Quality and effectiveness of counselling at antiretroviral therapy centres in India: capturing counsellor and beneficiary perspectives.

BACKGROUND: Ensuring the quality and effectiveness of counselling is imperative for enabling people living with HIV to cope with treatment adherence. Countrywide assessment of antiretroviral therapy (ART) centres was undertaken to assess the quality and effectiveness of counselling. The insights gained from the assessment are expected to build an improved understanding of the counselling aspect and contribute to informing decisions strengthening the counselling provided at ART centres. METHODS: Assessment of counselling at 357 ART centres entailed interviews with counsellors and beneficiaries using a structured questionnaire administered by trained technical experts. Two counsellors and five beneficiaries at each ART centre were interviewed to assess both the quality and effectiveness of counselling. Beneficiaries were selected from different risk groups to understand their varied concerns and experiences. RESULTS: During the assessment, 618 counsellors were interviewed (45% women); also, 1785 beneficiaries were interviewed, consisting of 892 (49.9%) men, 857 (48.1%) women and 36 (2.0%) transgender. Counsellors were found to be relatively well informed on topics pertaining to pre-ART, ART preparedness and positive healthy living, and the psychosocial support extended to patients. Counsellors surveyed were not aware of critical areas such as counselling of pregnant women (44.5%) , drug adherence (44.8%) and the use of information, education and communication material during counselling, and pill count. The majority of beneficiaries reported being informed on issues pertaining to retention; however, 30-40% of beneficiaries were not informed regarding the critical elements of adherence such as counselling on ART side effects (68.5%), pill count (62.8%) and information on access to social benefit schemes (25.7%). Factors such as client volume, the training of the counsellors and adequate space for counselling affected the quality of counselling. CONCLUSION: With concerted efforts in bridging the gaps in knowledge, infrastructure and information needs, India's national AIDS control programme (NACP) can enhance the counselling services at ART centres and improve the quality of services for patient retention.

Assessment of quality of antiretroviral therapy services in India, 2014-2015.

Background: Following a decade of provision of free antiretroviral therapy (ART) in India, a nationwide assessment of ART services was conducted to review quality of care at ART centers. This paper presents the methods and defines replicable model of undertaking large scale assessments. Methods: During the period January 2014-March 2015, 357 ART centers were reviewed under four domains, namely, operations, technical, monitoring and evaluation (M&E), and logistics. Mixed methods, comprising of desk review and on-site facility assessment; random sample of records, interviews with both health-care staff and people living with HIV (PLHIV) were used. Grading for each of the domain was done on a scale of 5, with 1 (Very poor) being the lowest and 5 (Excellent) as highest. Results: 1720 health-care staff and 1762 beneficiaries were interviewed; 34 600 patient cards were reviewed. Of the 357 centers assessed 60, 169 and 128 scored Excellent, Average and Poor, respectively, in operations domain; 147, 176, 34 in Technical domain; 215, 115, 27 in M&E domain; 263, 71, 23 centers in logistics domain scored Excellent, Average and Poor, respectively. About 95% (1698/1785) of PLHIV were satisfied with the care provided at ART centers. Conclusion: The methodology used for the assessment of ART centers in India yielded insights on the different domains that impact implementation and quality of service delivery. The design of this exercise may inform other researchers and managers planning similar large-scale assessments.

Feasibility of implementing an integrated tool for improvement of treatment quality and early-warning indicators for HIV drug resistance: a pilot study of centres in India.

