Manufacture Of Pharmaceutical Products Research Articles

Evaluation of Novel Process Indicators for Rapid Monitoring of Hydrogen Peroxide Decontamination Processes.

Geobacillus stearothermophilus spores on stainless steel discs are routinely used as biological indicators for the validation of hydrogen peroxide bio-decontamination processes. Given ongoing concerns about the reliability and response time of biological indicators, we explored the potential for an enzyme-based approach to decontamination process evaluation. Thermostable adenylate kinase enzyme was coated onto a solid support and exposed to hydrogen peroxide vapour, in parallel with standard commercial 6-log biological indicators, during a series of vapour-phase hydrogen peroxide cycles in a flexible film isolator. The exposed biological indicators were enumerated to define the degree of kill at different time intervals and the results compared to the thermostable adenylate kinase values, as determined by measuring adenosine triphosphate produced by residual active enzyme. Both biological indicators and the thermostable adenylate kinase indicators exhibited a biphasic inactivation profile during the process. There was significant variance between individual cycles, with some cycles showing complete inactivation of the biological indicators to the limit of detection of the assay, within 6 min, whereas biological indicators in some cycles were inactivated at a time greater than 12 min. The log-kill of the biological indicators at intermediate time points were plotted and compared to the fully quantifiable measurements derived from the thermostable adenylate kinase indicators at the same time points. The results demonstrated very similar inactivation profiles for the enzyme and for the biological indicators, thus it was possible to define a relationship between relative light units measurement and biological indicator kill. This indicates that it is possible to use thermostable adenylate kinase measurement as a direct measure of vapour-phase hydrogen peroxide bio-decontamination performance, expressed in terms of log reduction. Because thermostable adenylate kinase measurement can be achieved within a few minutes of vapour-phase hydrogen peroxide cycle completion, compared with a minimum of 7 days for the evaluation of biological indicator growth, this offers a potentially valuable tool for rapid vapour-phase hydrogen peroxide bio-decontamination cycle development and subsequent re-qualification.LAY ABSTRACT: Pharmaceutical product manufacture is performed in controlled cleanroom and closed chamber environments (isolators) to reduce the risk of contamination. These environments undergo regular decontamination to control microbial contamination levels, using a range of methods, one of which is to vaporize hydrogen peroxide (a chemical disinfectant) into a gas or an aerosol and disperse it throughout the environment, killing any microorganisms present. Biological indicators, which consist of a small steel coupon carrying a population of bacterial spores that are more resistant to hydrogen peroxide than are most microorganisms, are placed within the environment, and then tested for growth following treatment to ensure the process was effective. Confirmation of growth/no growth (and therefore hydrogen peroxide cycle efficacy) can take up to 7 days, which significantly increases time and cost of developing and confirming cycle efficacy. This study tests whether a new technology which uses a robust enzyme, thermostable adenylate kinase, could be used to predict biological indicator growth. The study shows this method can be used to confirm hydrogen peroxide cycle efficacy, by predicting whether the BI is killed at a specific time point or not and results are obtained in a few minutes rather than 7 days. This potentially offers significant time and cost benefits.

Knowledge Provenance Management System for a Dropwise Additive Manufacturing System for Pharmaceutical Products

The Knowledge Provenance Management System, KProMS, can capture the complete provenance of the data, information, and knowledge of a structured activity by modeling the details of the associated data generation steps of that activity as workflows. Its unique workflow representation captures relationships between the processing steps, material and information flows, and data input and output. In this paper, we demonstrate the use of KProMS to manage and analyze the experimental data of an innovative system for manufacturing drug products using dropwise additive manufacturing. Dropwise additive manufacturing of pharmaceutical products (DAMPP) uses drop on demand printing technology for depositing various drug formulations onto edible substrates. DAMPP requires and generates a range of data types, including camera and IR images, spectra, and numerical parameter values, both of real-time and off-line natures, and thus provide a rich illustration of KProMS capabilities to serve as knowledge management framework.

