Bioavailability assessment of a brompheniramine taste-masked pediatric formulation in a juvenile porcine model.

A brompheniramine taste-masked pediatric formulation was developed as part of the National Institutes of Health Pediatric Formulation Initiative to help address low patient compliance caused by the bitter taste of many adult formulations. To confirm that the taste-masked formulation can provide a similar pharmacological effect to the previous marketed adult formulations, a juvenile porcine model was used to screen the model pediatric formulation to compare the bioavailability between the marketed brompheniramine maleate and the taste-masked maleate/tannate formulation. Pigs were dosed orally with both formulations and blood samples were obtained from 0 to 48 h. Plasma samples were prepared and extracted using solid-phase extraction. The mass spectrometer was operated under selected ion monitoring mode. The selected ion monitoring channels were set to m/z 319.1 for brompheniramine and m/z 275.2 for the internal standard chlorpheniramine. Calibration curves were linear over the analytical range 0.2-20 ng/ml (r2 > 0.995) for brompheniramine in plasma. The intra- and inter-day accuracies were between 98.0 and 105% with 5.73% RSD precision. The bioanalytical method was successfully applied to a preclinical bioavailability study. The bioavailability profiles were not significantly different between the two formulations, which demonstrates that taste-masking with tannic acid is a promising approach for formulation modification for pediatric patients.

Nitroso Impurities in Drug Products: An Overview of Risk Assessment, Regulatory Milieu, and Control Strategy.

Many nitrosamines have been recognized to be carcinogenic for many decades. Despite the fact that several nitrosamine precursors are frequently used in the manufacturing of pharmaceutical products, their potential presence in pharmaceutical products has previously been overlooked due to a lack of understanding on how they form during the manufacturing process. From the risk assessment, it is clear that nitrosamines or their precursors may be present in any component of the finished dosage form. As a risk mitigation strategy, components with a high potential to form nitrosamine should be avoided. In the absence of suitable alternatives, sufficient measures to maintain nitrosamines below acceptable intake levels must be applied. Excipient manufacturing pathways must be extensively studied in order to identify probable excipient components that may contribute to nitrosamine formation. The manufacturers must not solely rely on pharmacopeial specifications for APIs and excipients, rather, they should also develop and implement additional strategies to control nitrosamine impurities. The formulation can be supplemented with nitrosating inhibitors, such as vitamin C, to stop the generation of nitrosamine. The purpose of this review is to identify key risk factors with regard to nitrosamine formation in pharmaceutical dosage forms and provide an effective control strategy to contain them below acceptable daily intake limits.

Data integrity issues in pharmaceutical industry: Common observations, challenges and mitigations strategies.

Data integrity (DI) reaffirms the pharmaceutical industry's commitment to manufacture drugs that are safe, effective and fulfil quality standards. At the same time, DI is a crucial tool for regulatory authorities to use in protecting public health. Recent FDA Form-483 observations and warning letters indicate that DI is the main issue the pharmaceutical industry is currently dealing with. Failure to comply with DI requirements may result in a high number of un-validated results, which may cause post-marketing issues and frequent product recalls. To address the underlying causes of DI problems, a comprehensive approach is necessary. The majority of DI issues are caused by poor quality culture, organizational or individual behaviour, leadership, processes, or technology. DI should be effectively integrated into the quality management system, and it should apply to both paper and electronic records. Employees should be trained on 21 CFR Part 11. Consistent review and audit are required to ensure that procedures are followed and audit trails are generated. Electronic systems, in addition to being an efficient solution (system integration, data verification at both input and output, security), offer advantages over traditional paper-based systems in terms of improved compliance with DI regulatory requirements. For example, many electronic system platforms provide enhanced security features and audit trail capabilities. Finally, management support for data governance is essential for successful implementation of DI. This article reviews commonly observed deviations by FDA pertaining to DI and discusses measures to be undertaken to avoid them.

In-use stability assessment of FDA approved metformin immediate release and extended release products for N-Nitrosodimethylamine and dissolution quality attributes.