With the rapid scale-up in use of antiretroviral therapy (ART), monitoring the quality of care and factors that may lead to emergence of HIV drug resistance (HIVDR) is an important focus point for programme managers. The National AIDS Control Organisation of India embarked on strengthening the ART programme for continuous quality improvement (CQI), using defined quality-of-care indicators (QCIs), including World Health Organization (WHO) early-warning indicators (EWIs) for HIVDR. In this feasibility study, done during July 2014, an integrated QCI and EWI tool developed by WHO India was pilot tested across 18 purposively selected ART centres. At seven ART centres, the EWI 1 target of >90% on-time pill pick-up was achieved for adult patients, while among the paediatric age group (<15 years old) it was not achieved by any centre. EWI 2 (retention of patients in ART care at 12 months after initiation) showed that two centres had retention of both adult and paediatric patients of >85% at 12 months of ART, while 11 centres had retention between 75% and 85%. EWI 3 (pharmacy stock-out) for adult and paediatric patients showed that 11 ART centres reported a minimum of one stock-out for the first-line ART drugs in the reporting period, while EWI 4 targets (pharmacy dispensing practices) were achieved by all the centres, for both adults and children. Average retention in care at 6, 12 and 24 months after ART initiation was 82%, 77% and 71%, respectively. This feasibility study showed that EWI analyses were much simpler to conduct if information was sought only for patients receiving ART, for whom the quality of record-keeping is better and more consistent. The activity has highlighted the need for improved quality of record-keeping at the facilities and implementation of specific interventions to ensure better patient follow-up. After modifications, use of the tool will be phased in across all the ART centres in India.

Presence of CD3+ tumor infiltrating lymphocytes is significantly associated with good prognosis in infiltrating ductal carcinoma of breast.

BACKGROUND: Aim of this study was to investigate the prognostic significance of CD3+ TILs in infiltrating ductal carcinoma (IDC) of the breast. MATERIALS AND METHODS: Immuno-histochemistry was done with CD3 antibodies in tissue sections of 127 breast cancer patients, and CD3+ intra-tumoral and stromal TILs were counted in relation to clinico-pathological variables. RESULTS: Intra-tumoral and stromal CD3+ TILs were significantly associated with positive lymph node status (P = 0.006, P = 0.043, respectively) without significant association with age, menopausal status, family history, and hormonal status. The higher CD3 intra-tumoral and stromal counts both showed significant association with good prognosis (P = 0.039, P = 0.044, respectively). The intra-tumoral count was higher than stromal count and was independently associated with disease-free survival in stage I and II cancer (P = 0.021). CONCLUSIONS: CD3+ TILs may serve as independent marker of good prognosis in IDC breast. The findings of this study need further validation on a larger sample size.

Chromatography process development in the quality by design paradigm I: Establishing a high-throughput process development platform as a tool for estimating "characterization space" for an ion exchange chromatography step.

This article describes the development of a high-throughput process development (HTPD) platform for developing chromatography steps. An assessment of the platform as a tool for establishing the "characterization space" for an ion exchange chromatography step has been performed by using design of experiments. Case studies involving use of a biotech therapeutic, granulocyte colony-stimulating factor have been used to demonstrate the performance of the platform. We discuss the various challenges that arise when working at such small volumes along with the solutions that we propose to alleviate these challenges to make the HTPD data suitable for empirical modeling. Further, we have also validated the scalability of this platform by comparing the results from the HTPD platform (2 and 6 µL resin volumes) against those obtained at the traditional laboratory scale (resin volume, 0.5 mL). We find that after integration of the proposed correction factors, the HTPD platform is capable of performing the process optimization studies at 170-fold higher productivity. The platform is capable of providing semi-quantitative assessment of the effects of the various input parameters under consideration. We think that platform such as the one presented is an excellent tool for examining the "characterization space" and reducing the extensive experimentation at the traditional lab scale that is otherwise required for establishing the "design space." Thus, this platform will specifically aid in successful implementation of quality by design in biotech process development. This is especially significant in view of the constraints with respect to time and resources that the biopharma industry faces today.

Comparative performance of decoupled input-output linearizing controller and linear interpolation PID controller: enhancing biomass and ethanol production in Saccharomyces cerevisiae.

