Critical Material Attributes Research Articles

Quality by design optimization of formulation variables and process parameters for enhanced transdermal delivery of nanosuspension.

This investigation aims to fabricate, characterize, and optimize organogel containing andrographolide nanosuspension to enhance transdermal drug delivery into and across the skinin vitro. We identified the critical material attributes (CMAs) and critical process parameters (CPPs) that impact key characteristics of andrographolide nanosuspension using a systematic quality-by-design approach. We prepared andrographolide nanosuspension using the wet milling technique and evaluated various properties of the formulations. The CMAs were types and concentrations of polymers, types and concentrations of surfactants, drug concentration, and lipid concentration. The CPPs were volume of milling media and milling duration. Mean particle size, polydispersity index, encapsulation efficiency, and drug loading capacity as critical quality attributes were selected in the design for the evaluation and optimization of the formulations. Furthermore, we developed and evaluated organogel formulation to carry andrographolide nanosuspension 0.05% w/w. Drug release and permeation studies were conducted to assess the drug release kinetics and transdermal delivery of andrographolide. We presented the alteration in the average particle size, polydispersity index, encapsulation efficiency, drug-loading capacity, and drug release among various formulations to select the optimal parameters. The permeation study indicated that organogel delivered markedly more drug into the receptor fluid and skin tissue than DMSO gel (n = 3, p < 0.05). This enhancement in transdermal drug delivery was demonstrated by cumulative drug permeation after 24h, steady-state flux, permeability coefficient, and predicted steady-state plasma concentration. Drug quantity in skin layers, total delivery, delivery efficiency, and topical selectivity were also reported. Conclusively, andrographolide nanosuspension-loaded organogel significantly increased transdermal drug delivery in vitro.

Comparative study between the Full Factorial, Box–Behnken, and Central Composite Designs in the optimization of metronidazole immediate release tablet

The purpose of this paper is to summarize the fundamentals, benefits and limitations of various models of Design of Experiments (DoE) such as 2-Level Full Factorial Design, Central Composite Design (CCD), and Box–Behnken Design (BBD) while establishing a comparison between these models by taking the Metronidazole immediate release (IR) tablets as a case study. Metronidazole IR tablets were prepared by wet granulation method. The Quality Target Product Profile (QTPP) and Critical Quality Attributes (CQA) were selected based on literature review and prior knowledge about the formulation. Critical Material Attributes (CMA) (concentration of binder, super disintegrant, and glidant), and Critical Process Parameters (CPP) (compression of the tablets) were identified based on their risk to the CQA. Screening and optimization of the CMA were performed using DoE. From the Full Factorial Design, it was observed that the disintegration time and dissolution at 30 min were significantly influenced by the selected CMAs. These significant factors were further optimized using CCD and BBD to achieve the constraints (minimum disintegration and maximum dissolution). The levels of povidone K30, crospovidone, and magnesium stearate were optimized to 10 mg, 32 mg, and 1.6 mg respectively using CCD and BBD.

Investigation of Rheological Properties of Molten Materials for Dripping Pills Based on Imaging Monitoring.

Rheological properties, as critical material attributes (CMAs) of solid dispersion drugs such as dripping pills, affect the melting, dispersion, and solidification. Therefore, characterization and assessments of rheological properties in the pharmaceutical process are important in enhancing drug stability and bioavailability. The study aimed to develop a method for analyzing the rheology of molten materials, assessing their consistency and how rheological properties affect the dripping process and pills quality. The rheological behavior of molten materials composed of Ginkgo biloba leaf extract (GBE) and polyethylene glycol (PEG) 4000 was characterized. Batch consistency of molten materials was evaluated. Image monitoring technology was utilized to capture and process images of the droplet formation process. We established the relationship between the rheological properties of molten materials and various attributes. The quality consistency of molten materials was evaluated, with 12 batches showing similarity above 0.8. The MLR models showed strong correlations (R2 > 0.80) between rheological properties and evaluation attributes. The rheological properties, including consistency coefficient, flow index, and viscosity at 80°C, were identified as critical rheological properties of the molten materials. Rheological property differences of molten materials have an impact on the morphology of droplet and quality performance. A rheological method was established, enabling quality consistency evaluation of molten materials in dripping pills. This study revealed the influence of rheological properties on droplet formation process and dripping pills quality, providing a reference for researches on material attributes control of other traditional Chinese medicine dripping pills.

