An Industry Perspective on Compatibility Assessment of Closed System Drug-Transfer Devices for Biologics

The Formulation Workstream of the BioPhorum Development Group (BPDG), an industry-wide consortium, has identified the increased use of closed system drug-transfer devices (CSTDs) with biologics, without an associated compatibility assessment, to be of significant concern. The use of CSTDs has increased significantly in recent years due to the recommendations by NIOSH and USP that they be used during preparation and administration of hazardous drugs. While CSTDs are valuable in the healthcare setting to reduce occupational exposure to hazardous compounds, these devices may present particular risks that must be adequately assessed prior to use to ensure their compatibility with specific types of drug products, such as biologic drugs, which may be sensitive. The responsibility of ensuring quality of biologic products through preparation and administration to the patient lies with the drug product sponsor. Due to the significant number of marketed CSTD systems, and the large variety of components offered for each system, a strategic, risk-based approach to assessing compatibility is recommended herein. In addition to traditional material compatibility, assessment of CSTD compatibility with biologics should consider additional parameters to address specific CSTD-related risks. The BPDG Formulation Workstream has proposed a systematic risk-based evaluation approach as well as a mitigation strategy for establishing suitability of CSTDs for use.     

A Systematic Approach to Drug Abuse Treatment Referral

Abstract

The clinical opiate withdrawal scale (COWS) is a clinician-administered, pen and paper instrument that rates eleven common opiate withdrawal signs or symptoms. The summed score of the eleven items can be used to assess a patient's level of opiate withdrawal and to make inferences about their level of physical dependence on opioids. With increasing use of opioids for treatment of pain and the availability of sublingual buprenorphine in the United States for treatment of opioid dependence, clinical assessment of opiate withdrawal intensity has received renewed interest. Buprenorphine, a partial opiate agonist at the mu receptor, can precipitate opiate withdrawal in patients with a high level of opioid dependence who are not experiencing opioid withdrawal. Since development of the first opiate withdrawal scale in the mid-1930s, many different opioid withdrawal scales have been used in clinical and research settings. This article reviews the history of opiate withdrawal scales and the context of their initial use. A template version of the COWS that can be copied and used clinically is appended. PDF formatted versions of the COWS are also available from the websites of the American Society of Addiction Medicine, the California Society of Addiction Medicine, the UCLA Integrated Substance Abuse Programs, and AlcoholMD.com.     

An Application of the Population Approach to Animal Pharmacokinetics During Drug Development

Abstract

Serum concentrations of a drug under development were obtained from an animal pharmacokinetic study using the one sample per animal design, and analyzed using the population data analysis program, NONMEM. A two compartment open model with IV administration was fitted to the data. Although sex and weight were not predictors of clearance (CL), sex helped to explain the variability in the volume of central compartment (V₁). the variability in CL and V₁ were 23.5 and 23.2%, respectively, while the variability in the transfer rate constants, k₁₂ and k₂₁ were infinitesimal. Removal of variability in these micro rate constants did not affect the NONMEM objective function. the inter-animal variability estimated in these parameters were actually a composite of inter-animal variability and residual intra-animal variability since there was no information in the data sets for the estimation of the latter. the typical population parameter values with relative standard errors (expressed as percent coefficient of variation) are: CL (ml/min) of 0.4 (7.8%), V_{1 male} (ml) of 19.1 (6.7%), and V_{1 female} (ml) of V_{1 male}* 0.8 (10.4%), k₁₂ (h^?1) of 0.01 (15.3%), and k₂₁ (h^?1) of 0.005 (38.5%). Although NONMEM permitted some explanation of variability (in a group of animals (rats) used in this quantic pharmacokinetic study) in terms of sex, efficient partitioning between inter-and residual intra-animal variability would require an increase in the number of samples per animal.     

Editorial: A Systems Approach to Drug Development and to Drug Therapy

Pharmaceutical Research -     

A Rational Approach to Drug Development: The Exploratory Phase

Abstract

Ibuprofen powders were blended with phospholipids to prepare physical mixtures or made into solid dispersions by the solvent method and their comparative dissolution profiles were studied. Ibuprofen exhibited significantly improved dissolution rates in phospholipid coprecipitates compared to either physical mixtures or the pure ibuprofen. the coprecipitates of phospholipid-ibuprofen were made at 1:10, 1:20, 1:30 and 1:40 ratios and dissolution profiles were monitored up to 90 minutes. Marginal increase in dissolution rates were observed by increasing the phosopholipid-ibuprofen ratio from 1:40 to 1:20 and further increase to 1:10 ratio did not produce any difference. the coprecipitates of phosopholipid-ibuprofen at a 1:20 ratio showed more than 2 fold increase in the total amount dissolved in water after 90 minutes compared to ibuprofen alone. No significant difference was observed among the three phospholipids in terms of enhancing dissolution rate of ibuprofen in water. When studies were conducted with 1:20 phospholipid—ibuprofen at pH 2.2 medium, the total amount dissolved in water after 90 minutes varied significantly among the phospholipids studied. DSPC showed best results followed by DPPC and DMPC respectively.     

