMC issues, such as critical instrumental and measurement process variables, quantification aspects of both API and excipients in the final dosage forms.  The regulatory utility of this emerging PAT tool has been examined to provide recommendations for the FDA reviewers, managers, and outside scientific community.

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DRUG DELIVERY and FORMULATIONS

Lab-Scale Pharmaceutical Manufacturing

Characterization and Functionality of Magnesium Stearate Derived from Bovine and Vegetable Sources

Principal Investigator: Mazen Hamad 

Public Health Issue: Magnesium stearate is the most widely used lubricant for tablet production in America.  Although the concentration of magnesium stearate in each tablet is low (typically around 1% w/w or less), the importance of the function of magnesium stearate is high.  Magnesium stearate imparts lubricity to a pharmaceutical blend to allow for smooth ejection of the resulting compressed tablet from the die of a tablet press.  Current analytical methods do not test the functionality of magnesium stearate, and therefore, the impact of changes in magnesium stearate is difficult to predict.

Regulatory Contribution: Pharmaceutical product quality is very sensitive to small changes in the concentration or properties of magnesium stearate. Recently a major manufacturer of magnesium stearate has switched the starting raw material for the magnesium stearate synthesis from a bovine-based material to materials of vegetable origin.  This will mean that most manufacturers will have to substitute the bovine sourced magnesium stearate with that of the vegetable source. The impact of this change on product quality and manufacturability is not known. The results of this research will help CDER understand the impact of the change in magnesium stearate source on the product performance.  

Research Approach: Bulk magnesium stearate from the two sources will be characterized by compendial as well as non-compendial methods. Several different product intermediates (granules) will be prepared and characterized. These granules will be lubricated and compressed by instrumented tablet press to evaluate the lubricant efficiencies for comparison. 

Mission Relevance and Outcomes: This research will allow the Agency to develop a consistent policy and deal with the potential changes in product quality with magnesium stearate substitution.

Lab-Scale Pharmaceutical Manufacturing 

A Quality by Design Approach for Predicting the Impact of Manufacturing Changes on In Vivo Product Performance

Principal Investigator: Robbe C. Lyon

Public Health Issue: Risk-based regulatory actions and decisions supporting the drug approval process depend on the scientific understanding of how formulation and manufacturing process factors affect product quality and performance. This is the underlying basis for the development, manufacture and quality assurance of the drug product throughout its lifecycle. The FDA Critical Path Initiative has identified the need for process control strategies to prevent or mitigate the risk of producing a poor quality product. Post-approval manufacturing changes may adversely impact drug product quality. Since safety and efficacy are established using clinical batches, it is essential that the same level of quality is assured in the product released to the public.

Regulatory Contribution: The ICH and the FDA have recently proposed initiatives and issued guidances that provide rational approaches to dealing with manufacturing issues that could impact the regulatory decision process. There is a need within the regulatory community and the pharmaceutical industry for case studies that put these principles into action and test these approaches.

Research Approach: The goal of this study is to incorporate QbD principles for developing a design space for a model drug product.  The prime objective is to test if a design space based on established acceptance criteria for in vitro performance will meet the established acceptance criteria for bioavailability. A design space will be defined for critical processing variables and formulation variables that impact in vivo product performance. While there may be several variables that affect the product variability in vitro, it is anticipated that the current study will identify which of these variables are actually relevant in vivo.

Mission Relevance and Outcomes: It is anticipated that this case study will serve as a practical example of the principles discussed in the ICH Q8 guidance, “Pharmaceutical Development.” This guidance has suggested that working within an approved design space may obviate the need for post-approval CMC submissions and regulatory oversight, and thereby provide relief both to industry and the Agency. This could lead to more flexible regulatory approaches to facilitate: risk based regulatory decisions (reviews and inspections); manufacturing process improvements, within the approved design space, without further regulatory review; and “real time” quality control, leading to a reduction of end-product release testing.

On-line Process Monitoring: Lab-Scale

Quality by Design and Process Understanding by PAT

Principal Investigator: Abhay Gupta 

Public Health Issue: Poor product design and process understanding ultimately leads to manufacturing-related problems as evident from sharp increase in the number of recalls during last 10 years.  This has resulted in poor availability of essential drugs, disruption of manufacturing operations and has even lead to a negative impact on new drug approvals.  Coupled with an aging population in the county, who wants cheaper drugs, the drug manufacturers are feeling pressure to bring down the prices.

