Research progress of protein complex systems and their application in food: A review.

Among the common natural biomolecules, the excellent properties of proteins have attracted extensive attention from researchers for functional applications, however, in native form proteins have many limitations in the performance of their functional attribute. However, with the deepening of research, it has been found that the combination of natural active substances such as polyphenols, polysaccharides, etc. with protein molecules will make the composite system have stronger functional properties, while the utilization of pH-driven method, ultrasonic treatment, heat treatment, etc. not only provides a guarantee for the overall protein-based composite system, but also gives more possibilities to the protein-composite system. Protein composite systems are emerging in the fields of novel active packaging, functional factor delivery systems and gel systems with high medical value. The products of these protein composite systems usually have high functional properties, mainly due to the interaction of the remaining natural active substances with protein molecules, which can be broadly categorized into covalent interactions and non-covalent interactions, and which, despite the differences in these interactions, together constitute the cornerstone for the stability of protein composite systems and for in-depth research.

Multifunctional alginate films blended with polyphenol-rich extract from unconventional edible sources: Bioactive properties, UV-light protection, and food freshness monitoring.

The development of active and smart packaging from non-conventional food sources is an ecological trend to ensure safe food supply in the food chain. The study aimed to develop multifunctional films based on alginate blended with different concentrations of purple onion peel (POPE) and butterfly-pea flower extract (BFE). The addition of the extracts increased the opacity of the films by 80 %, indicating greater UV-light barrier ability. The tensile strength and elongation at break of the films increased by 70 % and 30 %, while water vapor permeability decreased by 15 %. The interaction between the extract and the alginate positively modified the structure of the films, increasing the melting temperature of the films (112-131 °C). Mixing both extracts in the matrix generated materials with antioxidant activity, antimicrobial capabilities, and sensitivity to freshness factors (gases, pH, and temperature) superior to films added with a single extract, suggesting better active and intelligent performances. The films protected the color of food products against the effects of UV-light, being strongly capable of colorimetrically checking the deterioration of protein-rich products. Therefore, alginate films blended with POPE and BFE have a promising potential for developing smart materials, preserving, and monitoring the food quality.

Industry perspective on a holistic container closure integrity approach to parenteral combination products.

Biologics are being developed more and more as parenteral combination products with drug delivery devices. The maintenance of sterility is imperative for such medical devices throughout their life cycle. Therefore, the container closure integrity (CCI) should, preferably, be built into the overall process, and not just demonstrated during the final testing of the combination product. The integrity is an important Critical Quality Attribute (CQA) and in the scope of specific considerations and studies during the combination product life cycle i.e., design robustness, assembly processes, storage (to end of shelf life), and shipping prior to patient use. The goal of this paper is to summarize an industry holistic approach to ensure CCI, for a combination product, and to build a scientifically based justification that Quality (in terms of CCI) is built into the overall process. Current analytical approaches used for characterization or Good Manufacturing Practice (GMP) CCI testing during combination product development will be described. However, the use of quality by design (QbD) during product development can reduce or eliminate routine batch level or stability testing of the combination product.

Safety considerations for dietary supplement manufacturers in the United States.

Due to significant dietary supplement use in the US, product manufacturers must understand the importance of implementing a robust approach to establishing safety for all ingredients, including dietary ingredients, components, and finished dietary supplement products. Different regulatory pathways exist by which the safety of dietary ingredients can be established, and thus allowed to be marketed in a dietary supplement. For individual dietary ingredients, safety information may come from a variety of sources including history of safe use, presence of the ingredient in foods, and/or non-clinical and clinical data. On occasion safety data gaps are identified for a specific ingredient, particularly those of botanical origin. Modern toxicological methods and models can prove helpful in satisfying data gaps and are presented in this review. For finished dietary supplement products, issues potentially impacting safety to consider include claims, product labeling, overages, contaminants, residual solvents, heavy metals, packaging, and product stability. In addition, a safety assessment does not end once a product is marketed. It is important that manufacturers actively monitor and record the occurrence of adverse events reported in association with the use of their products, in accordance with the law. Herein, we provide a comprehensive overview of considerations for assessing dietary supplement safety.