Design of a Continuous Tubular Cooling Crystallizer for Process Development on Lab‐Scale

AbstractContinuous manufacturing of fine chemical, life science, and pharmaceutical products is under recent investigation in R&D. As cooling crystallization is an important unit operation for purification of products, continuously operated, scalable devices are required for process development on lab‐scale. A tubular crystallizer was developed, based on the coiled flow inverter design. Experimental characterization proved a narrow residence time distribution of the liquid phase close to ideal plug flow. Counter‐current air cooling allows for adjusting linear and curved temperature profiles. Unseeded operation with the L‐alanine (water) system demonstrated that nucleation has to be actively controlled to successfully apply intensified continuous cooling crystallization processes.

Performance based contracting in long-term supply relationships

The study investigates performance-based contracting in long term-supply relationships. Evidence in the context of supply relationships involving manufacturers of consumer and pharmaceutical products, service providers and grocery retailers indicates that the performance that companies buy and sell can be analyzed as specific combinations of effectiveness, efficiency and risk. While firms engage in a complex and time-consuming process to design and agree upon performance targets, incentive mechanisms and involved risks of buying and selling future performance, they often fail in achieving excellence in all performance targets.

Hot-melt extruded filaments based on pharmaceutical grade polymers for 3D printing by fused deposition modeling

Fused deposition modeling (FDM) is a 3D printing technique based on the deposition of successive layers of thermoplastic materials following their softening/melting. Such a technique holds huge potential for the manufacturing of pharmaceutical products and is currently under extensive investigation. Challenges in this field are mainly related to the paucity of adequate filaments composed of pharmaceutical grade materials, which are needed for feeding the FDM equipment. Accordingly, a number of polymers of common use in pharmaceutical formulation were evaluated as starting materials for fabrication via hot melt extrusion of filaments suitable for FDM processes. By using a twin-screw extruder, filaments based on insoluble (ethylcellulose, Eudragit® RL), promptly soluble (polyethylene oxide, Kollicoat® IR), enteric soluble (Eudragit® L, hydroxypropyl methylcellulose acetate succinate) and swellable/erodible (hydrophilic cellulose derivatives, polyvinyl alcohol, Soluplus®) polymers were successfully produced, and the possibility of employing them for printing 600μm thick disks was demonstrated. The behavior of disks as barriers when in contact with aqueous fluids was shown consistent with the functional application of the relevant polymeric components. The produced filaments were thus considered potentially suitable for printing capsules and coating layers for immediate or modified release, and, when loaded with active ingredients, any type of dosage forms.

Determination of breakage rate and breakage mode of roller compacted pharmaceutical materials

Roller compaction is a common unit operation in the manufacture of oral solid dose pharmaceutical products. The roller compactor can produce intermediate ribbons of compacted material that exhibit a range of mechanical properties. Both the breakage rate and the breakage mode of these intermediates will have an effect on the final particle size distribution (PSD), and are therefore important parameters in determining the performance of the final product in pharmaceutical manufacturing. The breakage rates of roller compacted ribbons of two pharmaceutical excipients, microcrystalline cellulose (MCC) and mannitol, were determined with two different approaches, i.e. by analysing the milling mass throughput and the change in mass in the largest granule size class. The self-similar solution of the breakage population balance equation provided an insight into size dependencies of breakage rates and the prevailing breakage mode for specific process parameters. The breakage rate was found to be dependent on the impeller speed, milling mesh aperture size and ribbon porosity, but not on grinding media fill level. For MCC ribbons the milling kinetic profile changed with the mesh aperture size, suggesting dependence of the breakage mode on screen size. Our work shows clear correlation between the amount of fines produced during milling and the underlying breakage mode. For the materials studied, it is evident that mannitol ribbons tend more toward an attrition breakage mode than MCC ribbons of equal porosity when milling with the same process settings.