Regulatory Contribution: The project supports the agency’s initiative called “Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach” by providing a case study of utilizing the concepts of Process Analytical Technology (PAT) for process understanding and hence designing the product with the desired quality attributes.

Research Approach: The goal of PAT is to understand and control the manufacturing process.  Quality by design and process understanding involves identifying sources of variability and understanding their effect on the final product quality.  The project involves a systematic approach towards understanding the fluid bed granulation process by performing a designed set of experiments. The experiments will result in a better understanding of the effects of different variables (instrumental, process, raw material, etc), including various interactions that may be taking place between different variables, on the quality of the finished product and the product performance of the final dosage form.  In addition to characterizing the granules using the conventional test, the project involves real-time monitoring of the granulation process to determine and detect influence of different variables on the final product quality. The information gained by a systematic understanding of the variables and interactions affecting the formulation process, including the real-time or near real-time process monitoring will lead to the development of more robust processing conditions.

Mission Relevance and Outcomes: Better process understanding will result in products with better quality with obvious advantages to the pharmaceutical industry, regulators, and public health, e.g., reduced production cycle time; reduction or prevention of rejects, scrap, and reprocessing; real-time release of products; increased automation resulting in improved operator safety and reduced human errors; and products with improved efficiency and managed variability.

On-line Process Monitoring: Lab-Scale 

Integrating Design of Experiment and Multivariate Statistical Approach for FDA’s Process Analytical Technology (PAT) Regulatory Utility

Principal Investigator: Huiquan Wu

Public Health Issues: The number of drug recalls due to manufacturing-related problems has been increasing over the past few years.  The FDA’s PAT Initiative and the Critical Path Initiative are strategic plans designed to highlight and address these challenges.  Experiment design (DOE) and multivariate statistics as critical PAT tools have been highlighted in the PAT Guidance, although they have not been widely adopted in the pharmaceutical manufacturing industry.  This reality presents challenges to both the industry and regulator, in terms of maintaining state of process control and providing scientific justifications for any CMC (Chemistry, Manufacturing, and Control) -related changes which may trigger product quality and safety issues.

Regulatory Contributions: Very few applications of DOE and statistical simulation in the areas of pharmaceutical product development, manufacturing, and quality assurance are available publicly.  This project aims to fill this information gap and provide a case study example to the Agency as how to integrate DOE and multivariate statistical approaches to establish manufacturing process control strategies and achieve the desired state of Quality-by-Design.

Research Approach: Two parallel approaches have been employed to address this very challenging topic.  Internally, a vigorous theoretical study including first principle modeling and multivariate modeling based on both literature and existing data, in conjunction with process characterization have been moving forward steadily.  Subtasks includes using DOE and Multivariate Data Analysis (MVDA) to understand pharmaceutical process variability; integrating MDVA and mass transfer modeling to understand the causal link between formulation/processing variables and quality attributes of final dosage form; developing process control strategies for pharmaceutical crystallization process;  and evaluating the pharmaceutical applications of emerging technologies.  External collaboration has been established to carry out a systematic experimental study on capsule filling process which is crucial but frequently problematic for many quality-related issues, such as segregation, content uniformity, etc.  A model drug system and appropriate manufacturing process were identified.  Intensive DOEs with integrated process/product characterization have been conducted to the model drug system (Aspirin/Microcrystalline Cellulose) and manufacturing process to identify critical process and formulation variables, and gain better process understanding.

Mission relevance and outcomes: This study is highly relevant to the FDA regulatory mission by providing case studies for PAT applications.  It focuses on critical aspects of CMC issues, such as critical process variables, design space, and risk analysis of process-related changes.  The regulatory utility of these critical PAT tools have been examined to provide recommendations for the pharmaceutical community.  The successful completion of this project may improve the quality and efficiency of the review process by promoting scientific and risk-based approaches for the regulatory decision-making process.

On-line Process Monitoring: Pilot-Scale

FDA-Pfizer CRADA: Quality by Design and Process Monitoring of Pharmaceutical Manufacturing at Pilot-Scale

Principal Investigator: Robbe C. Lyon

Public Health Issue: Significant opportunities exist for improving pharmaceutical development, manufacturing, and quality assurance through innovation in product and process development, process analysis, and process control. Efficient pharmaceutical manufacturing is a critical part of an effective U.S. health care system. The health of our citizens (and animals in their care) depends on the availability of safe, effective, and affordable medicines.