A Rational Approach to Drug Development: The Confirmatory Phase

A rational approach to drug development would be model-based, target label and knowledge driven where the objective is to characterize the response surface – the interplay of drug regimen/exposure, and patient factors to elicit response (efficacy/safety) – that would result in the right dose for the right patient at the time of marketing the drug. This implies using population PK/PD, knowledge discovery and creation approaches, clinical trial simulation, appropriate surrogate/clinical endpoints, and appropriate statistical analysis for the characterization of the response surface. It also implies interacting with regulatory authorities prior to the initiation of clinical development and throughout the phases of clinical development to ensure that appropriate data to support a new drug application are being generated. To enable further characterization of the response surface in the later phases of development (i.e. phase IIb and beyond) and registration, the confirm–learn aspect of the learn–confirm–learn paradigm of drug development is advocated as the basis for answering the crucial drug development questions – “Is the NCE tolerated and at what dose range?” and “Does it work within the tolerated dose range?”     

Product-Specific Impact of Viscosity Modulating Formulation Excipients During Ultra-High Concentration Biotherapeutics Drug Product Development

Developing ultra-high concentration biotherapeutics drug products can be challenging due to increased viscosity, processing, and stability issues. Excipients used to alleviate these concerns are traditionally evaluated at lower protein concentrations. This study investigates whether classically known modulators of stability and viscosity at low (<50 mg/mL) to high (>50 – 150 mg/mL) protein concentrations are beneficial in ultra-high (>150 mg/mL) concentration protein formulations and drug products. This study evaluates the effect of arginine monohydrochloride, proline, and lysine monohydrochloride on viscosity and concentratability at different high and ultra-high protein concentrations using a monoclonal antibody, mAbN, formulation as a candidate protein system. The effect of excipients on the viscosity and concentratability (rate and extent) was different at high versus ultra-high protein concentrations. These results highlight that classical excipients in literature known to modulate protein interactions at low protein concentrations and reduce viscosity at high protein concentrations may need to be evaluated at target protein concentrations in a product-specific manner while developing ultra-high concentration biologics drug products.     

Oral Dispersible System: A New Approach in Drug Delivery System

Dosage form is a mean used for the delivery of drug to a living body. In order to get the desired effect the drug should be delivered to its site of action at such rate and concentration to achieve the maximum therapeutic effect and minimum adverse effect. Since oral route is still widely accepted route but having a common drawback of difficulty in swallowing of tablets and capsules. Therefore a lot of research has been done on novel drug delivery systems. This review is about oral dispersible tablets a novel approach in drug delivery systems that are now a day''s more focused in formulation world, and laid a new path that, helped the patients to build their compliance level with the therapy, also reduced the cost and ease the administration especially in case of pediatrics and geriatrics. Quick absorption, rapid onset of action and reduction in drug loss properties are the basic advantages of this dosage form.     

Closed System Transfer Devices (CSTDs): Understanding Potential Over- and Under- Dosing of Liquid Vial Drug Products and How to Generally Mitigate

Closed system transfer devices (CSTDs) are a major challenge for drug manufacturers to assess and assure drug compatibility and acceptable dosing accuracy for a range of clinical administration strategies. In this article, we systematically investigate parameters affecting the loss of product during transfer by CSTDs from vials to infusion bags. We show that liquid volume loss increases with vial size, vial neck diameter, and solution viscosity - while dependent on stopper design. We further compared CSTDs’ performance with a traditional syringe transfer and learned that loss is larger for CSTDs than for syringe transfer. Based on experimental data, a statistical model was developed to predict drug loss upon transfer by CSTDs. The model predicted that, for single dose vials with USP<1151> conforming overfill, a complete extraction and transfer of the full dose can be assured for a broad range of CSTDs, product viscosities, and vial types (2R, 6R, 10R, 20R) if a flush (of syringe, syringe adaptor, bag spike) is performed. The model also predicted that complete transfer cannot be achieved for fill volumes ≤ 2.0 mL. For multi-dose vials and pooling of several vials, respectively, the effective dose transfer (i.e., ≥ 95%) for all CSTDs tested was predicted to be achieved if a minimum of 5.0 mL is transferred.     