Impact of process parameters on Mg–St content and tablet surface wettability in the external lubrication method for a rotary tablet press

External lubrication is a new alternative used in compression processes of the pharmaceutical industry to minimize the negative effect of lubricant and to resolve sticking problems. This method can also prevent the deterioration of tablet properties; e.g., reduced tensile strength and a retarded rate of drug dissolution. The current study prepared tablets using the external lubrication method with varying potential critical process parameters and clarified the process of external lubrication via statistical analysis. In accordance with past results, tablets prepared using the external lubrication method had better tablet properties (higher hardness and more rapid disintegration) than those prepared using the internal lubrication method. Quantitative analyses of the magnesium stearate content and contact angle showed that the wettability of the tablet surface increased with the magnesium stearate content. Analysis of variance showed that all potential critical parameters are influential for the magnesium stearate content, but not for the disintegration of tablets. In addition, predictions of the magnesium stearate content and disintegration time of tablets made using a model equation correlated well with observed values. The external lubrication method can thus be applied by identifying the critical process parameters in the compression process during the development and manufacture of pharmaceutical products.

On the Methods to Measure Powder Flow.

The flow of powders can often play a critical role in the manufacturing of pharmaceutical products. Many of these processes require good, consistent and predictable flow of powders to ensure continuous production of pharmaceutical dosages and to ensure their quality. Therefore, the flow of powders is of paramount importance to the pharmaceutical industry and thus the measuring and evaluating of powder flow is of utmost importance. At present, there are numerous methods in which the flow of powders can be measured. However, due to the complex and environment-dependent nature of powders, no one method exists that is capable of providing a complete picture of the behaviour of powders under dynamic conditions. Some of the most commonly applied methods to measure the flow of powders include: density indices, such as the Carr index and Hausner ratio, powder avalanching, the angle of repose (AOR), flow through an orifice, powder rheometry and shear cell testing.

Genetic and chemical diversity of native populations of Ocimum selloi Benth.

The present work aimed to characterize the chemical composition of essential oils and genetic diversity of three native populations of Ocimum selloi collected in Brazil southern and southeastern. Thus, with the proposals to subsidize genetic improvement programs for the species preservation and commercial application of the essential oil.A total of 60 samples from Iporanga and Piquete counties (State of São Paulo) and Adrianópolis county (State of Paraná) were analyzed by RAPD – genetic polymorphism – and GC–MS – chemical composition of essential oils. The data showed that the variation of the chemical composition of the essential oils of the samples was influenced by geographical region and genetic factors. The Piquete population was more homogeneous with respect to factors evaluated, and presented germacrene D, elemicin, trans-α-bergamotene, and bicyclogermacrene as the major components. Populations of Adrianópolis and Iporanga showed strong variability probably due to the gene flow between these populations, because they are geographically close. Most samples of these two regions had as major substances elemicin, β-selinene, and β-4-copaen-α-ol. The results showed a great genetic and chemical divergence among and inside the populations between, being the diversity inside the populations bigger than among populations. The oils presented potential for commercial use in the manufacture of veterinary, pharmaceutical, and agricultural products.

Adaptation of the quality by design concept in early pharmaceutical development of an intranasal nanosized formulation

Regulatory science based pharmaceutical development and product manufacturing is highly recommended by the authorities nowadays. The aim of this study was to adapt regulatory science even in the nano-pharmaceutical early development. Authors applied the quality by design (QbD) concept in the early development phase of nano-systems, where the illustration material was meloxicam. The meloxicam nanoparticles produced by co-grinding method for nasal administration were studied according to the QbD policy and the QbD based risk assessment (RA) was performed. The steps were implemented according to the relevant regulatory guidelines (quality target product profile (QTPP) determination, selection of critical quality attributes (CQAs) and critical process parameters (CPPs)) and a special software (Lean QbD Software®) was used for the RA, which represents a novelty in this field. The RA was able to predict and identify theoretically the factors (e.g. sample composition, production method parameters, etc.) which have the highest impact on the desired meloxicam-product quality. The results of the practical research justified the theoretical prediction. This method can improve pharmaceutical nano-developments by achieving shorter development time, lower cost, saving human resource efforts and more effective target-orientation. It makes possible focusing the resources on the selected parameters and area during the practical product development.