Metformin is a widely used first-line oral antidiabetic agent. TheFood and Drug Administration (FDA) confirmed the presence of the ofN-nitrosodimethylamine (NDMA) impurity, a carcinogenic, above the acceptable daily intake (ADI, 96 ng/day) in certain metformin products. The objective of the present study was to assess in-use stability of commercial metformin products for NDMA and dissolution quality attributes. Four immediate-release (M1-M4) and six extended-rerelease (M5-M10) metformin products were evaluated in the stability testing. All products were repacked in pharmacy vials and stored at 30 °C/75% RH for 12 weeks. Five products (M2, M3, M5, M7 and M10) had NDMA level above ADI limit (96 ng/day) before in-use stability exposure. NDMA in M2 (1164 ± 52.9 ng/tablet) and M3 (3776 ± 351.9 ng/tablet) products were 12 and 39 folds of ADI, respectively. Similarly, ER products, M5 (191 ± 94.1 ng/tablet), M7 (1473 ± 47.3 ng/tablet) and M10 (423 ± 55.8 ng/tablet) exhibited NDMA of 1.9, 15.3 and 4.4 folds of ADI, respectively. The impurity level significantly (p < 0.05) increased after 12-week stability exposure to 2.72, 2.47, 2.23 and 2.78 folds of initial values in M2, M3, M7 and M10. In summary, these findings suggested that carcinogenic impurity generation was affected by in-use stability condition exposure and it is expected that several more products currently in the market may also be recalled soon.

Additive Manufacturing with 3D Printing: Progress from Bench to Bedside.

Three-dimensional (3D) printing was discovered in the 1980s, and many industries have embraced it, but the pharmaceutical industry is slow or reluctant to adopt it. Spiritam® is the first and only 3D-printed drug product approved by FDA in 2015. Since then, the FDA has not approved any 3D-printed drug product due to technical and regulatory issues. The 3D printing process cannot compete with well-established and understood conventional processes for making solid dosage forms. However, pharmaceutical companies can utilize it where mass production is not required; rather, consistency, precision, and accuracy in quality are paramount. There are many 3D printing technologies available, and not all of them are amenable to pharmaceutical manufacturing. Each 3D technology has certain prerequisites in terms of material that it can handle. Some of the pertinent technical and regulatory issues are as follows: Current Good Manufacturing Practice, in-process tests and process control, and cleaning validation. Other promising area of 3D printing use is printing medications for patients with special needs in a hospital and/or pharmacy setting with minimum regulatory oversight. This technology provides a novel opportunity for in-hospital compounding of necessary medicines to support patient-specific medications. However, aspects of the manufacturing challenges and quality control considerations associated with the varying formulation and processing methods need to be fully understood before 3D printing can emerge as a therapeutic tool. With these points in mind, this review paper focuses on 3D technologies amenable for pharmaceutical manufacturing, excipient requirement, process understanding, and technical and regulatory challenges.

Defining Patient Centric Pharmaceutical Drug Product Design.

The term "patient centered," "patient centric," or "patient centricity" is increasingly used in the scientific literature in a wide variety of contexts. Generally, patient centric medicines are recognized as an essential contributor to healthy aging and the overall patient's quality of life and life expectancy. Besides the selection of the appropriate type of drug substance and strength for a particular indication in a particular patient, due attention must be paid that the pharmaceutical drug product design is also adequately addressing the particular patient's needs, i.e., assuring adequate patient adherence and the anticipate drug safety and effectiveness. Relevant pharmaceutical design aspects may e.g., involve the selection of the route of administration, the tablet size and shape, the ease of opening the package, the ability to read the user instruction, or the ability to follow the recommended (in-use) storage conditions. Currently, a harmonized definition on patient centric drug development/design has not yet been established. To stimulate scientific research and discussions and the consistent interpretation of test results, it is essential that such a definition is established. We have developed a first draft definition through various rounds of discussions within an interdisciplinary AAPS focus group of experts. This publication summarizes the outcomes and is intended to stimulate further discussions with all stakeholders towards a common definition of patient centric pharmaceutical drug product design that is useable across all disciplines involved.

Risk based in vitro performance assessment of extended release abuse deterrent formulations.