A decoupled input-output linearizing controller (DIOLC) was designed as an alternative advanced control strategy for controlling bioprocesses. Simulation studies of its implementation were carried out to control ethanol and biomass production in Saccharomyces cerevisiae and its performance was compared to that of a proportional-integral-derivative (PID) controller with parameters tuned according to a linear schedule. The overall performance of the DIOLC was better in the test experiments requiring the controllers to respond accurately to simultaneous changes in the trajectories of the substrate and dissolved oxygen concentration. It also exhibited better performance in perturbation experiments of the most significant parameters q (S,max), q (O2,max), and k ( s ), determined through a statistical design of experiments involving 730 simulations. DIOLC exhibited a superior ability of constraining the process when implemented in extreme metabolic regimes of high oxygen demand for maximizing biomass concentration and low oxygen demand for maximizing ethanol concentration.

Physico-chemical study of Vaikranta bhasma.

BACKGROUND: Vaikranta has very important place in Rasa sastra and is placed under Maharasa and Upratna group. It has been mentioned that vaikranta can be used in the place of diamond, which is a very precious stone and whose use is beyond the limit of the common man. Vaikranta possesses pharmacological and therapeutic properties similar to diamond, but still very few researchers have worked on it. AIMS AND OBJECTIVES: The main aim of the present study is to analyze vaikranta bhasma by employing various organoleptic methods mentioned in Ayurvedic science along with analysis as per tools available today. SETTINGS AND DESIGN: In the present study, vaikranta bhasma was prepared according to method mentioned in Rasa Ratna Samuccaya. Final product is prepared according to classical parameters described in Ayurvedic science. MATERIALS AND METHODS: Ayurvedic scholars have described various parameters for the qualitative evaluation of vaikranta bhasma, but all those are subjective in nature and cannot be evaluated numerically for reproducibility of the result. With this in mind, in the present study, tests as per Ayurvedic science and analytical parameters such as scanning electron microscopy, energy dispersive X-ray analysis, Fourier transform infrared spectrometry and inductively coupled plasma spectrometry were adopted to analyze the final product. RESULTS AND CONCLUSIONS: Data suggests that vaikranta bhasma is a multi-mineral compound, which contains iron and silica as major constituents and others are present as trace elements. The data obtained in this study suggest that quality specifications for vaikranta bhasma can be developed using tests described in Ayurvedic science along with analytical tools available today.

Use of computational fluid dynamics as a tool for establishing process design space for mixing in a bioreactor.

The concept of "design space" plays an integral part in implementation of quality by design for pharmaceutical products. ICH Q8 defines design space as "the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval." Computational fluid dynamics (CFD) is increasingly being used as a tool for modeling of hydrodynamics and mass transfer. In this study, a laboratory-scale aerated bioreactor is modeled using CFD. Eulerian-Eulerian multiphase model is used along with dispersed k-ε turbulent model. Population balance model is incorporated to account for bubble breakage and coalescence. Multiple reference frame model is used for the rotating region. We demonstrate the usefulness of CFD modeling for evaluating the effects of typical process parameters like impeller speed, gas flow rate, and liquid height on the mass transfer coefficient (k(L)a). Design of experiments is utilized to establish a design space for the above mentioned parameters for a given permissible range of k(L)a.

Recent developments in membrane-based separations in biotechnology processes: review.

Membrane-based separations are the most ubiquitous unit operations in biotech processes. There are several key reasons for this. First, they can be used with a large variety of applications including clarification, concentration, buffer exchange, purification, and sterilization. Second, they are available in a variety of formats, such as depth filtration, ultrafiltration, diafiltration, nanofiltration, reverse osmosis, and microfiltration. Third, they are simple to operate and are generally robust toward normal variations in feed material and operating parameters. Fourth, membrane-based separations typically require lower capital cost when compared to other processing options. As a result of these advantages, a typical biotech process has anywhere from 10 to 20 membrane-based separation steps. In this article we review the major developments that have occurred on this topic with a focus on developments in the last 5 years.

Review of computational fluid dynamics applications in biotechnology processes.