In-line porosity and hardness monitoring of tablets by means of optical coherence tomography

In-line monitoring of critical quality attributes (CQAs) during a tableting process is an essential step toward a real-time release strategy. Such CQAs can be the tablet mass, the API content, dissolution, hardness and tensile strength. Since dissolution testing is laborious and time-consuming and cannot be performed in-line, it is desirable to replace dissolution testing with predictive models based on other CQAs that affect the dissolution characteristics, such as the tablet porosity and hardness. Traditionally, porosity is determined offline via gas adsorption methods or other techniques, such as Terahertz spectroscopy or gas in scattering media absorption spectroscopy. Tablet hardness is typically established using a hardness tester. While these destructive tests can readily be performed at-line, they have limited applicability in in-line settings for a high-percentage inspection. Optical coherence tomography (OCT) has recently been proposed as a possible tool for determining quality attributes. This work describes the first application of OCT for the prediction of tablet porosity and hardness. OCT measurements of tablets produced in a ConsiGma 25™ tableting line and a Stylcam 200R compaction simulator in several compaction force settings were performed and correlated with the porosity and hardness. It was demonstrated that OCT can easily be installed in-line and provide real-time information about critical material attributes. These insights confirm the applicability of OCT as a real-time quality control tool and its potential to replace time-consuming and destructive offline measurements.

An orthogonal analytical platform for determining critical material attributes for in situ formation of thermosensitive hyaluronic acid-poly(N-isopropylacrylamide) copolymers

The developability assessment of the in situ formation of thermosensitive injectables requires the unequivocal determination of their lower critical solution temperatures (LCSTs). Herein, we established a standardized threshold for LCST detection by harmonizing and cross-validating the orthogonal methods using techniques such as nuclear magnetic resonance spectroscopy, light scattering, turbidimetry, backgrounded membrane imaging, and rheology. The selected techniques were in agreement and promptly disclosed unique features and instrumental biases of otherwise difficult interpretations in the characterization of thermosensitive polymers. Thus, various hyaluronic acid–poly(N-isopropylacrylamide) copolymers were synthesized via strain-promoted azide–alkyne cycloaddition to understand their critical material attributes. Structure–function relationships and behaviors of the copolymers were tested under in vitro-simulated in vivo conditions.

Development of intestinal colonic drug delivery systems for diverticular disease: A QbD approach

This study aimed to advance the development of intestinal colon-coated sustained-release matrix tablets of metronidazole for diverticulitis treatment, employing the Quality by Design (QbD) methodology. Comprehensive Risk analysis and Risk evaluation were conducted to assess the potential risks associated with Critical Material Attributes (CMA) and Critical Process Parameters (CPP). Ishikawa diagram, color-coded risk classification and the Risk Priority Number (RPN) were used as tools for risk evaluation. A Design of Experiments (DoE) was executed using a fractional factorial design, incorporating five key factors derived from the Risk analysis and Risk evaluation. Two levels and a central point were established for each factor, resulting in 28 batches of coated tablets. The manufacturing process involved direct compression, followed by a coating process using pH-dependent or time-dependent polymers. Characterization and dissolution studies were conducted on all batches, and the obtained results underwent analysis of variance (ANOVA).The findings demonstrated the robustness and reproducibility of both the direct compression and coating processes. Statistical analysis identified HPMC/chitosan ratio, blending time, coating polymer, and coating weight gain as factors significantly impacting drug release. A Design Space was established to delineate the interplay of these factors, offering insights into various combinations influencing drug release behavior. Thus, the design space for 10 % weight gain formulations includes a range of HPMC/CH ratios between 2.7–3 and mixing times between 10 and 12 min; for 20 % weight gain formulations it includes a range of HPMC/CH ratios up to 2 and mixing times between 10 and 16 min. Multiple Linear Regression between technological and biopharmaceutical variables were optimized facilitating scale-up operations. Batches with a 10 % weight increase and varied HPMC viscosity grades and coating polymers achieve ∼50 % drug release at 24 h; however, batches with a 20 % weight increase along, with either high proportions of HPMC and short blending times or low proportions of HPMC and longer blending times, achieve slow release of metronidazole. This study contributes to optimizing metronidazole colonic delivery systems, enhancing their potential efficacy in diverticulitis treatment.