High strength extended release opioid products, which are indispensable tools in the management of pain, are associated with serious risks of unintentional and potentially fatal overdose, as well as of misuse and abuse that might lead to addiction. The issue of drug abuse becomes increasingly prominent when the dosage forms can be readily manipulated to release a high amount of opioid or to extract the drug in certain products or solvents. One approach to deter opioid drug abuse is by providing novel abuse deterrent formulations (ADF), with properties that may be viewed as barriers to abuse of the product. However, unlike regular extended release formulations, assessment of ADF technologies are challenging, in part due to the great variety of formulation designs available to achieve deterrence of abuse by oral, parenteral, nasal and respiratory routes. With limited prior history or literature information, and lack of compendial standards, evaluation and regulatory approval of these novel drug products become increasingly difficult. The present article describes a risk-based standardized in-vitro approach that can be utilized in general evaluation of abuse deterrent features for all ADF products.

A long-term stability study of Prussian blue: A quality assessment of water content and cesium binding.

Prussian blue (PB) is the active pharmaceutical ingredient (API) of Radiogardase, the first approved medical countermeasure for the treatment of radiocesium poisoning in the event of a major radiological incident such as a "dirty bomb" or nuclear attack. The purpose of this study is to assess the long-term stability of Prussian blue drug products (DPs) and APIs under laboratory storage condition by monitoring the loss in water content and the in vitro cesium binding. The water content was measured by thermal gravimetric analysis (TGA). The in-vitro cesium binding study was conducted using a surrogate model to mimic gastric residence and intestinal transport. Free cesium was analyzed using a validated flame atomic emission spectroscopy (AES) method. The binding equilibrium was reached at 24h. The Langmuir isotherm was plotted to calculate the maximum binding capacity (MBC). Comparison of the same PB samples with 2003 data samples, the water content of both APIs and DPs decreased on an average by approximately 12-24%. Consequently, the MBC of cesium was decreased from 358mg/g in 2003 to 265mg/g @ pH 7.5, a decrease of approximately 26%. The binding of cesium is also pH dependent with lowest binding at pH 1.0 and maximum binding at pH 7.5. At pH 7.5, the amount of cesium bound decreased by an average value of 7.9% for APIs and 8.9% for DPs (for 600ppm initial cesium concentration). These findings of water loss, pH dependence and decrease in cesium binding are consistent with our previously published data in 2003. Over last 10 years the stored DPs and APIs of PB have lost about 20% of water which has a negative impact on the PB cesium binding, however PB still meets the FDA specification of >150mg/g at equilibrium. The study is the first quantitative assessment of the long-term stability of PB and directs that proper long-term and short-term storage of PB is required to ensure that it is safe and efficacious at the time of an emergency situation.

Long-term stability study of Prussian blue - a quality assessment of water content and thallium binding.

The purpose of this study is to assess the long-term stability of Prussian blue (PB) drug product (DP) and active pharmaceutical ingredient (API) under laboratory storage conditions by monitoring the loss in water content and the corresponding change of the in vitro thallium binding capacity that represents product performance. The bound water content and the in vitro thallium binding capacity of PB DPs and APIs were measured in 2003 and 2013, respectively. Water content, a critical quality attribute that directly correlates to the thallium (Tl) binding capacity was measured by thermal gravimetric analysis (TGA). The thallium binding study was conducted by testing PB in buffered solutions over the human gastrointestinal pH range with thallium concentrations ranging from 600 to 1,500 ppm. Samples were incubated at physiological temperature of 37°C in a shaking water bath to mimic gastric flux and intestinal transport. The binding equilibrium was reached at 24h. Following incubation, each sample was filtered and the free thallium was analyzed using a validated inductively coupled plasma spectroscopic method (ICP). The Langmuir isotherm was plotted to calculate maximum binding capacity (MBC). Compared with 2003, the water content of DP-1 decreased by about 14.1% (from 15.6 to 13.4 mol), and the MBC of DP-1 decreased by about 12.5% (from 714 to 625 mg/g) at pH 7.5. When low concentration of thallium (600 ppm) was used at pH 7.5, the Tl binding remained comparable for both API-1 (286 vs 276 mg/g) and DP-1 (286 vs 268 mg/g). Similarly, the Tl binding remained unchanged for both API-1 (237 vs 255 mg/g) and DP-1 (234 vs 236 mg/g) at pH 5.0. However, at pH 1.0 the binding was reduced 32.3% and 25.9% for API-1 and DP-1, respectively. Since the majority of binding takes place in the upper GI tract where pH around 5 can be expected, and therefore, the Tl binding capacity of PB should be comparable for new and aged samples. The findings that Tl binding changes with the water loss of PB and pH conditions are consistent with our previously published data. The study also represents the first quantitative assessment of the long-term stability of PB. Over last 10 years, PB DPs and APIs have lost about 20% water under ambient laboratory storage conditions which are consistent with a controlled warehouse environment. While the maximum binding capacity of PB to thallium was decreased after about 10 years of long-term storage, it is still very effective, suggesting that the shelf life of PB should be much longer than the manufacturer ascribed expiration date of 2008 under proper storage conditions.