Dropwise Additive Manufacturing of Pharmaceutical Products for Melt-Based Dosage Forms

The US Food and Drug Administration introduced the quality by design approach and process analytical technology guidance to encourage innovation and efficiency in pharmaceutical development, manufacturing, and quality assurance. As part of this renewed emphasis on the improvement of manufacturing, the pharmaceutical industry has begun to develop more efficient production processes with more intensive use of online measurement and sensing, real-time quality control, and process control tools. Here, we present dropwise additive manufacturing of pharmaceutical products (DAMPP) as an alternative to conventional pharmaceutical manufacturing methods. This mini-manufacturing process for the production of pharmaceuticals utilizes drop on demand printing technology for automated and controlled deposition of melt-based formulations onto edible substrates. The advantages of drop-on-demand technology, including reproducible production of small droplets, adjustable drop sizing, high placement accuracy, and flexible use of different formulations, enable production of individualized dosing even for low-dose and high-potency drugs. In this work, DAMPP is used to produce solid oral dosage forms from hot melts of an active pharmaceutical ingredient and a polymer. The dosage forms are analyzed to show the reproducibility of dosing and the dissolution behavior of different formulations.

Real-Time Process Management Strategy for Dropwise Additive Manufacturing of Pharmaceutical Products

This paper presents a real-time process management (RTPM) strategy for Dropwise Additive Manufacturing of Pharmaceutical Products (DAMPP), a mini-manufacturing method for pharmaceutical dosage forms. The semicontinuous, small-scale nature of DAMPP allows for more automation and control than traditional large-scale batch pharmaceutical manufacturing processes and can be used to manufacturing drug products with precise amounts of active pharmaceutical ingredients (API), suitable for production of high-potency drug products or individualized medicine. The RTPM strategy for DAMPP consists of advanced process control to ensure that every dosage unit meets quality specifications. We use temperature control systems and an imaging system linked to a LabVIEW automation program. The system is successful in controlling deposition of both solvent-based and melt-based dosage forms. It controls process and product temperature and monitors each drop visually. It records data pertinent to each deposited drop, determines the drop volume and thus API amount deposited, and automatically detects and diagnoses process faults. With a proper automation, control, and monitoring strategy, DAMPP is a viable manufacturing method for pharmaceutical dosage forms.

ASSESSMENT OF GMP COMPLIANCE IN WATER TREATMENT SYSTEMS OF PHARMACEUTICAL INDUSTRIES IN ETHIOPIA

Water is widely used as a raw material, ingredient, and solvent in the processing, formulation, and manufacture of pharmaceutical products, and assessing its quality is of paramount importance. To the best of the authors’ knowledge, there hasn’t been any baseline assessment made with regard to the implementation status of Good Manufacturing Practices (GMP) principles in water treatment systems of pharmaceutical industries in Ethiopia. Hence, to assess the level of compliance to GMP in water treatment systems of pharmaceutical industries in Ethiopia, a national survey was conducted in all pharmaceutical industries of the country. Data were collected by employing quantitative and qualitative methods. Self-administered questionnaires were distributed to nine pharmaceutical industries and the response rate was 8 (88.5%). According to the results, none of the industries had an influent and effluent total organic carbon monitoring system. Among the available storage tanks for purified water and water for injection, 7 (87.5%) of them were of a sanitary material. However, in 4 (50%) industries pipes were not made of sanitary material, purified water was not kept circulating at 70-80 o C and there were dead legs in the water lines. The validation results were investigated and corrective action was taken only in 1 (12.5%) of the industries. The compliance of the water treatment systems of most of the industries to WHO GMP principles was found to be below the standard in many aspects. Therefore, it is recommended that the industries should exert maximum efforts to comply with GMP principles.