Regulatory Contribution: The goal of the PAT guidance is to enhance process understanding and control the manufacturing process, which is consistent with risk-based regulatory approaches. This guidance encourages the effective use of the most current pharmaceutical science and engineering principles and knowledge, throughout the life cycle of a product, to improve the efficiencies of both the manufacturing and regulatory processes.  There is a need within the regulatory community and the pharmaceutical industry for case studies that put these principles into action and test these approaches.

Research Approach: This research project has focused on pilot-scale manufacturing of Dilantin capsules as a CRADA with Pfizer. Initially, the blending of phenytoin sodium with excipients was monitored by on-line near-infrared (NIR) spectroscopy and at-line chemical imaging techniques. Subsequently, on-line monitoring by power consumption, blend temperature and headspace humidity have been implemented.  Protocol 1 was designed to test the instrument measurement capabilities and to correlate spectral data to product performance (capsule dissolution). Process variables include blending time, API particle size and I-bar speed. Performance results indicate that capsule dissolution increases with API milling and decreases with I-bar speed and blending time. Monitoring the process by NIR spectroscopy indicates multiple blending processes: rapid (chemical mixing) and slow (physical changes). The physical changes (powder density and API dehydration) appear to correlate with product performance. Protocol 2 was proposed to develop a design space for the process variables, I-bar speed and blending time. The goal is to determine a proper blending endpoint in real time from the spectral data.

Mission Relevance and Outcomes: The goal of this project is to ensure optimal regulatory applications of PAT and concurrently to acquire, utilize and disseminate knowledge related to PAT applications. It is anticipated that applications of PAT will increase product quality and advance the scientific basis and efficiencies of product/process development, manufacturing, review assessment, and inspection activities. Since pilot-scale manufacturing facilities are not available at the FDA, this collaboration provides the Agency with an opportunity to conduct on-line research related to the implementation and validation of PAT tools. It also provides access to Pfizer’s industry leading expertise in the area of on-line PAT and chemical imaging of pharmaceutical products.

On-line Process Monitoring: Pilot-Scale

FDA-Novartis Quality by Design CRADA

Principal Investigator: Mansoor A. Khan 

Public Health Issue: Significant opportunities exist for improving pharmaceutical development, manufacturing, and quality assurance through innovation in product and process development, process analysis, and process control. Efficient pharmaceutical manufacturing is a critical part of an effective U.S. health care system. The health of our citizens (and animals in their care) depends on the availability of safe, effective, and affordable medicines.

Regulatory Contribution: The goal of quality by design (QbD) is to enhance process understanding and control the manufacturing process, which is consistent with risk-based regulatory approaches. The PAT guidance encourages the effective use of the most current pharmaceutical science and engineering principles and knowledge, throughout the life cycle of a product, to improve the efficiencies of both the manufacturing and regulatory processes.  There is a need within the regulatory community and the pharmaceutical industry for case studies that put these principles into action and test these approaches.

Research Approach: This research project considers every unit operation in the manufacturing of the API and the formulated product in the production of a dispersible tablet. The first step was to define the critical quality attributes based on clinical relevance. The process parameters that impact the critical quality attributes were determined by an extensive risk-based assessment. Lab-scale and pilot-scale experiments were designed to systematically vary process parameters to identify critical parameters. The limitations imposed on the critical parameters by product performance delineate the design space. The initial challenge is to link the results from numerous experimental designs to create a composite multivariable design space. An additional challenge is to scale-up the composite design space to a full-scale design space followed by validation experiments conducted at commercial-scale. Process monitoring and control strategies were developed using the following on-line sensors: near-infrared spectroscopy for API drying, powder blending and tablet content uniformity; particle size distribution measurements for API milling; power consumption for wet granulation; and delta T measurements for drying of wet granules.

Mission Relevance and Outcomes: The approach and designs used to conduct this project will serve as a template for applying QbD principles to a complete pharmaceutical manufacturing process. It is anticipated that applications of QbD will increase product quality and advance the scientific basis and efficiencies of product/process development, manufacturing, review assessment, and inspection activities. This collaboration provides the Agency with an opportunity to conduct pilot-scale and commercial-scale on-line research related to the implementation and validation of PAT tools. This project will serve as a case study for future QbD projects.

Nanoparticles: Preparation, Characterization, and Permeability

Principal Investigator: Rakhi B. Shah

Public Health Issue:  Nanoparticles are complex drug delivery systems capable of delivering important therapeutic agents to novel receptors or targets in the body.  They are now being submitted as INDs and NDAs.  The regulatory concern is the lack of available information and in-house knowledge to ensure consistency of product quality, stability, safety, and efficacy.  The FDA regulation of “nanotechnology” products is based on the concepts of "risk management", i.e., risk identification, risk analysis, and risk control.  There is a safety concern for these "nano" sized particles as they have potential to cross the biological membranes and highly regulated blood-brain or blood-placenta barrier.