Understanding pharmaceutical quality by design.

This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes its objectives. QbD elements include the following: (1) a quality target product profile (QTPP) that identifies the critical quality attributes (CQAs) of the drug product; (2) product design and understanding including identification of critical material attributes (CMAs); (3) process design and understanding including identification of critical process parameters (CPPs), linking CMAs and CPPs to CQAs; (4) a control strategy that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for each step of the manufacturing process; and (5) process capability and continual improvement. QbD tools and studies include prior knowledge, risk assessment, mechanistic models, design of experiments (DoE) and data analysis, and process analytical technology (PAT). As the pharmaceutical industry moves toward the implementation of pharmaceutical QbD, a common terminology, understanding of concepts and expectations are necessary. This understanding will facilitate better communication between those involved in risk-based drug development and drug application review.

Pharmaceutical characterization and thermodynamic stability assessment of a colloidal iron drug product: iron sucrose.

The study objective was to evaluate the thermodynamic stability of iron sucrose complexes as determined by molecular weight (m.w.) changes. The first part of the study focused on the effect of thermal stress, pH, electrolyte or excipient dilution on the stability of a colloidal iron drug product. Part two focused on the physical and chemical evaluation of the colloidal nature of iron sucrose using a series of characterization experiments: ultracentrifugation, dialysis, particle size, zeta potential, and osmotic pressure analysis. A validated Taguchi-optimized high performance gel permeation chromatography method was used for m.w. determinations. Results indicate m.w. of the iron sucrose complex remained unchanged after excipient dilution, ultracentrifugation, dialysis, and electrolyte dilution. Electrolyte dilution studies indicated the lyophilic nature of the iron sucrose colloid with a particle size of 10nm and zeta potential of 0 mV. The complex deformed at low pH and reformed back at the formulation pH. The complex is stable under mild-to-moderate temperature <50°C but aggregates following prolonged exposure to high temperatures >70°C. In conclusion, the resistance of the complex to breakdown by electrolytic conditions, excipient dilution, ultracentrifugation and the reversible complexation after alteration of formulation pH suggest iron sucrose is a lyophilic colloid in nature and lyophilic colloidals are thermodynamically stable.

A quality by design (QbD) case study on liposomes containing hydrophilic API: I. Formulation, processing design and risk assessment.

The purpose of this study was to extend QbD principles to liposomal drug products containing a hydrophilic active pharmaceutical ingredient (API) to demonstrate both the feasibility and the advantages of applying QbD concepts to liposome based complex parenteral controlled release systems. The anti-viral drug Tenofovir was selected as a model compound. Desired properties for two of the key liposome drug product qualities, namely the particle size and drug encapsulation efficiency, were defined and evaluated. It was observed that the liposome preparation process significantly affects liposome particle size, and this resulted in considerable variation in the drug encapsulation efficiency. Lipid chain length did not have a significant effect on drug encapsulation efficiency. However, lipid concentration did affect the drug encapsulation efficiency with higher lipid concentrations resulting in higher drug encapsulation. The use of risk assessment in this study assisted the identification of eight high risk factors that may impact liposome drug encapsulation efficiency and particle size.

A QbD case study: Bayesian prediction of lyophilization cycle parameters.