Invoking Learned Intermediary Rule in Malaysia

In the realm of pharmaceutical liability, failure to warn or to provide sufficient information such as adverse reaction or allergies of pharmaceutical products may cause manufacturers to be liable under the traditional common law of tort for the harm or death it causes. This article shows that manufacturers of prescribed pharmaceutical products may escape such liability if information and warnings have been conveyed to physicians; a learned intermediary between the manufacturers and the patients. The learned intermediary rule acts as a defence mechanism for manufacturers of pharmaceutical products as the physician is deemed as an intervening force that breaks the chain of causation in the law of negligence. Hence, the main focus of this article is to examine whether Malaysian courts would accept such a defence if invoked by the manufacturers. The objective of the article is to analyze and identify the learned intermediary between the manufacturer of a prescribed pharmaceutical products and patients under the relevant Malaysian statutes, particularly Poison Act 1952 and Medicines (Advertisement and Sale) Act 1956. In achieving the above objective, the authors adopts historical, comparison and also critical analysis methods. The finding of this article is that, it is an offence for pharmaceutical products to be sold or supplied directly to patients and strictly requires a learned intermediary such as physician to prescribe such products. Thus, it is concluded that the defence has its merits and therefore it is unlikely patients would be able to obtain compensation if this defence is invoked. DOI: 10.5901/mjss.2015.v6n2p428

Grewia bicolor seed oil: Putative pharmaceutical, cosmetic and industrial uses

The physicochemical characterisation, seed oil content and fatty acid profile of oil extracts from Grewia bicolor seeds collected in Zimbabwe were performed using standard extraction and chromatographic techniques. The main objective was to determine the potential domestic and industrial usefulness of the G. bicolor seeds. The G. bicolor seeds yielded 4.80% of brownish-orange oil that had an acceptable odour. The seed oil consisted of saturated (20.20%), monounsaturated (25.10%) and polyunsaturated (54.41%) fatty acids. Palmitic acid (11.46%), stearic acid (5.77%), oleic acid (19.33%) and linoleic acid (54.41%) were the main fatty acids in G. bicolor seed oil. The oil had a high acid value (0.53mgKOH/g), iodine value (39.21g I2/100g oil) and saponification value (130.43mgKOH/g) compared to published data on other nutritionally and ethnomedicinally important plant seed oils.We conclude that the G. bicolor seeds are low oil yielding, whose oil could be used as a potential source of palmitic, stearic, oleic and linoleic acids and may potentially be utilized as an industrial ingredient in the manufacture of soaps, pharmaceutical products, and cosmetics. Further studies are required to explore the possibility of using this seed oil in industry.

Validation study on how to avoid microbial contamination during pharmaceutical production.

Every person involved in pharmaceutical product manufacturing has the responsibility to assure the quality of the product being produced. The aim of this paper is to validate quality assurance throughout the process of manufacturing pharmaceutical products. Additionally, within aseptic manufacturing, certain monitoring and information needs to be collected on a routine basis to continually assess the state of control of the complete operation. The basis for assessing the state of control is to have rigorous and defined information flow processes. Once the information is collected, quality assurance involves the ability to assess, evaluate, and make appropriate decisions to ensure the product has the required safety, identity, strength, quality, and purity. Quality assurance study is the process of bringing all of the information together, evaluating the information, making decisions, refining systems, and applying process knowledge. This process begins in the early stages of drug development when not a lot of specific process information about the process is known, but it is important to allow for development to progress, building knowledge about process. However, even in early development, sterility assurance requirements should be largely the same at all stages of development and routine commercial manufacturing.

Characterisation of Physical, Spectral and Thermal Properties of Biofield treated Resorcinol

Resorcinol is widely used in manufacturing of several drugs and pharmaceutical products that are mainly used for topical ailments. The main objective of this study is to use an alternative strategy i.e., biofield treatment to alter the physical, spectral and thermal properties of resorcinol. The resorcinol sample was divided in two groups, which served as control and treated group. The treated group was given biofield treatment and both groups i.e., control and treated were analysed using X-ray diffraction (XRD), Fourier transform-infrared (FT-IR) spectroscopy, UV-Visible (UVVis) spectroscopy, Differential scanning calorimetry (DSC) and Thermogravimetric analysis (TGA). The results showed a significant decrease in crystallite size of treated sample i.e., 104.7 nm as compared to control (139.6 nm). The FTIR and UV-Vis spectra of treated sample did not show any change with respect to control. Besides, thermal analysis data showed 42% decrease in latent heat of fusion. The onset temperature of volatilization and temperature at which maximum volatilization happened was also decreased by 16% and 12.86%, respectively. The significant decrease in crystallite size may help to improve the spreadability and hence bioavailability of resorcinol in topical formulations. Also increase in volatilization temperature might increase the rate of reaction of resorcinol when used as intermediate. Hence, biofield treatment may alter the physical and thermal properties of resorcinol and make it more suitable for use in pharmaceutical industry.