Quality by design for mRNA platform purification based on continuous oligo-dT chromatography

Oligo-deoxythymidine (Oligo-dT) ligand-based affinity chromatography is a robust method for purifying mRNA drug substances within the manufacturing process of mRNA-based products, including vaccines and therapeutics. However, the conventional batch mode of operation for oligo-dT chromatography has certain drawbacks that reduce this process’s productivity. Here, we report a new continuous oligo-dT chromatography process for the purification of in vitro transcribed mRNA, which reduces losses, improves the efficiency of oligo-dT resin use, and intensifies the chromatography process. Furthermore, the quality by design (QbD) framework was used to establish a design space for the newly developed method. The optimisation of process parameters, including salt type, salt concentration, load flow rate and mRNA load concentration both in batch and the continuous mode, achieved >90% yield (mRNA recovery) along with >95% mRNA integrity and >99% purity. The productivity of continuous chromatography was estimated to be 5.75-fold higher, and the operating cost was estimated 15% lower, when compared to batch chromatography. Furthermore, the QbD framework was further used to map the relationship between critical quality attributes (CQAs) and key performance indicators (KPIs) as a function of critical process parameters (CPPs) and critical material attributes (CMAs).

A two-stage mechanistic reduced-order model of pharmaceutical tablet dissolution: Population balance modeling and tablet wetting functions

We propose a two-stage reduced-order model (ROM) of pharmaceutical tablet dissolution that is comprised of (i) a mechanistic dissolution function of the active pharmaceutical ingredient (API) and (ii) a tablet wetting function. The former is derived from a population balance model, using a high-resolution finite volume algorithm for a given API crystal size distribution and dissolution rate coefficient. The latter is obtained from the mechanistic understanding of water penetration inside a porous tablet, and it estimates the rate at which the API is exposed to the buffer solution for a given formulation and the dimensions of the tablet, contact angle, and surface tension between the solid and liquid phases, liquid viscosity, and mean effective capillary radius of the pore solid structure. In turn, the two-stage model is mechanistic in nature and one-way coupled by means of convolution in time to capture the start time of the API dissolution process as water uptake, swelling, and disintegration take place. The two-stage model correlates dissolution profiles with critical process parameters (CPPs), critical material attributes (CMAs), and other crucial critical quality attributes (CQAs). We demonstrate the model’s versatility and effectiveness in predicting the dissolution profiles of diverse pharmaceutical formulations. Specifically, we formulate and fabricate acetaminophen and lomustine solid tablets using different API content and size distributions, characterize their dissolution behavior, and estimate capillary radius as a function of tablet porosity. The estimations generated by the proposed models consistently match the experimental data across all cases investigated in this study.

Quality by design steered approach for co-encapsulation of timolol maleate and dorzolamide hydrochloride in injectable liposomes

Glaucoma is caused by high intraocular pressure, which can causes blindness. Combinations of timolol and dorzolamide are used for its treatment with a requirement of multiple dosing with dosing being twice or four times a day. Conventional eye drops have poor pre-corneal retention and is thus less available for action. This study utilizes principles of Quality by Design for formulation of injectable liposomes coloaded with timolol maleate and dorzolamide HCl, which overcomes limitations of conventional eye drops. For implementation of Quality by Design principles a systematic approach involving defining Quality Target Product Profile, identification of Critical Quality Attributes, mapping Critical Quality Attributes to Critical Process Parameters and Critical Material Attributes, Failure Mode and Effect Analysis based risk assessment, Taguchi screening, and 32 full factorial Design of Experiments design were utilized. A robust model for formulation of coloaded liposomes was successfully developed. Design of Experiments approach allowed to obtain optimized batch having particle size of 116.1 nm, encapsulation efficiency of dorzolamide HCl of 72.12 % and encapsulation efficiency of timolol maleate of 71.94 %. In-vitro drug release showed a sustained release for 4 days. The prepared formulation was in the desired osmolarity range. Biosafety was proved using histopathological characterization. In-vivo studies for assessing the Intra Ocular Pressure reduction showed that there was no significant difference in Intra Ocular Pressure reduction between prepared liposomes and marketed formulation but were superior than marketed formulation because of less fluctuations in Intra Ocular Pressure. Prepared coloaded injectable liposomes lays the foundation for further research in the area and can be translated from to bench side for commercial clinical use.