As stipulated by ICH Q8 R2 (1), prediction of critical process parameters based on process modeling is a part of enhanced, quality by design approach to product development. In this work, we discuss a Bayesian model for the prediction of primary drying phase duration. The model is based on the premise that resistance to dry layer mass transfer is product specific, and is a function of nucleation temperature. The predicted duration of primary drying was experimentally verified on the lab scale lyophilizer. It is suggested that the model be used during scale-up activities in order to minimize trial and error and reduce costs associated with expensive large scale experiments. The proposed approach extends the work of Searles et al. (2) by adding a Bayesian treatment to primary drying modeling.

Quality-by-Design (QbD): an integrated process analytical technology (PAT) approach for real-time monitoring and mapping the state of a pharmaceutical coprecipitation process.

In this work, an integrated PAT approach was developed for monitoring a pharmaceutical (naproxen) and a polymer (eudragit) coprecipitation process: real-time in-line near-infrared (NIR) absorbance monitoring, real-time on-line turbidity monitoring, and in situ crystal size monitoring. The data and information obtained through these three monitoring techniques confirmed the observation of the onsets of three distinct stages: incubation, nucleation, and crystal growth. The process trajectory constructed based on results of applying principal component analysis (PCA) to either process NIR spectra data or process turbidity profile, clearly demonstrated that various distinguishable process events, including incubation, nucleation, and crystal growth, could be accurately tracked and differentiated. These findings were further supported by process knowledge and information, such as process design, process sequence, thermodynamic and mass-transfer analysis. Therefore, this work provides a case study that illustrated a rational approach to develop a science-based and knowledge-based process monitoring strategy, which is essential for establishing both a suitable process control strategy and an operational process space for a pharmaceutical unit operation.

Thermodynamic stability assessment of a colloidal iron drug product: sodium ferric gluconate.

A high performance gel permeation chromatography (HP-GPC) method was developed, validated and used to determine the molecular weight (MW) of sodium ferric gluconate following various stress conditions. The intra-day accuracy (90-103%), intra-day precision (1.5-2.7%), inter-day accuracy (91-105%), inter-day precision (1.3-3.2%) were within acceptable range stated in FDA guidance. The MW of sodium ferric gluconate remained unchanged after: (1) autoclaving (121 degrees C), (2) moderate thermal stress (30 days at 50 degrees C or 7 days at 70 and 90 degrees C), (3) excipient dilution, (4) basic buffer dilution (pH of 8 and 9), (5) ultracentrifugation, (6) dialysis, and (7) electrolyte dilution. However sodium ferric gluconate showed signs of instability at higher temperatures (>90 degrees C) after 30 days and at pH of 10-11. Sodium ferric gluconate was found to be a lypophilic colloidal solution with an average particle size of 10 nm and a zeta potential of -13 mV. The colloid osmotic pressure was 3.5 mmHg and remained unchanged after moderate thermal stress. Additionally, in-house drug products with similar MW to sodium ferric gluconate were produced by three different synthetic procedures, suggesting that this colloidal iron drug product might be thermodynamically stable.

Controlled release of a self-emulsifying formulation from a tablet dosage form: stability assessment and optimization of some processing parameters.

The objective of this study was to evaluate the effect of some processing parameters on the release of lipid formulation from a tablet dosage form. A 17-run, face-centered cubic design was employed to evaluate the effect of colloidal silicates (X(1)), magnesium stearate mixing time (X(2)), and compression force (X(3)) on flow, hardness, and dissolution of Coenzyme Q(10) (CoQ(10)) lipid formulation from a tablet dosage form. The optimized formulation was subsequently subjected to a short-term accelerated stability study. All preparations had a flowability index values ranging from 77 to 90. The cumulative percent of CoQ(10) released within 8h (Y(5)) ranged from 40.6% to 90% and was expressed by the following polynomial equation: Y(5)=49.78-16.36X(1)+2.90X(2)-3.11X(3)-0.37X(1)X(2)+1.06X(1)X(3)-1.02X(2)X(3)+11.98X(1)(2)+10.63X(2)(2)-7.10X(3)(2). When stored at 4 degrees C, dissolution rates were retained for up to 3 months. Storage at higher temperatures, however, accelerated lipid release and caused leakage, and loss of hardness. Processing parameters have a profound effect on the release of lipid formulations from their solid carriers. While optimized controlled release formulations could be attained, further considerations should be made to prepare "liquisolids" that are physically stable at higher storage temperatures.