[Development and Assessment of a New Oral Selenium Fast-disintegrating Tablets].

Selenium is an essential trace element and its deficiency causes myositis, myocardial damage, and other symptoms. Patients receiving long-term intravenous nutrition or tube-feeding in particular are deficient in essential trace elements, including selenium, and require regular supplementation. In Japan, injectable selenium-containing products are listed on the National Health Insurance drug price list, and oral solutions are prepared and used in hospitals. However, these formulations have problems related to preservation and require complicated administration procedures. In this study, we developed a new fast-disintegrating tablet formulation of selenium, using SmartEx® (D-mannitol·low substituted hydroxypropylcellulose (L-HPC)·fully hydrolyzed polyvinyl alcohol (PVA) mixture) as a coprocessing additive, that can be administered orally or by feeding tube. The tablet formulation had excellent disintegrable capability, sufficient hardness, and did not cause tube blockage when administered in the simple suspension method. In addition, the tablet formulation showed no changes in properties in an accelerated test without packaging for 42 d, indicating that it could be stored for a long period. Fast-disintegrating tablets prepared with SmartEx® are expected to improve the adherence and quality of life of patients who require selenium supplementation.

Biodegradable nano-reinforced packaging with improved functionality to extend the freshness and longevity of Plums Oemleria cerasiformis.

Food packaging reinforced with Zn-doped TiO2 nanoparticles with enhanced prerequisite film-forming and biodegradable traits was prepared to augment fresh food storage. Pure and tailored metal (Zinc, Copper, and Selenium) doped TiO2 nanoparticles were synthesized and analyzed through multiple characterization techniques (optical spectra, XRD patterns (X-Ray Diffraction), Dynamic Light Scattering, and Scanning Electron Microscopy). The synthesized nanoparticles were tested for their Minimum Inhibitory Concentrations, antimicrobial potential against common lethal food pathogens, and cytotoxicity. Compared to Cu- and Se-doped nanoparticles, Zn-doped TiO2 nanoparticles displayed the most potent antimicrobial activity with insignificant cytotoxicity and were incorporated into the food packaging materials. The developed nano-reinforced food packaging efficaciously augmented the freshness of plums (Oemleria cerasiformis) for 16 days (42 ± 2 °C). The physicomechanical characterization of the nano-reinforced packaging establishes its utility in food packaging applications. The developed biodegradable packaging undergoes complete decomposition within 12 days of storage in natural soil.

Assessment of Functional and Physical Performances of Pre-filled Syringes in Deep Cold Storage Conditions.

The recent emergence of new drug technologies such as messenger ribonucleic acid-based vaccines developed to fight the outbreak of the COVID-19 global pandemic has driven increased demand for delivery solutions capable of withstanding deep cold storage conditions down to -50°C, and even down to -80°C. Although significant data exist for deep cold storage in vials, little evidence is available for pre-filled syringes. Because pre-filled syringes serve as both the storage container and the delivery mechanism, there are additional risks to performance that must be evaluated, such as plunger gliding performance, syringe lubrication, silicone layer stability, and container closure integrity (CCI). In the present study, a comprehensive assessment of functional and physical performances of pre-filled syringes (PFS filled with water) was performed after one or multiple freeze/thaw (F/T) cycles between ambient temperature and various temperature cycles including -40°C, -50°C or -80°C for both 'staked needle' and 'luer lock' configurations. The experiments were guided by historical normative methods such as ISO 11040-4 and USP <1207> and combined with headspace gas analysis for barrel-stopper tightness testing. In addition, they were complemented with a novel approach, namely in situ real-time optical imagery, to track plunger stopper movement during the F/T cycle. The findings indicated that there is no significant impact on the functional performances from F/T down to -80°C, whereas no CCI risk was found after F/T down to -50°C.

Recommendation of Single Time Point Leachables Testing for Lyophilized Biotechnology Products Stored in Rubber Stoppered Glass Vial Systems.