Exploration of moisture activated dry granulation for the development of gastroretentive tablets aided by SeDeM diagram

Moisture activated dry granulation (MADG) is an attractive granulation process. However, only a few works have explored modified drug release achieved by MADG, and to the best of the authors knowledge, none of them have explored gastroretention. The aim of this study was to explore the applicability of MADG process for developing gastroretentive placebo tablets, aided by SeDeM diagram. Floating and swelling capacities have been identified as critical quality attributes (CQAs). After a formulation screening step, the type and concentration of floating matrix formers and of binders were identified as the most relevant critical material attributes (CMAs) to investigate in ten formulations. A multiple linear regression analysis (MLRA) was applied against the factors that were varied to find the design space. An optimized product based on principal component analysis (PCA) results and MLRA was prepared and characterized. The granulate was also assessed by SeDeM.In conclusion, granulates lead to floating tablets with short floating lag time (<2 min), long floating duration (>4 h), and showing good swelling characteristics. The results obtained so far are promising enough to consider MADG as an advantageous granulation method to obtain gastroretentive tablets or even other controlled delivery systems requiring a relatively high content of absorbent materials in their composition.

Integration of Quality by Design (QbD) Principles in the Engineering of an Oral Delivery Nanosystem Loaded with Fenofibrate

Background: Fenofibrate (FEN) is the FDA-approved drug used in the treatment of hyperlipidemia. FEN possesses limited bioavailability orally due to its low solubility. As a result, more frequent and larger doses are needed, which increases the likelihood of adverse effects. Objectives: This study aimed to develop and optimize polymeric nanoparticles loaded with Fenofibrate (FEN) using the solvent evaporation method. Method: A Quality by Design (QbD) approach was used to ensure the quality of the finished product by evaluating the impact of critical material attributes (CMAs) and critical process parameters (CPPs) on the critical quality attributes (CQAs) of nanoparticles. The impact of CMAs (quantity of polycaprolactone, % polyvinyl alcohol, and % sodium lauryl sulphate) on particle size and Drug Entrapment Efficiency (DEE) was studied using Box-Behnken Design. Results: The optimized nanoparticles have 246.5 ± 4.38 nm particle size and 77.53 ± 0.9% DEE. SEM and TEM were used to analyze the surface morphology of nanoparticles. Furthermore, In-Vitro drug release study of optimized formulation was performed to confirm the efficacy of the polymeric nanoparticles. Conclusion: The solvent evaporation method was utilized to effectively formulate FEN-loaded polymeric nanoparticles and optimized through QbD principles to achieve minimum particle size and maximum % DEE

Reactivity of N terminal histidine of peptides towards excipients/impurity of excipients: A case study of liraglutide excipient compatibility study

The selection of quality excipients is a crucial step in peptide formulation development. Apart from excipient incompatibility, process-related impurities or degradants of an excipient can interact with peptide-active pharmaceutical ingredients, forming the interaction products. The formaldehyde has been reported as an impurity of excipient in polyethylene glycol, glycerol, magnesium stearate, microcrystalline cellulose, mannitol, etc. The peptide contains various amino acids such as histidine, lysine, and arginine having free amine groups. These amine groups act as strong nucleophile and can increase the reactivity of peptides. PLGA is the most widely used biodegradable polymer in sustained-release formulations. The hydrolysis of PLGA generates glycolic acid and lactic acid impurities, which can form the interaction product with the amines of peptides. During the formulation development of Liraglutide, we have found few interaction products. The systematic characterization and mechanistic understanding of these interaction products lead us to imidazopyrimidine, glycolyl, and lactolyl moieties. These interaction products have been characterized thoroughly with the use of LC-HRMS, MS/MS, and hydrogen-deuterium exchange mass studies. The study revealed that the reactivity of N-terminal histidine must be considered for formulation development. Moreover, the quality of excipients with respect to presence of impurities must be considered as critical material attributes.