A System for Evaluating Local Alcohol and Drug Use Prevention Initiatives

Local alcohol and drug use prevention in Sweden has witnessed a substantial surge in recent years, with government funding for local coordinators in every municipality. Whether this has contributed to the recent decline in alcohol use among young people is unknown. The ESAPP project evaluates local alcohol and drug prevention in the 18 municipalities that comprise Stockholm. In order to obtain knowledge of prevention activities and their role in outcomes and to stimulate sharing of experiences, a Web-based reporting system was developed in collaboration with the local coordinators. There has been considerable variation in the use of this reporting system and its potential has not been realized.     

A Rational, Systematic Approach for the Development of Vaccine Formulations

With the continuous emergence of new infectious diseases and new strains of current diseases, such as the novel H1N1 influenza in 2009, in combination with expanding competition in the vaccine marketplace, the pressure to develop vaccine formulations right the first time is increasing. As vaccines are complex, costly, and have high risk associated with their development, it is necessary to maximize the potential for development of a successful formulation quickly. To accomplish this goal, the historical empirical approach to formulation development needs to be updated with a rational, systematic approach allowing for more rapid development of safe, efficacious, and stable vaccine formulations. The main components to this approach are biophysical characterization of the antigen, evaluation of stabilizers, investigation of antigen interactions with adjuvants, evaluation of product contact materials, and monitoring stability both in real time and under accelerated conditions. An overview of investigations performed for each of these components of formulation development is discussed. The information gained in these studies is valuable in forming the base of knowledge for the design of a robust formulation. With the use of continually advancing technology in combination with maintaining a rational, systematic approach to formulation development, there is a great increase in the probability of successfully developing a safe, effective, and stable vaccine formulation.     

On the Risk of Nitrosamine Contamination During Drug Product Blister Packaging

Most N-Nitrosamine compounds are found to be genotoxic in several animal species. Some are classified as probable or possible human carcinogens and very low acceptable daily intake has been established such as 96 ng/day for N-nitrosodimethylamine (NDMA) and 26.5 ng/N-nitrosodiethylamine (NDEA). The pharmaceutical industry has considered all processing areas for potential formation or contamination of N-nitrosamine. One risk is the potential contamination of nitrosamine during drug product blister packaging using lidding foils containing nitrocellulose, and different approaches have been used by pharmaceutical companies to evaluate and mitigate this risk. Herein we share a perspective from IQ Consortium N-nitrosamine Working Group on some of the approaches and corresponding results. From these assessments, it was concluded that the risk of nitrosamine contamination during blister packaging is negligible. The approaches shared in this perspective can be incorporated into risk assessment for nitrosamine contamination during drug product packaging at other pharmaceutical companies.     

A New Approach in Gastroretentive Drug Delivery System Using Cholestyramine

We prepared cellulose acetate butyrate (CAB)-coated cholestyramine microcapsules as a intragastric floating drug delivery system endowed with floating ability due to the carbon dioxide generation when exposed to the gastric fluid. The microcapsules also have a mucoadhesive property. Ion-exchange resin particles can be loaded with bicarbonate followed by acetohydroxamic acid (AHA) and coated with CAB by emulsion solvent evaporation method. The drug concentration was monitored to maintain the floating property and minimum effective concentration. The effect of CAB: drug-resin ratio (2:1, 4:1, 6:1 w/w) on the particle size, floating time, and drug release was determined. Cholestyramine microcapsules were characterized for shape, surface characteristics, and size distribution; cholestyramine/acetohydroxamic acid interactions inside microcapsules were investigated by X-ray diffractometry. The buoyancy time of CAB-coated formulations was better than that of uncoated resin particles. Also, a longer floating time was observed with a higher polymer:drug resin complex ratio (6:1). With increasing coating thickness the particle size was increased but drug release rate was decreased. The drug release rate was higher in simulated gastric fluid (SGF) than in simulated intestinal fluid (SIF). The in vivo mucoadhesion studies were performed with rhodamine-isothiocyanate (RITC) by fluorescent probe method. The amount of CAB-coated cholestyramine microcapsules that remained in the stomach was slightly lower than that of uncoated resin particles. Cholestyramine microcapsules were distributed throughout the stomach and exhibited prolonged gastric residence via mucoadhesion. These results suggest that CAB-coated microcapsules could be a floating as well as a mucoadhesive drug delivery system. Thus, it has promise in the treatment of Helicobacter pylori.     