As a popular format of primary container closure systems, rubber stoppered glass vials are often used in storing and delivering lyophilized and liquid formulated therapeutic protein products. Assessing extractables and leachables from rubber stoppered glass vial systems is required to ensure drug product quality and patient safety. Lyophilized biopharmaceutical drug products are generally considered as less impacted by leachables during storage and transportation than the liquid formulated drug products. Single time point leachables testing for lyophilized biopharmaceutic drug products is recommended. The recommendation is based on our published comprehensive leachable data collected at multiple time points for five lyophilized drug products stored in different rubber stoppered glass vial systems with additional supporting comprehensive leachable data collected for nineteen liquid formulated drug products stored in different syringe and vial systems, which is statistically and scientifically sound. The leachable data evaluated herein were generated based on a holistic approach which ensured successful qualification of different vial systems as primary containers and delivery systems for various biotherapeutic products. The organic and elemental impurities of the leachable profiles of all the twenty-four drug product samples were below the limit of detection at all the time points. For lyophilized drug products, product surface interaction during storage time and shipping is unlikely. Timing of single time point leachables testing can be flexible. Performing leachables testing at one-year time point is recommended as it allows for enough time for chemicals to leach out from product contact surfaces into drug products and thus provides the earliest opportunity for mitigation of unpredicted leachables of concern, if any. However, testing at other stability time points can also be considered depending on the development strategy of the sponsor. Therefore, recommendation of single time point leachables testing for lyophilized drug products stored in rubber stopped glass vials at an appropriate time point is a scientifically sound approach.

The effect of blister packaging Iron and Folate on adherence to medication and hemoglobin levels among pregnant women at National Referral Hospital antenatal clinics in a low to middle income country: a Randomised Controlled Trial (The IFAd Trial).

INTRODUCTION: Anemia in pregnancy is an important global public health problem. It is estimated that 38% of pregnant women worldwide are anemic. In Africa, literature from observational studies show 20% of maternal deaths are attributed to anemia. In Uganda, 50% of pregnant women have iron deficiency anaemia. The proportion of pregnant women receiving Iron-Folic acid (IFA) supplementation has improved. However, the number of IFA pills consumed is still low. We carried out a randomized controlled trial to determine the effect of dispensing blister and loose packaged IFA pills on adherence measured by count on next return visit and hemoglobin levels among pregnant women at two National Referral Hospitals in Kampala, Uganda. METHODS: This trial was conducted between April and October 2016. Nine hundred fifty pregnant women at ≤28 weeks were randomized to either the blister (intervention arm) or loose (control arm) packaged IFA. The participants completed the baseline measurements and received 30 pills of IFA at enrolment to swallow one pill per day. We assessed adherence by pill count and measured hemoglobin at four and 8 weeks. The results were presented using both intention-to-treat and per-protocol analysis. RESULTS: There were 474 participants in the control and 478 in the intervention arms. Adherence to IFA intake was similar in the two groups at 4th week (40.6 and 39.0%, p = 0.624) and 8th week (51.9 and 46.8%, p = 0.119). The mean hemoglobin level at 4 weeks was higher in the blister than in the loose packaging arms (11.9 + 1.1 g/dl and 11.8 + 1.3 g/dl, respectively; p = 0.02), however, similar at week 8 (12.1 + 1.2 and 12.0 + 1.3, respectively; p = 0.23). However, over the 8-week period blister packaging arm had a higher change in hemoglobin level compared to loose package (blister package 0.6 ± 1.0; loose packaging 0.2 ± 1.1; difference: 0.4 g/dL (95% CI: 0.24-0.51 g/dL); p = 0.001. There were no serious adverse events. CONCLUSIONS: Our results showed no effect of blister packaging on IFA adherence among pregnant women. However, our findings showed that blister packaged group had a higher hemoglobin increase compared to loose iron group. TRIAL REGISTRATION: No. PACTR201707002436264 (20 /07/ 2017).

Observation and Mitigation of Leachables from Non-Product Contact Materials in Electromechanical Delivery Devices for Biotechnology Products.