Biosurfactant: A Potent Antimicrobial Agent

Surfactant is an important class of chemicals with wide domestic and industrial application Synthetic surfactant however used to increase the contaminant solubility are often toxic representing an additional source of contamination Microbially produced surface active compounds i e biosurfactants are less toxic biodegradable and have potential uses in large oil recovery operations removal of oil spills biodegradation of hydrocarbons from the soil production of detergent agro industries manufacture of pharmaceutical products etc One of potential areas in which the usefulness of biosurfactants has been studied is its antimicrobial activity which is catching good attention worldwide The biosurfactants acts as an effective antimicrobial agent against a number of pathogenic organisms In the present research work a systematic isolation and screening program was under taken for obtaining biosurfactant producing bacteria After sampling in mineral salt medium a total of isolates were screened from the samples collected from Uran sea coast Mumbai and local Garage and Petrol pump After primary and secondary screening procedures like hemolysis emulsification index oil spread technique and surface tension measurement isolates namely Y and X were selected The emulsification index for the isolates was in petrol and diesel in hrs The isolates reduced surface tension of the MS medium as follows Y Dynes cm to Dynes cm and X Dynes cm to Dynes cm in a period of hrs The MS medium was optimized by Plackett Burman design for the isolates The biosurfactants was purified by acid precipitation method The antimicrobial activity tested for the purified surfactant was effective against nbsp E coli nbsp NCIM nbsp B subtilis nbsp NCIM and nbsp S aureus nbsp NCIM

Oligosaccharidic fractions derived from Triticum vulgare extract accelerate tissutal repairing processes in in vitro and in vivo models of skin lesions

Ethnopharmacological relevanceTriticum vulgare has been extensively used in traditional medicine thanks to its properties of accelerating tissue repair. The aqueous extract of Triticum vulgare (TVE) is currently an active component used by Farmaceutici Damor in the manufacture of certain pharmaceutical products already marketed in Italy and abroad under the brand name Fitostimoline®, in the formulation of cream and medicated gauze and is commonly used for the treatment of decubitus ulcers, sores, burns, scarring delays, dystrophic diseases, and, more broadly, in the presence of problems relating to re-epithelialization or tissue regeneration. The active components of Fitostimoline®-based products determine a marked acceleration of tissutal repairing processes, stimulate chemotaxis and the fibroblastic maturation, and significantly increase the fibroblastic index, which are crucial points in the repairing processes. The aim of the present paper was to identify and characterize the active fractions of TVE responsible for the pharmacological effect in tissutal repairing processes. Materials and methodsSeveral fractions obtained from TVE by ultrafiltration procedures and HPAE chromatography were tested to measure their growth-enhancing activity on NIH-3T3 fibroblasts. The healing action of the same fractions, prepared as cream formulation, was assessed in rat subjected to two different models of skin lesion, skin scarification and excision. ResultsOur results showed a pro-proliferative effect of the fractions ST-98 and K>1000 in NIH-3T3 fibroblasts. Moreover these fractions formulated as cream preparations were effective also in in vivo models of skin lesion. ConclusionsThe results of the present study showed that these active fractions of TVE are responsible for its pro-proliferative effect.

The Application of an Automated Control Strategy for an Integrated Continuous Pharmaceutical Pilot Plant

Continuous manufacturing offers potential opportunities for the improved manufacturing of pharmaceutical products. A key challenge is the development of an appropriate control strategy. The experimental application of an automated control strategy is presented for an end-to-end continuous pharmaceutical pilot plant. The process starts from an advanced intermediate compound and finishes with the tablet formation steps. The focus of the experimental results is on the design and performance of the control loops needed to produce a slurry of an active pharmaceutical ingredient and a solvent with specified material properties. The results demonstrate that automated control can successfully keep critical material attributes close to the desired set points for a sustained period of operation. This work aims to contribute to the development of future continuous pharmaceutical processes by providing a realistic case study of automated control of an integrated, continuous, pharmaceutical pilot plant.