 Regulatory Contribution:  Research in the laboratory will help the reviewers look proactively into the issues related to product quality, product variability, and safety issues of nanoparticles prepared by different methods.  It will allow us to look at the submissions more objectively with well defined product quality attributes and specifications.  The data will be helpful for white papers, guidance, and workshops in future.

 Research Approach:   This study focuses on nanoparticles preparation, characterization, in-vitro permeability across various biological membranes and in-vivo organ distribution.  The nanoparticles of a poorly soluble API will be prepared by different methods.  The API with a stabilizer and other excipients when sprayed in controlled conditions produces nanoparticles.  The effect of process and formulation variables will be systematically studied by “Quality by design” approach.  The other method for nanoparticles preparation will rely upon emulsification technique.  The drug product’s permeability will be evaluated in-vitro through biological membranes which will be correlated with in vivo organ distribution studies.  The project will test the hypotheses that the product performance and variability are related to key nanoparticle attributes such as particle size, particle size distribution, zeta potential, interfacial properties, turbidity, dissolution, and permeability.

 Mission Relevance and Outcomes:  The project serves the mission of ensuring safety, product quality, consistency, and performance of the nanoparticles.  It will help in the evaluation of submissions, and development of white papers and the guidance of nanoparticles.  Based on this study, critical variables controlling size of these nanoparticles will be identified which will be correlated with the permeability and toxicity.

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BIOPHARMACEUTICS

 

 Dose Dumping of Extended Release Drug Products in Alcohol

 Principal Investigator: Mansoor A. Khan

 Public Health Issue: Certain extended release dosage forms release API above specifications by dose dumping in the presence of alcohol.  The dose dumping is known to cause elevated API plasma levels and may be lethal in certain cases.  Dose-dumping might be a result of poor product design and drug-excipient interaction with alcohol.  However the information related to product failure due to alcohol is very limited.  Very recently FDA has issued a public health advisory to inform patients and health care providers that palladone, a potent narcotic painkiller, because of its potential for severe side effects when consumed with alcohol, is withdrawn from the market.  Hence there is a need to understand the various processes involved in manufacturing of drug products and their vulnerability in alcoholic media.

 Regulatory Contribution: The study will help develop a decision tree for various types of extended release formulations’ dose dumping potential in presence of alcohol.  This will significantly impact the continuity of pre-approved drug products and approvability of new drug products.

 Research Approach: Controlled release formulations are designed to release the drug in a programmable manner.  Polymers of various solubility profiles have been used in order to act as release retardants.  Release in the presence of alcohol has seldom been studied.  Polymers which act as dissolution retardants in aqueous media might be soluble in alcohol.  However, based on the processing method used, the formulation might be vulnerable to alcohol.  Various types of extended release drug formulations (matrix type and reservoir type) will be formulated and analyzed for their vulnerability in alcohol.

 Mission Relevance and Outcomes: Safety of the extended release products is likely to be ensured by this research.  It will identify critical variables and establish guidelines for formulation designs that are not susceptible to alcohol.  The decision tree will help classify the already approved products as rugged, vulnerable, or uncertain depending upon their release behavior in alcohol.

Biopharmaceutical Evaluation of Drug Substances and Products

 Principal Investigator: Donna A. Volpe

 Public Health Issue: FDA/CDER’s bioavailability and bioequivalence guidance outlines methods for classifying drugs and immediate release solid oral drug products according to permeability, solubility and dissolution properties based upon the biopharmaceutics classification system (BCS).  It explains when a waiver for in vivo bioavailability and bioequivalence studies may be requested based on the BCS approach.  Such biowaivers can reduce the number of clinical trials during IND, NDA and ANDA stages of drug development along with post-approval changes to the product.

 Regulatory Contribution: There is a necessity to integrate into regulatory biopharmaceutical studies improved in vitro models and endpoints that will assist in risk assessment from drug development through post-marketing changes.  Laboratory research is utilized to evaluate drug substances (permeability, solubility, gastrointestinal stability) and products (dissolution).