Intelligent industry-oriented oro-solid formulation of famotidine: Advanced statistical optimization and Ex-Vivo characterization

BackgroundSol-Gel is the conventional approach for in-situ formulation having several limitations, including instability, stringent storage conditions, dose inaccuracy, inconsistent drug release, and patient inconvenience. ObjectivesThe aim of the present investigation was to design and characterize an intelligent oro-solid in-situ targeted dosage form of Famotidine (FTD) incorporating the cross-linked chitosan-vanillin (CrL-CSV) which instantly converted into a gel upon contact with acidic media. Material and MethodsCrL-CSV was designed using microwave-assisted method inculcating FTD and vanillin (VNL). Interaction was observed using FTIR and DSC. QbD was applied to develop intelligent formulation. Taguchi design was accomplished to screen significant critical material attributes (CMAs) and process parameters (CPPs). Box-Behnken design (BBD) was used to correlate the CMAs/CPPs: the amount of CS, VNL, microwave time, and critical quality attributes (CQAs): % FTD release, mucoadhesive strength, and viscosity. CrL-CSV were evaluated using various in-vitro, ex-vivo characterization and stability. Results and DiscussionFTIR and DSC revealed no interaction between the FTD and excipients. The amount of CS, VNL, and microwave time were screened as significant variables due to the high S/N ratio and delta value from the Taguchi design. A significant effect of CMA/CPP on the CQAs was observed in BBD. The optimum CrL-CSV was designed accomplishing 8.74 % chitosan (CS), 0.94 % VNL exposing 80sec in microwave. Immediate gelling (<1min.), desired viscosity (51432.6cps), optimal mucoadhesion strength (0.40 N), better control on drug release (91.5 % in 8 h) and high stability were achieved in the optimum batch of CrL-CSV. ConclusionAn intelligent formulation inculcating the CrL-CSV was developed, which has instant gelling time, high mucoadhesion time, and strength, and controlled release with desired physical properties. Progressive tools like Taguchi and BBD was explored. The formulation can be helpful at industry as it increases patient compliance, processing and stability.

Quality-by-design driven approach in the formulation of an anti-ulcer and gastro-protective oral suspension

Objective This work aims to present a Quality-by-Design (QbD) step-by-step methodology to formulate anti-ulcer and gastro-protective oral suspensions. Methods Sucralfate was used as a drug model. The Quality Target Product Profile was established early during preformulation. Viscosity, resuspendability, pH, and density were assessed through the screening of several suspension platforms based on different prototype compositions. A compatibility study between the active pharmaceutical ingredient and the excipients was performed by thermal analysis and infrared spectroscopy. An Ishikawa fishbone diagram and Failure Mode and Effect Analysis were employed to identify the Critical Material Attributes (CMAs), Critical Process Parameters (CPPs), and Critical Quality Attributes (CQAs). CMAs’ and CPPs’ impact on identified CQAs was further assessed through a 22 full factorial experimental design at normal conditions after manufacture and one month at super-accelerated stress conditions. Results: The lead prototype exhibited no physicochemical incompatibilities. The risk assessment tools revealed that the concentration of the wetting agent and the total concentration of thickening agents represented critical factors for the quality profile of the preparation in terms of viscosity. The optimized formulation comprising 1.125 w/v% total concentration of Natrosol 250 HX and Avicel RC 591 exhibited an enhanced performance according to the established profile. Conclusions The analytical and physicochemical tests showed the robustness and compliance of the final preparation with the quality profile. The proposed step-by-step methodology based on QbD, Design of Experiments, and Quality Risk Management presented in our research holds practical implications for local industries and formulation scientists involved in the development of oral suspensions.

Olaparib Process Development Employing Quality by Design (QbD) Principles.