Battery-powered drug delivery devices are widely used as primary containers for storing and delivering therapeutic protein products to improve patient compliance and quality of life. Compared to conventional delivery approaches such as pre-filled syringes, battery-powered devices are more complex in design requiring new materials/components for proper functionality, which could cause potential product safety and quality concerns from the extractable and leachables (E&L) of the new materials/components. In this study, E&L assessments were performed on a battery-powered delivery device during the development and qualification of the device, where novel compound 2­hydroxy-2-methylpropiophenone (HMPP) and related compounds were observed in both E&L. The source of the HMPP and related compounds was identified to be the nonproduct contact device batteries, in which HMPP photo-initiator was used as a curing agent in the battery sealant to prevent leakage of the battery electrolytes. Toxicology assessment was performed, which showed the levels of HMPP observed in the device lots were acceptable relative to the permitted daily exposure. A drug product HMPP spike study was also performed, where no product impact was observed. Based on these assessments, an action threshold and specification limits could be established as a control strategy, if needed, to mitigate the potential risks associate with the observed leachables. As a full resolution, seven battery candidates from different suppliers were screened and one new battery was successfully qualified for the delivery devices. Overall, the holistic E&L approach was fully successful in the development and qualification of the battery-powered devices for biotherapeutic products delivery ensuring product quality and patient safety. Non-product contact materials are commonly rated as low or no risk and typically considered as out of scope of E&L activities for delivery systems following industry benchmark and regulatory agency guidance. This case study is novel as it brings into attention the materials that might not normally be in consideration during the development process. It is highly recommended to understand materials in the context of intended use on a case-by-case basis and not to generalize to ensure successful development and qualification.

A review about industrialization of Chinese materia medica decoction pieces.

Chinese materia medica decoction pieces (CMMDPs), one of the three pillars of the Chinese materia medica industry, are a key link in the Chinese materia medica industrial chain. Industrialization is the only way for the modernization of CMMDPs. This review mainly summarizes the characteristics, history, current situation and prospect of CMMDPs industry, providing a new reference for promoting the flourishing development of the industrialization of CMMDPs and for serving massive health industry. The literature was collected from databases including Web of Science, PubMed, Elsevier and CNKI (Chinese). CMMDPs industry has the characteristics of regionalism, resource dependency, customer diversity and low industrial concentration. Deeply processed products include traditional Chinese medicine (TCM) formula granules, small-packed decoction pieces, ultrafine decoction pieces, puffed decoction pieces, compressed decoction pieces and instant decoction pieces. Integration of treatment and processing at the place of origin is emerging. However, there is still room for improvement, for example, the manufacturing technologies of CMMDPs industry need to be continually improved. The management of CMMDPs' normalized production also needs to be strengthened. The quality of CMMDPs should be strengthened supervision and it should establish the objective and feasible quality evaluation system for CMMDPs. At present, China has attached unprecedented importance to the development of TCM, and issued a number of supporting policies, sparing no effort to support its development.

Holistic Extractables and Leachables Program: Evaluations of Prefilled Syringe Systems for Biotechnology Products.

Prefilled syringes (PFS) are a container and delivery device of choice for storing and administering therapeutic protein products to patients. Addressing concerns and regulatory expectations related to the risk to biologic drug product quality and patient safety from PFS requires implementation of an extractable and leachable program based on understanding of materials, risk assessment, review of existing literature, and testing supported by a sound scientific foundation. Extractables and leachables data generated as part of a thorough and holistic program are presented for five PFS systems, including glass and plastic syringes filled with 12 biologic drug products encompassing the implementation of traditional and single-use biotechnology manufacturing processes. The comprehensive extractables and leachables data presented demonstrate and substantiate a holistic extractable and leachable program designed to ensure product quality and patient safety.

Development of Biodegradable Whey-Based Laminate Functionalised by Chitosan-Natural Extract Formulations.