 Research Approach: The BCS guidance provides in vitro test specifications and acceptance criteria for conducting solubility, permeability, stability and dissolution studies for classification purposes.  Laboratory demonstration on the applicability of method suitability for the development of Caco-2 cell culture models for the permeability classification of drug substances promotes the use of in vitro methods of classification.  Other research in this area includes a literature database of permeability values for model drugs to examine experimental effects on outcome; excipient effects on a drug’s intestinal permeability as determined in an in vitro cell and tissue models; in vivo bioavailability models; and characterization of novel drug delivery systems (e.g., nanoparticles, liposomes) for their effect on intestinal permeability and product dissolution.

 Mission Relevance and Outcomes: Research provides assistance in the review of biowaiver applications and establishes a database of methods utilized by sponsors for permeability classification.  It also leads to regulatory policies that provide a basis for setting product quality and performance specifications, and reduce regulatory burden on industry.  Furthermore, laboratory- and clinical-based studies of drugs will provide a scientific basis for revising the BCS guidance. 

 In Vitro Cellular Uptake of Stressed Liposomal Drug Products

 Principal Investigator: Donna A. Volpe

 Public Health Issue: Liposome drug products (LDP) contain drug substances encapsulated in lipid bilayer microvesicles designed for prolonged release and/or targeted delivery of drugs.  A key concern is product quality as related to liposome integrity and stability, which may lead to changes in the product performance in vivo.  Currently, there is lack of appropriate in vitro cell-based models to measure drug uptake of the LDPs.  Development of such a method may offer a better way to mimic drug uptake in vivo and establish a possible link between the quality of a LDP in vitro to performance of the product in vivo.

 Regulatory Contribution: There is a regulatory concern regarding the stability and integrity of LDPs.  Physiochemical changes in drug substance stability were noted in two LDPs following temperature, oxidative, and pH stress conditions in a parallel Division of Pharmaceutical Analysis project.  For this purpose, an in vitro cell model is evaluated to determine whether temperature or pH stress conditions can alter the cytotoxic activity or uptake of LDPs. 

 Research Approach: Two products were chosen to represent different liposome compositions (Doxil™, DaunoXome™) along with their corresponding drug substance (doxorubicin, daunorubicin).  A murine macrophage (J774A.1) and a human ovarian (SKOV-3) cell line serve as tissue targets for the LDPs and drugs in both the cytotoxicity and uptake experiments.  Microtiter tetrazolium and cellular uptake assays were used to determine whether exposure to temperatures (22°C, 50°C) outside normal storage conditions (4°C) or atypical pH conditions (pH 5, pH 8) alter the LDP’s toxic effects or entry into the cell lines.

 Mission Relevance and Outcomes: CDER has received a number of drug applications for LDPs.  Therefore, the reviewers need a scientific foundation to make regulatory decisions based upon a better understanding of the LDPs biological, physical and chemical characteristics.  This research utilizes cell cultures to study cytotoxicity and uptake of LDPs, which can provide a tool for ensuring product quality and performance. The results can be compared to changes seen in morphology and physicochemical properties of the liposome products.  The results of this research in combination with a similar project in the Division of Pharmaceutical Analysis on morphology and physiochemical properties will also help the reviewers provide guidance/recommendations for sponsors of LDP applications in regards to post-approval changes, stability, liposome integrity, and generic products.

Gastric Stability of Venlafaxine

 Principal Investigator: Donna A. Volpe

 Public Health Issue: FDA/CDER’s bioavailability/bioequivalence guidance recommends methods for classifying drugs and immediate release solid oral drug products according to permeability, solubility and dissolution properties.  It explains when a waiver for in vivo bioavailability and bioequivalence studies may be requested based on the approach of the biopharmaceutics classification system (BSC).  Documenting that drug loss from the gastrointestinal tract is due to intestinal membrane permeation, rather than a degradation process, assists in ascertaining the drug’s permeability classification.

 Regulatory Contribution: Gastrointestinal stability is a drug substance property examined as part of a biowaiver application.  A reviewer request was made to determine the in vitro gastric stability of venlafaxine to enable better classification of the drug’s intestinal permeability. 

 Research Approach:  The purpose of this study was to examine the stability of venlafaxine in simulated gastric (SGF) and intestinal (SIF) fluids.  Methodology and acceptance criteria for in vitro gastric stability studies are outlined in the guidance.  Stability in the gastrointestinal tract is investigated by incubating (37°C) venlafaxine in SGF and SIF representative of in vivo contact of the drug with these fluids.  Drug levels were then measured with a validated stability-indicating assay.  Significant degradation (>5%) of a drug assessed in this manner could suggest potential instability in the gastrointestinal tract.  Venlafaxine was stable in SGF (pH ~1.2) for the 1-hour incubation period and in SIF (pH 6.8) up to 3 hours with <1.5% relative concentration difference all time points. 

