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Between October 2020 and March 2022, FDA's Center for Drug Evaluation and Research (CDER) completed two pilot programs to assess the quality management maturity (QMM) of drug manufacturing establishments. Mature quality systems promote proactive detection of vulnerabilities, prevent problems before they occur, and foster a culture that rewards process and system improvements. A CDER QMM program may help to advance supply chain resiliency and robustness and mitigate drug shortages. One pilot program evaluated seven establishments located within the U.S. that produce finished dosage form products marketed in the U.S. A second pilot program evaluated eight establishments located outside the U.S. that produce active pharmaceutical ingredients used in drug products marketed in the U.S. The execution of these pilot programs afforded FDA the opportunity to learn important lessons about the establishment QMM assessment process, scoring approach, assessor behaviors, and perceptions of the assessment questions, reports, and ratings. Many of the participating establishments reported that the QMM pilot assessments helped to identify their strengths, weaknesses, and new areas for improvement which they had not previously identified through internal audits or CGMP inspections. There has been a great deal of interest in the outcomes of CDER's QMM pilot programs and this paper describes, for the first time, the lessons CDER learned and will continue to heed in the development of a QMM program., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Importance: Health care practitioners and patients must have information to support their confidence in the quality of prescription pharmaceuticals., Objective: To determine whether there were clear and substantive differences in major quality attributes between difficult-to-make solid oral dosage form pharmaceutical products marketed in the US., Design, Setting, and Participants: This quality improvement study analyzed US Food and Drug Administration-collected samples of 252 drug products marketed in the US and manufactured in the US, Canada, Europe, India, and the rest of Asia. These drug products were immediate-release solid oral dosage forms considered difficult to make on the basis of product quality history. This sampling included 35 innovator and 217 generic drug samples manufactured by 46 different firms containing 17 different active ingredients. Statistical analysis was performed from February to November 2019., Main Outcomes and Measures: All products were tested within their shelf life on the basis of the legally recognized tests of the US Pharmacopeia for the major quality attributes of dosage unit uniformity and dissolution. These tests measure dosage consistency and drug release, respectively. The consistency of either attribute was used to calculate a process performance index to describe the variability in manufacturing., Results: All 252 drug product samples met the US market standards for dosage unit uniformity and dissolution, although the process performance index (Ppk) for dissolution fell below the level of 4-sigma capability (ie, <1 error per 1600) for 11 different manufacturers and for generics in 4 of 5 regions, including the US. As part of a retrospective analysis, manufacturers performing above the median Ppk for either dissolution or dosage unit uniformity submitted fewer product quality defect reports (mean field alert reports of 0.22 and 0.63, respectively) than those falling at or below the median Ppk for these attributes (mean field alert reports of 2.1 and 1.7, respectively)., Conclusions and Relevance: All samples met the US market standards for dosage unit uniformity and dissolution, indicating acceptability for use by patients regardless of manufacturer or region. To our knowledge, this is the largest sampling study of pharmaceutical manufacturers for the US market and these data provide objective insight into the quality of prescription drugs with high manufacturing risks.

Failures surrounding pharmaceutical quality, particularly with respect to product manufacturing issues and facility remediation, account for the majority of drug shortages and product recalls in the United States. Major scientific advancements pressure established regulatory paradigms, especially in the areas of biosimilars, precision medicine, combination products, emerging manufacturing technologies, and the use of real-world data. Pharmaceutical manufacturing is increasingly globalized, prompting the need for more efficient surveillance systems for monitoring product quality. Furthermore, increasing scrutiny and accelerated approval pathways provide a driving force to be even more efficient with limited regulatory resources. To address these regulatory challenges, the Office of Pharmaceutical Quality (OPQ) in the Center for Drug Evaluation and Research (CDER) at the U.S. Food and Drug Administration (FDA) harbors a rigorous science and research program in core areas that support drug quality review, inspection, surveillance, standards, and policy development. Science and research is the foundation of risk-based quality assessment of new drugs, generic drugs, over-the-counter drugs, and biotechnology products including biosimilars. This is an overview of the science and research activities in OPQ that support the mission of ensuring that safe, effective, and high-quality drugs are available to the American public., (Published by Elsevier B.V.)

The bead sizes used in approved modified release capsules labeled for sprinkling on food was investigated to generate bead size guidelines for generic products labeled for sprinkling. The conclusions from a survey of FDA databases were corroborated with experimental data obtained by measuring the bead sizes of several reference-listed drugs on the market labeled for administration by sprinkling on food. The experimental data show that majority of the marketed products were found to have bead sizes of less than 1,500 microm (1.5 mm). Based on this information, a bead size of less than 1,500 microm should generally be considered acceptable for use in generic products labeled for sprinkling.