This study focuses on multivariate experimental design and statistical analysis to optimize the process of Olaparib 1. Quality by design (QbD) methodology was adopted for optimization of the Olaparib process consisting of three reaction steps: (1) amidation, (2) deprotection, and (3) acylation. Every chemical conversion was studied in isolation, employing risk assessment to identify key material attributes and key process parameters that may have the potential to impact the reaction. Thereafter, the screening design of experiment (DoE) was employed to scrutinize the factors that significantly impacted yield. Moving forward, the scrutinized factors which were found to impact the responses, the set of critical material attributes (CMAs) and critical process parameters (CPPs), were considered for optimization by applying I-Optimal design to define design space arriving at a robust setting wherein the predefined targets were supposedly optimal. To our delight, we got 95, 91, and 75% yield with more than 99% purity in amidation, deprotection, and acetylation, respectively, which enabled us to systematically identify design space to meet the desired quality target of the product consistently. More importantly, to distinguish the CMAs and CPPs, these elements ought to be monitored to have control of the quality parameter throughout the active pharmaceutical ingredient (API) value chain until commercial manufacturing followed by marketing. Eventually, we have developed a greener process in comparison to precedented one for Olaparib 1.

A Review on Quality by Design

The recent advancement in pharmaceutical quality, known as "quality by design" or "QbD," is crucial. Every regulatory authority for pharmaceutical products has placed a high priority on quality. In terms of services, goods, and procedures, quality means client satisfaction. All pharmaceutical items can be made with higher quality by using QbD. This essay discusses the use of Quality by Design (QbD) in the pharmaceutical industry and how it may be used to guarantee the accuracy of pharmaceutical analyses. It's critical to recognise your desired product performance report within this notion of being throughout product design and growth. the quality target product profile (QTPP), the target product profile (TPP), and the identification of essential quality attributes (CQA). Understanding the effects of critical process parameters (CPP), critical material attributes (CAM), and raw material.

QbD Assisted Development of a Compartment and Sequential Drug Delivery System for Periodontotherapy.

Periodontitis, the burgeoning disease, is at an alarming stage. Although this has triggered dedicated research in this area, as the disease itself demands a multi-component therapy, there is an unmet need for a compartment and sequential drug delivery system to ameliorate disease symptoms completely. The hypothesized work consists of multitherapeutic agents such as an antibiotic, a COX-II inhibitor, an MMP inhibitor, and a bone regenerating agent in an insitu gel. However, for the development of the system, as mentioned above, a thorough investigation at each stage is necessary; therefore, the quality-by-design approach was adopted. Furthermore, the current work is a pursuit of studying the quality by design aspects for the fabrication of a compartment system, i.e., in-situ gel for periodontal delivery. The proposed system in-situ gel consists of antibiotic and nano-encapsulating microcapsules. Furthermore, the microcapsules contain a COX-II inhibitor and nanoparticles of MMP inhibitor and bone regenerating agent for complete amelioration of periodontitis. To develop the system as per the QbD approach, the first initial trials and runs were conducted, which helped to decide the quality target product profile (QTPP). However, based on QTPP, critical quality attributes (CQA), critical process parameters (CPP), and critical material attributes (CMAs) were decided for each stage product, i.e., in-situ gel, microcapsules, and nanoparticles. To assess the influence of CPPs and CMAs on CQAs, Pareto charts were constructed, and various risks, along with possible failure modes were studied. In conclusion, the above work will serve as a well-designed scientific mouthpiece for developing a compartment system for periodontotherapy.

QbD Approach-Based Preparation and Optimization of Hydrophobic Ion-Pairing Complex of Lysozyme with Sodium Dodecyl Sulphate to Enhance Stability in Lipid-Based Carriers.