 Mission Relevance and Outcomes: The stability of a drug substance in gastric and intestinal fluids provides evidence whether drug loss from the gastrointestinal tract takes place by intestinal permeability or by a degradation process in these fluids prior to membrane absorption.  Using data from the stability study, CDER reviewers are able to clarify the BCS classification of venlafaxine which can lead to a biowaiver of bioavailability studies by a sponsor in NDA or ANDA applications.  This can result in fewer clinical trials and more efficient regulatory reviews.


Quality Research for Therapeutic Botanicals

 Principal Investigator:  Agnes A. NguyenPho

 Public Health Issue: Under the Dietary Supplement Heath and Education Act of 1994, botanical products are sold as dietary supplements in the US and are exempted from quality standard.  Despite the lack of quality standard, American consumers continue to use botanical products not only as supplements but also as complementary and alternative therapies.

 Regulatory Contribution:  The project will provide data supporting the feasibility of  quality attributes for botanicals as listed in CDER guidance for Botanical Drug Products.

 Research Approach:  The demonstration of quality or authenticity of botanical products is much easier if one is able to demonstrate equivalence between a material known to be authentic and the marketed product. To achieve this challenging task in herbal products one needs to have what is known as reference material.  Since the quality needs to be established in either the raw or finished products, botanical reference material needs to have a “suite” of materials consisting of ground dried authentic plant material, extract of the plant material, and finished product(s).  Under the collaboration between CFSAN, NIH, and NIST we were able to develop a suite of ephedra-containing standard reference materials (SRMs) and are currently working on our next five standard reference materials.  For the suite of ephedra SRMs, the ephedra alkaloids profile or “fingerprint” was determined by liquid chromatography (LC) with UV absorbance detection, LC with mass spectrometry and tandem mass spectrometry.  Other analytes such as caffeine, synephrine, pesticides, and toxic metals were also determined in the ephedra SRMs.

 Mission Relevance and Outcomes: The research will assist in CDER review of botanical drug products and provide researchers with quality control standards for the analysis of botanical products. 

Prussian Blue Binding and Characterization Studies

 Principal Investigator: Patrick J. Faustino

 Public Health Issue: Prussian blue, an inorganic iron hexacyanoferrate compound can enhance the excretion of radioactive isotopes of cesium and thallium ions following internal exposure, thereby reducing the radioactive burden to the body. Because of the wide applicability in industry, cesium and thallium have been identified, as potential components of a radiological dispersal device (RDD) also know as a “dirty bomb”. Prussian blue is the first FDA approved medical countermeasure for the treatment of internal radioactive metal contamination in the event of a major radiological incident.

 Regulatory Contribution: Due to the molecular structure (41% cyanide) and the nature of the crystal (bound water for ion exchange) the characterization of Prussian blue API’s and investigation drug products was undertaken to assure safety and efficacy of this radioprotectant.  DPQR laboratories developed a novel in vitro system to models gastric residence time and GI transit and (2) analytical test methods to evaluate the safety (cyanide release) and efficacy (cesium and thallium binding to Prussian blue) profiles. This OPS rapid response project directly supported the regulatory review and approval of the NDA in October 2003. Additional work contributed to the selection of product lots for the Strategic National Stockpile.

 Research Approach: Development of novel chemical imaging and near-infrared spectroscopic tools has allowed for the opportunity to assess physiochemical properties such as particle size and moisture content, that affect the safety and efficacy profiles of Prussian blue. Ongoing work with these new technologies is focused on better understanding these product quality attributes and additionally developing process monitoring tools and novel release testing procedures. Additionally chemometric models are being developed that may assist with the stability assessments of the national stockpiles. This work may ensure a more standardized clinical outcome by ensuring the product quality of Prussian blue.

 Mission Relevance and Outcomes: The spectroscopic and imaging technologies were highlighted at the FDA Science Forum as novel “critical path” tools that address the safety and industrial dimension of the “Critical Path for medical products. This project has and will continue to significantly assist the Agency’s ability to protect the public health in the event of a major radiological incident.