The United States Food and Drug Administration (FDA) has received numerous reports of serious adverse events, including death, in patients using fentanyl transdermal systems (FTS). To gain a better understanding of these problems, the current research focuses on the in vitro characterization of fentanyl reservoir (Duragesic) and matrix (Mylan) systems with respect to drug release and skin permeation under conditions of elevated temperature and compromised skin. In addition, different synthetic membrane barriers were evaluated to identify the one that best simulates fentanyl skin transport, and thus may be useful as a model for these systems in future studies. The results indicate that reservoir and matrix FTS are comparable when applied to intact skin at normal skin temperature but the kinetics of drug delivery are different in the two systems. At 40 degrees C, the permeation rate of fentanyl was twice that seen at 32 degrees C over the first 24 h in both systems; however, the total drug permeation in 72 h is significantly higher in the reservoir FTS. When applied to partially compromised skin, matrix FTS has a greater permeation enhancement effect than reservoir FTS. The intrinsic rate limiting membrane of the reservoir system served to limit drug permeation when the skin (barrier) permeability was compromised. Different ethylene vinyl acetate membranes were shown to have fentanyl permeability values encompassing the variability in human skin. Results using the in vitro model developed using synthetic membranes suggest that they mimic the effect of compromised skin on fentanyl permeability. Especially for highly potent drugs such as fentanyl, it is important that patients follow instructions regarding application of heat and use of the product on compromised skin.

Purpose: To understand and evaluate the stability and skin permeation profiles of fentanyl reservoir systems as a function of patch age., Methods: Drug release and skin permeation studies were performed using a modified USP apparatus 5 with a novel sample preparation technique., Results: The amount of fentanyl present in the EVA/adhesive layer (EAL) increased from about 17% of label claim (LC) at 5 months to 25% LC at 22 months. The increase in the drug concentration was mainly observed in the peripheral EAL. Simultaneously, the alcohol content of the patch decreased as a function of patch age. A significant effect of patch age on the drug content in the EAL and the drug release from the system was observed; however, skin permeation studies did not indicate an increase in drug delivery rate., Conclusions: Novel sample preparation technique with USP Apparatus 5 allowed determination of in vitro skin permeation rates for fentanyl transdermal patches with different designs. Permeation rates with cadaver skin as substrate were found not to change with patch age despite changing drug concentration in the EAL.

The qualification process for ensuring that a paddle or basket apparatus is suitable for its intended use is a highly debated and controversial topic. Different instrument qualification and suitability methods have been proposed by the pharmacopeias and regulatory bodies. In an effort to internationally harmonize dissolution apparatus suitability requirements, the International Pharmaceutical Federation's (FIP) Dissolution/Drug Release Special Interest Group (SIG) reviewed current instrument suitability requirements listed in the US, European, and Japanese pharmacopeias and the International Conference on Harmonization (ICH) Topic Q4B on harmonization of pharmacopoeial methods, in its Annex 7, Dissolution Test General. In addition, the SIG reviewed the Food and Drug Administration (FDA) Draft Guidance for Industry, "The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2-Current Good Manufacturing Practice (CGMP)" and the related ASTM Standard E2503-07. Based on this review and several in-depth discussions, the FIP Dissolution/Drug Release SIG recommends that the qualification of a dissolution test instrument should be performed following the calibration requirements as indicated in the FDA (draft) guidance. If additional system performance information is desired, a performance verification test using US Pharmacopeia Reference Standard tablet or an established in-house reference product can be conducted. Any strict requirement on the use of a specific performance verification test tablet is not recommended at this time.

Heparin and low molecular heparins are extensively used in the treatment of a wide range of diseases in addition to their classic anticoagulant activity and can be found coating medical devices such as catheters, stents and filters. Early in 2008, a sharp increase in heparin-associated severe adverse events, including over 80 deaths, was linked to the presence of a contaminant identified as hypersulfated chondroitin sulfate (OS-CS). OS-CS is one of several oversulfated glycosaminoglycans (GAGs) of different origins that can potentially cause similar clinical problems underscoring the need to develop robust screening methods for contaminants in existing and future lots of heparin. This study demonstrates that oversulfated GAGs block the activity of Taq polymerase used for real time PCR. Based on this finding we developed a simple, rapid, sensitive and high throughput screening method to detect and quantify oversulfated chondroitin sulfate (OS-CS) and other potential oversulfated contaminants in commercial lots of heparin. This method requires less than 100 miliUnits (mU) of heparin as starting material, therefore avoiding the need to lyophilize and concentrate samples, and has a limit of detection of <1 ng for all oversulfated GAGs tested.

Long term stability measurements were made for the nitrogen mustard mechlorethamine HCl at a concentration of 0.02% in six topical formulations: Aquaphor ointment, Transcutol, Labrasol, 10% Transcutol in Aquaphor, 10% Transcutol in Labrasol, and Aquaphilic ointment. The drug decomposed gradually in Aquaphor ointment at room temperature, dropping to 95% in 4 weeks, 85% in 12 weeks, and 78% in 39 weeks. On the other hand, the drug decomposed rapidly in Aquaphilic ointment, giving an assay of less than 20% of its initial concentration after 24h at room temperature. Generally, mechlorethamine HCl was more stable in Aquaphor ointment than in formulations containing Transcutol or Labrasol. However, the addition of the free radical inhibitor, BHT, significantly enhanced the stability of mechlorethamine in Transcutol and Labrasol formulations. Four BHT-stabilized Transcutol and Labrasol formulations gave assays in ranges of 92-99% at the end of 4 weeks, 77-98% at the end of 12 weeks, and 38-93% at the end of 41 weeks.