In this research, antimicrobial polysaccharide chitosan and natural extracts were used as surface coating of a plastic laminate with an integrated whey layer on the inside. The aim was to establish the biodegradable and active concept of packaging laminates. For this purpose, chitosan nanoparticles (CSNPs) with embedded rosemary or cinnamon extracts were synthesised and characterised. Additionally, a whey-based laminate was functionalised: i) chitosan macromolecular solution was applied as first layer and ii) cinnamon or rosemary extracts encapsulated in CSNPs were applied as upper layer (layer wise deposition). Such functionalised whey-based laminate was physicochemically characterized in terms of elemental surface composition, wettability, morphology and oxygen permeability. The antimicrobial activity was tested against Staphylococcus aureus, Escherichia coli, Aspergillus flavus and Penicillium verrucosum. The antioxidant properties were determined using the ABTS assay. It could be shown that after functionalization of the films with the above-mentioned strategy, the wettability was improved. Furthermore, such whey-based laminates still show excellent barrier properties, good antimicrobial activity and a remarkable antioxidative activity. In addition to the improved biodegradability, this type of lamination could also have a positive effect on the shelf-life of products packaged in such structured films.

The my experience of taking medicines (MYMEDS) questionnaire for assessing medicines adherence barriers in post-myocardial infarction patients: development and utility.

BACKGROUND: The 'My Experience of Taking Medicines' (MYMEDS) questionnaire is a self-reporting tool for identifying modifiable adherence barriers among individuals prescribed post-myocardial infarction (MI) secondary prevention medicines (SPM) in clinical practice. It was found to be a useful tool to support the conduction of patient-centred consultation in cardiology outpatient leading to improved outcomes including better adherence to SPM and patient satisfaction. This study describes the rationale and development of the MYMEDS tool, its performance and usefulness in identifying modifiable barriers to adherence in cardiology medical practice including user feedback of 204 consecutive post-MI patients who completed an evaluation based on MYMEDS. METHODS: Modifiable non-adherence factors were initially identified based on literature review and stakeholder feedback. A draft MYMEDS questionnaire was piloted in 10 patients and adapted accordingly. The final version comprises six sections, covering current medicines, understanding and satisfaction with medicines, concerns about medicines, practical adherence barriers, fitting medicines into daily routine, and adherence to individual SPMs. The questionnaire was mailed to post-MI patients who then attended an outpatient medicines optimisation clinic. RESULTS: Mean age was 70.5 years and 67.6% were male. The tool was effective in revealing modifiable adherence barriers that could be addressed during the consultation. There were high rates of concern that SPMs could be harmful (33.2%) or overprescribed (43.2%), practical issues with swallowing medicines (8.2%), opening packaging (7.3%) or accessing repeat prescriptions (5.2%), forgetfulness (19.7%), and concerns about inconvenience (13.5%). Mean number of barriers per patient was 1.8 ± 1.5. The medications most commonly associated with non-adherence were statins (21.5%), angiotensin II receptor blockers (21.1%), and antiplatelet agents (18.5%). In total, 42.5% of patients acknowledged non-adherence behaviour. Patient feedback on MYMEDS was positive, with near-unanimous agreement that it was simple, clear and not too long, and that it enabled them to raise any concerns they had about their medicines. Patients reported that their individual medicines related needs were better addressed. CONCLUSIONS: MYMEDS is a practical tool that can successfully identify modifiable barriers to SPM adherence which can be addressed in a clinical setting. It can be easily rolled out in daily clinical practice to enable individualised person-centred medicines optimisation consultation.

Iron Packaging Regulations in the United States and Pediatric Morbidity: A Retrospective Cohort Study.

Iron poisoning was a leading cause of pediatric morbidity and mortality. We sought to assess whether the removal of strict iron packaging requirements in 2003 resulted in an increase in iron-related morbidity and mortality in pediatric exposures. We performed a retrospective cohort study utilizing the National Poison Data System from 2000 to 2017. A total of 4110 exposures met inclusion criteria: 847 from before (2000-2003) and 3263 after removal of unit-dose package regulations (2004-2017). The incidence of any marker of severity (7.2% vs 3.8%; odds ratio = 0.51, 95% confidence interval = 0.37-0.69) and frequency of deferoxamine use were both higher in the early time period (2.6% vs 1.0%; odds ratio = 0.38, 95% confidence interval = 0.22-0.66). There was no difference in the frequency of key serious effects (acidosis, elevated transaminases, hypotension). Despite removal of iron packaging regulations in the United States, there continues to be a decrease in the incidence of severe iron exposures in children.