Prussian Blue and Antimicrobials: In Vitro Drug-Drug Interactions and In Vivo Bioavailability Studies

 Principal Investigator: Patrick J. Faustino

 Public Health Issue: Insoluble Prussian blue (Radiogardase®) is an FDA-approved drug product which can enhance the excretion of radioactive isotopes of cesium and thallium ions following internal exposure resulting from a major radiological incident such as a “dirty bomb”. There is a scientific concern about Prussian blue’s potential interaction with oral antimicrobials. Thus, science-based in vitro and in vivo studies which can provide the necessary information to clarify Prussian blue labeling are of regulatory importance. Of Public Health concern is the current clinical protocol for the treatment of mass casualties with cesium contamination and potential Acute Radiation Syndrome involves combination therapy of Prussian blue and antimicrobials.

 Regulatory Contribution: CDER’s Division of Product Quality Research (DPQR) laboratories, in collaboration with CDER’s Office of Counter-Terrorism and Emergency Coordination (OCTEC), have conducted in vitro studies which have shown a significant loss of various antimicrobials including tetracycline, doxycycline, and ciprofloxacin from solution following incubation with Prussian blue. This loss of antimicrobials is believed to be a result of physical absorption of the antimicrobial molecule onto the Prussian blue crystal lattice.  Additionally, current CDER in vitro laboratory studies have found that antimicrobials negatively impact the efficacy of Prussian blue by inhibiting cesium binding to Prussian blue. This information will support the revision of Prussian blue labeling and provide recommendations to the Agency and the Centers for Disease Control for appropriate treatment protocols for mass casualties.

 Research Approach: Development of appropriate analytical and spectroscopic procedures such as high-performance liquid chromatography, inductively coupled plasma and atomic emission spectroscopy have provided effective tools to efficiently assess the in vitro drug-drug interactions that affect the efficacy profiles of Prussian blue and commonly used antimicrobials such as tetracycline, doxycycline and ciprofloxacin.  Pre-clinical in vivo studies have been initiated to investigate the bioavailability of tetracycline when given in combination with Prussian blue. Additional in vivo studies with other antimicrobials such as doxycycline and ciprofloxacin may ensure a more effective clinical treatment protocol for Acute Radiation Syndrome.

 Mission Relevance and Outcomes: This project will significantly assist the Agency’s ability to protect the public health in the event of a major radiological incident by providing clinically relevant information to assist in the operational planning for the treatment of mass casualties with internal radioactive contamination and acute radiation syndrome.

Thermodynamic and Kinetic Stability of Colloidal Iron Drug Products

 Principal Investigator: Yongsheng Yang

 Public Health Issue: There are currently three different types of parenteral iron formulations that are marketed in the US, iron dextran, iron sucrose, and iron gluconate.  All the marketed products are macromolecular complexes of ferric ion (FeIII+) with bound carbohydrate ligands, and all are colloidal formulations.  Currently there are no generic versions of parenteral iron formulations that would enhance product availability and reduce pharmaceutical costs to the American Public.

 Regulatory Contribution: Bioequilivalence studies conducted previously have been unable to establish bioequilivalence for any colloidal drug product complex due to the endogenous and variable nature of iron in human population groups as well as significant in vivo product iron release variability. The proposed study will provide information to assess the thermodynamic properties and verify stability of parenteral iron colloidal drug products. Scientifically, the concept that bioequivalence should be self evident for colloidal formulations that are in thermodynamic equilibrium, stable and have equivalent chemical compositions. If scientifically proven, ANDA sponsors could be granted an in vivo bioequivalence waiver thereby increasing the likelihood for the introduction of a generic colloidal iron drug product into the marketplace.

 Research Approach: If a colloidal iron formulation has a molecular weight that is strongly correlated with ferric iron/excipient ratio, the degree of dilution, and if the molecular weight does not change under moderate stress conditions, then this would provide scientific evidence that the formulation is in thermodynamic equilibrium and therefore thermodynamically stable. To determine thermodynamic stability, drug products will be exposed to moderate stress conditions based upon temperature and time (accelerated and long-term) in controlled stability chambers. Additionally, the effect of varying the iron/excipient ratios of formulation diluent will be evaluated by adding gluconate, sucrose or diluent to the formulated products. After being stressed, the products will be evaluated with gel permeation chromatography (GPC) to assess changes in molecular weight.

 Mission Relevance and Outcomes: A better understanding of complex iron drug products utilizing this critical path approach will assist the review of ANDA applications by providing a novel scientific approach to establish bioequilivalence.