Hydrophobic ion pairing (HIP) complexation was found to be an efficient approach in modulating the release and enhancing the stability and encapsulation of hydrophilic macromolecules such as proteins in hydrophobic nano/microcarriers. The present work strives to develop and optimize the preparation of the HIP complex of the antimicrobial enzyme lysozyme (LYZ) with the ion-pairing agent (IPA) sodium dodecyl sulphate (SDS) relying on the quality-by-design (QbD) approach. The quality target product profile (QTPP) includes the achievement of maximal lipophilicity in a reversible manner to enable the maintenance of biological activity. The related critical quality attributes (CQAs) were defined as complexation efficacy, complex stability, enzyme recovery and activity. Three risk assessment (RA) tools were used to identify and rank the critical process parameters (CPPs) and critical material attributes (CMAs). From this assessment, the pH of the medium, LYZ:SDS molar ratio and drying conditions were determined as high-risk factors that need to be investigated. To the best of our knowledge, for the first time, electrostatic titration was used as a smart approach to determine the optimum molar ratio at different pH values. Based on the predefined CQAs, pH 8 with an LYZ/SDS molar ratio of 1:8 was found to be the optimal condition for complexation efficiency and recovery (%) of a biologically active enzyme. A cost-effective drying process based on a ventilated oven was developed, which resulted in complex qualities comparable to those obtained by the commonly used freeze-drying method. In a nutshell, the optimum conditions for the preparation of the LYZ/SDS HIP complex were efficiently facilitated by the rational application of QbD principles and the utilization of efficient electrostatic titration and ventilated oven-drying methods.

Quality by Design Considerations for Drop-on-Demand Point-of-Care Pharmaceutical Manufacturing of Precision Medicine.

Distributed and point-of-care (POC) manufacturing facilities enable an agile pharmaceutical production paradigm that can respond to localized needs, providing personalized and precision medicine. These capabilities are critical for narrow therapeutic index drugs and pediatric or geriatric dosing, among other specialized needs. Advanced additive manufacturing, three-dimensional (3D) printing, and drop-on-demand (DoD) dispensing technologies have begun to expand into pharmaceutical production. We employed a quality by design (QbD) approach to identify critical quality attributes (CQAs), critical material attributes (CMAs), and critical process parameters (CPPs) of a POC pharmaceutical manufacturing paradigm. This theoretical framework encompasses the production of active pharmaceutical ingredient (API) "inks" at a centralized facility, which are distributed to POC sites for DoD dispensing into/onto delivery vehicles (e.g., orodispersible films, capsules, single liquid dose vials). Focusing on the POC dispensing/dosing processes, QbD considerations and cause-and-effect analyses identified the dispensed API quantity and solid-state form (CQAs), as well as the nozzle diameter, system pressure channel, and number of drops dispensed (CPPs) for detailed investigation. Final assay quantification and content uniformity CQAs were measured from demonstrative levothyroxine sodium single-dose liquid vials of glycerin/water, meeting the standard acceptance values. Each POC facility is unlikely to maintain full quality control laboratory capabilities, requiring the development of appropriate atline or inline methods to ensure quality control. We developed control strategies, including atline ultraviolet-visible (UV-vis) verification of the API ink prior to dispensing, inline drop counting during dispensing, intermediate atline-dispensed volume checks, and offline batch confirmation by liquid chromatography-tandem mass spectrometry (LC-MS/MS) following production.

CPV Monitoring - Optimization of Control Chart Design by Reducing the False Alarm Rate and Nuisance Signal

The Food and Drug Administration’s 2011 Process Validation Guidance and International Council for Harmonization Quality Guidelines recommend continued process verification (CPV) as a mandatory requirement for pharmaceutical, biopharmaceutical, and other regulated industries. As a part of product life cycle management, after process characterization in stage 1 and process qualification and validation in stage-2, CPV is performed as stage-3 validation during commercial manufacturing. CPV ensures that the process continues to remain within a validated state. CPV requires the collection and analysis of data related to critical quality attributes, critical material attributes, and critical process parameters on a minimum basis. Data is then used to elucidate process control regarding the capability to meet predefined specifications and stability via statistical process control (SPC) tools. In SPC, the control charts and Nelson rules are commonly used throughout the industry to monitor and trend data to ensure that a process remains in control. However, basic control charts are susceptible to false alarms and nuisance alarms. Therefore, it is imperative to understand the assumptions behind control charts and the inherent false alarm rates for different Nelson rules. In this article, the authors have detailed the assumptions behind the usage of control charts, the rate of false alarms for different Nelson rules, the impact of skewness and kurtosis of a data distribution on the false alarm rate, and methods for optimizing control chart design by reducing false alarm rates and nuisance signals.