Stability of commercial parenteral lipid emulsions repacking to polypropylene syringes.

To accommodate small fluid volumes, repackaging of intravenous lipid emulsions is frequently performed in hospitals providing parenteral nutrition to neonates and smaller pediatric patients. The physical stability of lipid commercial parenteral emulsions repacked and stored in polypropylene syringe up to 30 days at room temperature, refrigerator and 40°C was determined to establish options for extended storage. Lipid emulsions in the manufacturers' original containers were used as references. Commercial lipid emulsions (20% of oil phase), ClinOleic, Intralipid, Smoflipid, Omegaven and Lipofindin LCT/MCT were repackaged under aseptic conditions in polypropylene syringes and stored at 4°C, 25°C and 40°C without light protection. Samples were assayed periodically over 30 days using validated, stability-indicating methods. Lipid emulsions in the manufacturers' containers stored in the same conditions were as references. Analysis of variance showed differences in the physical parameters due to temperature (p<0.05) and study day (p<0.05) but not the type of the emulsion (p = 0.98). The parenteral lipid emulsions in polypropylene syringe exhibited identical (except Z-avarage at 40°C, t = 30 days) to original containers time-dependent behavior taking into account the mean globule size, pH, and zeta potential measurements. Size of oily droplets of all test conditions remained below the United States Pharmacopeia limits. The results allow safe repacking of commercial lipid emulsion in a syringe, which is a necessary condition for supplying parenteral nutrition using the two-in-one method for newborns. However, longer storage than 12 h of repacked emulsion needs microbiological studies.

Introducing the Alba® Primary Packaging Platform. Part 2: Inorganic Extractables Evaluation.

Sensitivity of drugs to one or more elements of the primary packaging is a serious concern for the pharmaceutical industry. Biologics in particular are highly sensitive, leading to a higher risk of incompatibility and stability test failure as worst-case scenario.This potential incompatibility-and the consequent formulation instability due to the interactions between the drug and the primary container surface-may have multiple causes: the intrinsic nature of the container surface, leachables coming from the materials used, substances coming from the production process, or silicone oil droplets or other particles.The Alba primary packaging platform was designed to have the same interface between the drug and the glass container surface on the different primary packaging containers in order to minimize the emergence of instabilities at later stages of formulation development. Alba containers are internally treated with an innovative cross-linked coating based on silicone oil lubricant, and the additional rubber components have been selected to minimize the possible differences between the container typologies.This paper shows in great detail the reduction of the inorganic extractables released and the comparability of the performances of the different containers obtained using Alba technology.The improvement has been demonstrated by stressing the containers with different extract solutions; Alba-coated containers show a strong reduction of inorganic extractables and of corrosion degree compared to spray-on siliconized and bulk products. The containers included in the Alba platform present comparable results, and this represents a strong advantage during the drug formulation development by facilitating the transition from one container to another.LAY ABSTRACT: The sensitivity of drugs to one or more elements of the primary packaging is a serious concern for the pharmaceutical industry. Biologics in particular are highly sensitive, leading to a higher risk of incompatibility and stability test failure worst-case scenario.This potential incompatibility-and the consequent formulation instability due to the interactions between the drug and the primary container surface-may have multiple causes: the intrinsic nature of the container surface, leachables coming from the materials used, substances coming from the production process, or silicone oil droplets or other particles.The Alba primary packaging platform was designed to minimize these problems associated with the interaction between the drug and its primary packaging. This paper shows in great detail and with robust data the inorganic extractables release reduction and the delamination risk mitigation obtained using the Alba technology.

Comparing Physical Container Closure Integrity Test Methods and Artificial Leak Methodologies.

