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  1. Center for Drug Evaluation and Research | CDER

Division of Pharmaceutical Analysis Research Programs

1114 Market St. Room 1002
St. Louis, Missouri 63101
Phone: (314) 539-2135 Fax: (314) 539-2113

Lucinda Buhse, Ph.D., Director
Benjamin Westenberger, Deputy Director

Research Programs

The Food and Drug Administration is responsible for ensuring that safe and effective drugs are available to the public from both the innovator and the generic drug industry. This is accompanied with an equal commitment under Prescription Drug User Fee Act (PDUFA) to shorten the time of the approval process. The Division of Pharmaceutical Analysis (DPA) through the verification of New Drug Applications (NDA) analytical procedures ensures that methods are available to demonstrate the quality of new drug formulations. For generic pharmaceutical products, DPA is responsible for evaluating samples collected at clinical laboratories to ensure fraud by substitution has not been committed during the generation of bioequivalence data.

Because the possibility of bioterrorism is a reality of our times, government agencies must be able to distribute suitable pharmaceutical products to the public without delay. In general, only adult solid oral dosage products have been stockpiled and, in order to provide instructions to the public on how to reproducibly administer adult formulations to infants and children, stability, dose uniformity and palatability of drugs in various foods and drinks must be assessed. To address the needs of pediatric formulations during an emergency, the Food and Drug Administration (FDA) is expected to issue emergency instructions for creating a pediatric preparation for infants and small children from stockpiled solid dosages such as capsules or tablets. DPA evaluates of stability, dose uniformity and palatability of home-prepared dosages and results are used as the basis for procedures to create emergency home preparation instructions.

Chromatographic Methods
Ensuring the quality of pharmaceuticals requires the application of suitable analysis methods. However, when the drug substance and/or the drug product matrix are complex, simple analysis methods are often inadequate. Extemporaneous compounding can exacerbate this problem as new, previously unknown, product matrices are often created. DPA develops sophisticated methodology to address special problems as necessary to assure pharmaceutical quality, assess bioequivalence of generic products and provide guidance for reviewers in their negotiations with drug firms.

Biotech Product Characterization –Identification, Degradation, Aggregation
Increasingly, recombinant proteins and protein related products are being formulated as biopharmaceuticals. However, little is known regarding how these proteins behave in solution or how formulation affects protein stability. The functions of a protein are strongly dependent on the interactions between itself and its environment. Bioactivity of proteins can be affected by contamination, protein degradation and protein aggregation. DPA is evaluating technologies to characterize biotech products in terms of identity, stability, and purity.

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The safety of pharmaceuticals is the most critical mission of the Food and Drug Administration. Unsafe drugs can reach the consumer by a number of pathways including foreign Internet purchases or elevated impurity levels. In addition, the safety of approved, compliant pharmaceuticals can be compromised because of drug-drug or drug-food interactions.
The Division of Pharmaceutical Analysis (DPA) provides the Agency with analytical data necessary to make decisions on the safety of drugs available to the public. Examples include evaluating products purchased from foreign Internet sites and measuring the lead concentrations in pharmaceutical products.

Dissolution testing is used as an in vitro surrogate for drug release in formulation development and bioequivalence.  Dissolution tests are also used as quality control measures for most solid dosage form drugs.  An understanding of the sources of variability in this test methodology is critical to setting specifications and interpreting results. Variability inherent in the test method as well as poor product performance can cause failed dissolution results leading to recalls and causing higher drug prices and shortages. DPA is exploring ways to improve set up and qualification of equipment and methods. A well designed and controlled method can detect product design failures that may be contributing to variable clinical trial results.