A New Microphotolysis Based Approach for Mapping the Mobility of Drugs in Microscopic Drug Delivery Devices

Pharmaceutical Research -     

药品监管部门建立质量管理体系的实施路径

建立并运行监管质量管理体系是药品监管部门保证监管活动达到预期目的、持续提升工作质量和效率的必由之路.当前药品监管部门建立质量管理体系面临着缺乏专职质量管理队伍、体系标准语言晦涩难懂、质量管理观念有待转变、体系与业务存在"两张皮"等工作难点.为此,药品监管部门按照做好顶层设计、做好组织保障、明确体系范围、积极借用外脑、抓...     

Using a Model-based Material Sparing Approach for Formulation and Process Development of a Roller Compacted Drug Product

Pharmaceutical Research - The present work details a material sparing approach that combines material profiling with Instron uniaxial die-punch tester and use of a roller compaction mathematical...     

A Proposal for an Alternative Approach to Particle Size Method Development During Early-Stage Small Molecule Pharmaceutical Development

Particle size analysis in the pharmaceutical industry has long been a source of debate regarding how best to define measurement accuracy; the degree to which the result of a measurement or calculation conforms to the true value. Defining a “true” value for the size of a particle can be challenging as the output of its measurement will differ because of variations in measurement approaches, instrumental differences and calculation methods. Consequently, for “real” particles, a universal “true” value does not exist and accuracy is therefore not a definable characteristic. Accordingly, precision is then a measure of the ability to reproducibly achieve a measurement of unknown relevance.This article proposes, in place of accuracy, a means to define the “appropriateness” of a measurement in line with the critical quality attributes (CQA) of the material being characterized. The decision as to whether the measurement is correct should involve a link to the CQA; that is, correlation should be demonstrated, without which the measured particle size cannot be defined as a critical material attribute.Correspondingly, methods should also be able to provide sufficient precision to demonstrate discrimination relating to variation in the CQA. The benefits and challenges of this approach are discussed.     

A Two-Stage Response Surface Approach to Modeling Drug Interaction

Studies of drug combinations have become increasingly important, especially in treating malignant cancers. Researchers are interested in identifying compounds that act synergistically when combined. Such synergy is usually measured through an interaction index. The existing statistical methods, in general, estimate the interaction index using pooled data from compounds administered individually and in combination. In this article, we propose a two-stage response surface approach. Parameters of monotherapy dose–response curves are estimated and then incorporated in estimating the interaction index through a quadratic response surface model. Using multiple simulation studies, we demonstrate that the new method gives less biased estimates for both monotherapy dose–response curves and interaction index. Also developed is a bootstrapping method that allows constructing a confidence interval for interaction index at any combination dose levels. An example is provided to illustrate the method.     

新形势下药品监督执法队伍建设的探讨

本文根据我国药品产、销、用单位发展实际，和监督执法队伍建设的现状，提出了６项建议。经初步应用，收到了较好效果。     

A Novel Approach to Justify Dissolution Differences in an Extended Release Drug Product using Physiologically Based Biopharmaceutics Modeling and Simulation

Dr Reddy's Laboratories Ltd. developed generic version of XYZ extended release tablets (ER) and achieved bioequivalence as per criteria mentioned by USFDA in both fasting and fed conditions for higher strength formulation (1200 mg). However, on comparison of multimedia dissolution profiles in pH 4.5 acetate media, the f2 similarity value was <50. The lower strength formulation (600 mg) demonstrated faster dissolution profile. This was identified as strength-dependent sink condition difference and in vitro multiunit dissolution studies were used to justify sink differences between the higher and lower strengths. Additionally, a Physiologically Based Biopharmaceutics Model (PBBM) was developed using GastroPlus^TM. The validity of this model was established using in-house human pharmacokinetic data. Further, this model was used to justify the insignificant in vivo impact of the faster dissolution profile for the lower strength formulation. This work provides a novel and less explored approach that can be used to obtain biowaiver for lower strength formulations when the standard biowaiver criteria cannot be met. This work also demonstrates the usefulness of PBBM to justify dissolution dissimilarity between dose proportional formulations and to evaluate its biopharmaceutics risk without the need for actual in vivo studies.