The sterility of drug products intended for parenteral administration is a critical quality attribute (CQA) because it serves to ensure patient safety and is thus a key requirement by health authorities. While sterility testing is a probabilistic test, the assurance of sterility is a holistic concept including adequate design of manufacturing facilities, process performance, and product design. Container closure integrity testing (CCIT) is necessary to confirm the integrity of a container closure system (CCS), until the end of a product's shelf life. The new and revised United States Pharmacopeia (USP) General Chapter <1207> is a comprehensive guidance on CCI. Nevertheless, practical considerations including the choice of CCIT methods, the acceptance criteria, or the positive control samples (artificial leaks) must be addressed by the pharmaceutical manufacturer.This study is the first to provide a systematic comparison of four commonly used physical CCIT (pCCIT) methods [Helium (He) leak, vacuum decay, laser-based headspace analysis (HSA), and dye ingress] and four commonly used modes of creating artificial leaks (laser-drilled micro holes, copper wire introduced leaks, and two types of capillary leaks).The results from these experiments provide comprehensive data to allow a direct comparison of the capabilities of the individual methods. The results confirmed that the He leak detection method, which is considered the "gold-standard" for pCCIT regarding method sensitivity, indeed demonstrates the highest detection sensitivity (lowest detection limit). In comparison to the dye ingress method, HSA and vacuum decay also demonstrated better detection sensitivity in our study.Capillary leaks with orifice diameter (capillary leak with flow according to an ideal orifice) and micro holes yielded similar leak rates, whereas capillaries with nominal diameters yielded significantly lower leak rates. In conclusion, method sensitivity cannot be compared by means of a leak diameter, but requires the consideration of multiple impacting factors (e.g., path length, uniformity).LAY ABSTRACT: Sterility of drug products intended for parenteral administration is a critical quality attribute to ensure patient's safety and is thus a key requirement by health authorities. The absence of microbial contamination must be demonstrated by container closure integrity (CCI) of the container closure system (CCS). Currently, the revised United States Pharmacopeia (USP) General Chapter <1207> provides the most extensive guidance on how CCI should be assessed. Nevertheless, practical considerations on the choice of an appropriate CCIT method, artificial leaks or the choice of an acceptance criteria are lacking and must be addressed by the pharmaceutical manufacturer.This study provides a systematic comparison of four commonly used physical CCIT (pCCIT) methods [Helium (He) leak, vacuum decay, laser-based headspace analysis (HSA) and dye ingress] and four commonly used modes of creating artificial leaks (laser-drilled micro holes, copper wire introduced leaks, and two types of capillary leaks).

Integrating a diabetes and hypertension case management package within primary health care: a mixed methods feasibility study in Bangladesh.

BACKGROUND: Almost three quarters of non-communicable disease (NCD) deaths, and 82% of premature NCD deaths, occur in low- and middle-income countries. Bangladesh has an estimated 7 million hypertensives and 10 million diabetics, and primary care is struggling to respond. Our aim was to develop and support implementation of a diabetes and hypertension case management package, and assess its appropriateness, feasibility and acceptability in two NCD clinics within two primary-care centres in Bangladesh. METHODS: We used a convergent mixed methods design. We first assessed the level of appropriate hypertension and cardiovascular disease patient management, based on a composite outcome indicator using data from patients' treatment cards. Appropriate management was primarily informed by International Diabetes Federation (IDF) and World Health Organisation (WHO) guidelines. We then performed qualitative in-depth interviews with doctors and patients to explain these quantitative findings and to understand the challenges to achieving appropriate patient management in the NCD clinics. RESULTS: Eighty-one newly diagnosed patients were recruited. Over 3 months, 53.1% (95% CI 42.3% to 63.6%) of patients were appropriately managed. We found incomplete diagnosis (especially missing hypertension diagnosis alongside diabetes) and non-provision of follow-up appointments were the main causes of the relatively low level of appropriate management. We conducted interviews with 11 patients and 8 health professionals and found a shortage of human resources, reporting materials, available drugs and diagnostic equipment. This undermined patients' willingness to attend clinics and doctors' willingness to offer follow-ups. Hands-on skill-building training was valuable in increasing doctors' competence for appropriate management, but was seen as a novel training method and faced constraints to implementation. CONCLUSIONS: A clinical guide, skill-based training and recording package can be implemented in routine primary care and can lead to appropriate management of around half of diabetic and hypertensive patients in a low-income country. However, considerable health systems challenges must be addressed before more patients can be managed appropriately.