Background: There is an urgent need to determine whether oversulfated chondroitin sulfate (OSCS), a compound contaminating heparin supplies worldwide, is the cause of the severe anaphylactoid reactions that have occurred after intravenous heparin administration in the United States and Germany., Methods: Heparin procured from the Food and Drug Administration, consisting of suspect lots of heparin associated with the clinical events as well as control lots of heparin, were screened in a blinded fashion both for the presence of OSCS and for any biologic activity that could potentially link the contaminant to the observed clinical adverse events. In vitro assays for the activation of the contact system and the complement cascade were performed. In addition, the ability of OSCS to recapitulate key clinical manifestations in vivo was tested in swine., Results: The OSCS found in contaminated lots of unfractionated heparin, as well as a synthetically generated OSCS reference standard, directly activated the kinin-kallikrein pathway in human plasma, which can lead to the generation of bradykinin, a potent vasoactive mediator. In addition, OSCS induced generation of C3a and C5a, potent anaphylatoxins derived from complement proteins. Activation of these two pathways was unexpectedly linked and dependent on fluid-phase activation of factor XII. Screening of plasma samples from various species indicated that swine and humans are sensitive to the effects of OSCS in a similar manner. OSCS-containing heparin and synthetically derived OSCS induced hypotension associated with kallikrein activation when administered by intravenous infusion in swine., Conclusions: Our results provide a scientific rationale for a potential biologic link between the presence of OSCS in suspect lots of heparin and the observed clinical adverse events. An assay to assess the amidolytic activity of kallikrein can supplement analytic tests to protect the heparin supply chain by screening for OSCS and other highly sulfated polysaccharide contaminants of heparin that can activate the contact system., (Copyright 2008 Massachusetts Medical Society.)

Recently, certain lots of heparin have been associated with an acute, rapid onset of serious side effects indicative of an allergic-type reaction. To identify potential causes for this sudden rise in side effects, we examined lots of heparin that correlated with adverse events using orthogonal high-resolution analytical techniques. Through detailed structural analysis, the contaminant was found to contain a disaccharide repeat unit of glucuronic acid linked beta1-->3 to a beta-N-acetylgalactosamine. The disaccharide unit has an unusual sulfation pattern and is sulfated at the 2-O and 3-O positions of the glucuronic acid as well as at the 4-O and 6-O positions of the galactosamine. Given the nature of this contaminant, traditional screening tests cannot differentiate between affected and unaffected lots. Our analysis suggests effective screening methods that can be used to determine whether or not heparin lots contain the contaminant reported here.

Purpose: These studies evaluated the ability of common household food and drink products to mask the bitter taste of three selected anti-terrorism drugs., Methods: Three anti-terrorism drugs (doxycycline, ciprofloxacin hydrochloride, and potassium iodide) were mixed with a variety of common household food and drinks, and healthy adult volunteers evaluated the resulting taste and aftertaste. In parallel, the ASTREE Electronic Tongue was used to evaluate taste combinations. Stability of the mixtures over time was monitored, as was the dosage uniformity across preparations., Results: Foods and drinks were identified that satisfactorily masked the bitter flavor of each drug. Dose uniformity and stability were also acceptable over the range studied, although some combinations were significantly less stable than others. The electronic tongue was able to differentiate between tastes, but ranked masking agents in a different order than human volunteers., Conclusions: Doxycycline, potassium iodide, and ciprofloxacin, which are stockpiled in solid tablet form, can conveniently be prepared into more palatable formulations, using common household foods and drinks. The electronic tongue can be used to perform an initial screening for palatability.

Current definitions of lotions, gels, creams and ointments vary depending on literature source, market history or traditional use. This often leads to confusion when deciding which dosage form to prescribe and/or purchase. The existing classification of topical dosage forms needs to be re-examined to ensure that definitions for different dosage forms are based on consistent scientific principles and that dosage forms can be distinguished from one another. The purpose of this study is to obtain a scientifically based, systematic classification of dosage forms for topical drugs. A variety of prescription and over-the-counter topical products currently marketed as lotions, gels, creams, and ointments are evaluated using different techniques including rheology (viscosity and shear rate versus shear stress), loss on drying (LOD), specific gravity, surface tension, thermogravimetric analysis (TGA), water absorption, dilution properties, microscopic evaluation, transmittance of visible light, appearance and composition. Rheology is the most discriminating property separating creams and lotions. Water plus volatiles (as measured by LOD) and composition separate ointments and creams. Composition and thermal behavior separate gels from the other dosage forms. Based on these findings, new definitions and a decision tree are presented to assist in the determination of the appropriate nomenclature for a topical dosage form.