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DRUG STABILITY

 Shelf Life Extension Program

 Principal Investigator: Jeb S. Taylor

 Public Health Issue: There is a need to maintain the availability of the national drug stockpiles for military operations and civilian readiness for national disasters without the need to fully replace the stockpiles every few years.

 Regulatory Contribution: The FDA developed an approach to shelf life extension by laboratory testing of the original and aged products to predict the continued stability of products. The Division of Field Science Laboratories (ORA) centrally manages the program, which provides the interface with the military and coordinates laboratory examination. The goal of the program is to provide assurance that extended drug products meet the same quality standards as original product and to provide an effective and efficient program for maintaining national drug stockpiles.

 Research Approach: Our Division of Product Quality Research analyzes the analytical data and makes decisions regarding shelf life extensions. Over 2800 lots representing 178 drug products have been tested to date with greater than 80% of the lots extended past their original expiration date. The program provides DPQR with numerous research opportunities including examples of stability failures leading to mechanistic studies and examples of test failures leading to the development new or more robust methods.

 Mission Relevance and Outcomes: This program is designed to save the Federal Government, and the U.S. taxpayer, significant monetary resources by selecting mission critical drug products purchased and stockpiled by Department of Defense and testing them for potency and stability to extend their effective shelf life. The program provides CDER with significant resources including: extensive history of product stability, discovery of product deficiencies, discovery of inadequate or inappropriate release tests and potential for product improvement.

Repackaging Product Stability

Principal Investigator: Mansoor A. Khan

 Public Health Issue: Drug products are often repacked by pharmacists and repackaging companies from their original packaging bulk containers.  The stability of the drug products, in their original packaging, is extensively tested by the drug manufacturers.  But, this is not the case with the repackaged products, which are currently assigned an expiration of 6 months, or the expiration date of the original product, which ever is earlier.  There is regulatory concern regarding the stability of repackaged drugs and the extension of expiration from 6 months to 12 months among FDA reviewers.

 Regulatory Contribution: The study constitutes a part of the work needed by the Office of Compliance to determine if there are possible differences in the stability of several drug products in original versus repackaging.  The drug products used include solid and liquid dosage forms. The result of this study will support the regulatory decision-making process regarding the expiry dating of the repackaged drug products.

 Research Approach: This study is focused on five drug products (phenytoin, gabapentin, metoprolol, ranitidine, furosemide) exposed to two different storage conditions based upon temperature, relative humidity (RH), and time in original and repackage containers.  After the storage period, the products are being evaluated by in vitro test procedures using NDA or USP release tests (dissolution, potency, content uniformity) and physical tests (NIR, FTIR, TGA, DSC, hardness [tablets]).  These test procedures will detect physical and chemical changes that might be taking place during the storage period, and enhance our ability to determine if the product will be safe to use for one year after repackaging as a unit dose.  Physical and chemical changes, if any, that might be taking place during the storage period, can be detected by these test procedures.

 Mission Relevance and Outcomes: The project will enhance our ability to determine if the drug products are safe to use for one year after repackaging as unit dose.

Comparison of the Stability of Whole versus Split Tablets

 Principal Investigator: Abhay Gupta

 Public Health Issue: Solid drug dosage forms are often split to divide a dose into smaller amounts to meet individual patient needs.  There is also a push among healthcare plans to have patients purchase larger doses to be split as a means to reduce medication costs.  Tablets may be cut by the pharmacist for the patient or by the patient and stored for several weeks.

 Regulatory Contribution: The regulatory concern is that the stability of these split tablets may not be the same as the intact product.  While many medications are not appropriate for tablet splitting based upon their shape or formulation, others should not be split due to stability issues.

 Research Approach: The purpose of this study is to compare the stability of whole versus split tablets of commercially available drug products (e.g., Neurontin, Largesic and Norel tablets) following storage over a 9-week period at 25°C and 30°C with 60% relative humidity (RH) using chemical and physical tests.  The project involves dispensing whole or split tablets into amber pharmacy vials and placing in stability chambers at the two temperature and RH conditions.  After the designated storage periods, the products are being evaluated with in vitro assays assessing dissolution, potency, moisture loss and tablet hardness. Near-infrared spectroscopy and imaging, Raman spectroscopy, thermogravimetric analysis, and differential scanning calorimetry are also being used to identify differences between the whole and the split tablets.

 Mission Relevance and Outcomes: The project is part of the division’s mission of product characterization to ensure drug product quality.  Results will enable reviewers, pharmacists and consumers to answer the question whether a drug product may be split and stored for a limited time frame without altering its chemical or physical product qualities.