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Transdermal Drug Delivery Systems (TDDS)
Transdermal drug delivery systems (TDDS), also known as "patches," are dosage forms designed to deliver a therapeutically effective amount of drug across a patient’s skin. Two critical factors affecting TDDS performance are permeability and adhesion. The FDA has received numerous reports of "adhesion lacking" for several TDDS and serious adverse events, including death, for patients using Fentanyl Transdermal Systems (FTS) prompting issuance of a Public Health Advisory regarding the safe use of this potent narcotic medication for pain management. Poorly adhered patches result in low drug permeation and lack of efficacy. In contrast, conditions such as heat, occlusion or compromised skin can cause an overdose. Although in vivo human testing is the most reliable method for evaluation of TDDS adhesion and drug release, the time, money and safety considerations involved in human trials prohibit extensive use of in vivo methods. FDA reviewers need to understand the potential risks involved in the use of FTS in the presence of heat, occlusion and compromised skin. In this study DPA is developing novel in vitro testing methods to evaluate critical attributes of drug release and adhesion of TDDS.

Inhalation Pharmaceuticals
Inhalation drugs, in the forms of nasal sprays, metered-dose inhalers (MDI), dry powder inhalers (DPI), and nebulizers, are traditionally used for treatment of asthma and chronic obstructive pulmonary disease (COPD). Now, inhalation products are being used and considered for delivery of a large variety of pharmaceutical products including vaccines, migraine medication and insulin. Analytical methods need to be in place to ensure the quality of inhalation drugs and to allow for assessment of equivalency for generics. DPA is evaluating sources of variability in current methodologies and evaluating new technologies for characterizing inhalation products. An understanding of the limitations and abilities of these new techniques is crucial to the Agency as a knowledge base for guidance development and drug application evaluation by reviewers. An understanding of the sources of variations in in vitro testing of inhalation products, and the limitations and capabilities of new techniques for PSD measurements will lead to improved regulatory decision-making and help the Agency to develop guidance to the pharmaceutical industry to ensure quality and equivalency of inhalation products.

Nanotech Drug Products – Characterization of Nano Particulate-containing Sunscreens 
An in vivo toxicology assessment of dermal penetration of TiO2 and its possible toxicological implications is being conducted in pigs, in collaboration with NCTR.  In addition, DPA, in collaboration with NIST, is assessing methodologies to determine the particle size of ZnO and TiO2 in sunscreen formulations.  There are many methods to determine particle size/particle size distribution for bulk, unformulated material.  However, these methodologies may not apply to formulated materials and subsequently, particle size measurements become far more challenging.

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Spectroscopic Characterization of Drug Substances and Drug Products
The quality of pharmaceutical finished dosage forms is of major concern to the FDA. Process Analytical Technology (PAT) tools include spectroscopy and spectroscopic imaging which provide non-destructive measures of critical quality attributes such as API content, approved drug polymorphic form, homogeneity, coating thickness and the internal structure of regular and complex solid dosage forms. DPA studies focus on evaluating terahertz, near infrared (NIR) and Raman spectroscopy and imaging to study pharmaceutical materials and finished dosage forms. Understanding the advantages and limitations of these technologies for pharmaceutical manufacturing is vital for support of regulatory decision-making concerning application of process analytical technologies in pharmaceutical manufacturing.

Transdermal Drug Delivery Systems
Transdermal drug delivery Systems (TDDSs) represent a class of dosage forms which offer many advantages compared to traditional routes of administration. With the advent of physical and chemical penetration enhancement methods, the number of systemic disorders treated by these devices will only increase. Drug databases, such as the Drug Quality Reporting System (DQRS), cite repeated incidents where product quality shortcomings, particularly in regard to proper adhesion, have led to no therapeutic or severe adverse effects (e.g. death). DPA is developing a formal risk-based approach to the study of these systems to define a general framework in which processing steps and product quality attributes critical to safety and efficacy could be identified. The Agency is committed to a risk-based approach in the drug/device review process. Already manufacturers are encouraged to submit risk analyses as part of their drug/device applications to demonstrate that issues, relating to the likelihood of harm associated with the use of a product and an assessment of its severity, have been given due consideration. The unique attributes and risks associated with TDDSs make them suitable to illustrate the use of risk assessment tools.

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