Computational fluid dynamics (CFD) is well established as a tool of choice for solving problems that involve one or more of the following phenomena: flow of fluids, heat transfer,mass transfer, and chemical reaction. Unit operations that are commonly utilized in biotechnology processes are often complex and as such would greatly benefit from application of CFD. The thirst for deeper process and product understanding that has arisen out of initiatives such as quality by design provides further impetus toward usefulness of CFD for problems that may otherwise require extensive experimentation. Not surprisingly, there has been increasing interest in applying CFD toward a variety of applications in biotechnology processing in the last decade. In this article, we will review applications in the major unit operations involved with processing of biotechnology products. These include fermentation,centrifugation, chromatography, ultrafiltration, microfiltration, and freeze drying. We feel that the future applications of CFD in biotechnology processing will focus on establishing CFD as a tool of choice for providing process understanding that can be then used to guide more efficient and effective experimentation. This article puts special emphasis on the work done in the last 10 years.

Process analytical technology (PAT) for biopharmaceutical products.

The "Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century--A Risk Based Approach" initiative announced by the FDA in August 2002 to improve and modernize pharmaceutical manufacturing facilitated adoption of process analytical technology (PAT) by the pharmaceutical industry. The potential for improved operational control and compliance resulting from continuous real-time quality assurance was highlighted as a likely benefit that would result from PAT implementation. A considerable amount of work has been done on this topic by academic and industrial contributors in the last decade. In this paper, we will start with a brief overview of evolution of PAT concepts and a review of their application in the wider pharmaceutical industry. The rest of the paper focuses on PAT applications for biotech processes with emphasis on developments in the last five years. It is our observation that while significant advances have been accomplished with regard to our ability to analyze/monitor key process and quality attributes in the biotech industry, much more needs to be done with regard to utilizing the collected data for subsequent control of the process, to achieve optimum yield and product quality. The latter is necessary to achieve the benefits that will result from PAT implementation.

Process analytical technology (PAT) for biopharmaceutical products: Part I. concepts and applications.

Process analytical technology (PAT) has been gaining momentum in the biotech community due to the potential for continuous real-time quality assurance resulting in improved operational control and compliance. In this two part series, we address PAT as it applies to processes that produce biotech therapeutic products. In the first part, we address evolution of the underlying concepts and applications in biopharmaceutical manufacturing. We also present a literature review of applications in the areas of upstream and downstream processing to illustrate how implementation of PAT can help realize advanced approaches to ensuring product quality in real time. In the second part, we will explore similar applications in the areas of drug product manufacturing, rapid microbiology, and chemometrics as well as evolution of PAT in biotech processing.

Process analytical technology (PAT) for biopharmaceutical products: Part II. Concepts and applications.

Implementing real-time product quality control meets one or both of the key goals outlined in FDA's PAT guidance: "variability is managed by the process" and "product quality attributes can be accurately and reliably predicted over the design space established for materials used, process parameters, manufacturing, environmental, and other conditions." The first part of the paper presented an overview of PAT concepts and applications in the areas of upstream and downstream processing. In this second part, we present principles and case studies to illustrate implementation of PAT for drug product manufacturing, rapid microbiology, and chemometrics. We further present our thoughts on how PAT will be applied to biotech processes going forward. The role of PAT as an enabling component of the Quality by Design framework is highlighted. Integration of PAT with the principles stated in the ICH Q8, Q9, and Q10 guidance documents is also discussed.

Enhancement of electroosmotic flow in capillary electrochromatography.

A major impediment to enhancing the speed of separation in capillary electrochromatography (CEC) is the upper limit on the electroosmotic flow (EOF) velocity by the maximal zeta potential of the chromatographic surface. Here, a new approach to speeding up EOF, suggested by Yang and El Rassi (Electrophoresis 1999, 20,18-23), is examined critically. It entails the use of a tandem arrangement of a separating column and an auxiliary column, the sole function of which is to boost EOF velocity in the separating column and thus facilitate faster analysis by CEC. Based on the principle of conservation of mass and current and using experimental data obtained in a wide range of conditions, the flow velocities in the separating and auxiliary columns were evaluated. The results show that an equidiameter open tubular auxiliary column offers a greater enhancement of EOF velocity than a packed column. Nevertheless, within the scope of the experiments the enhancement of EOF velocity by as much as 50% by using open tubular auxiliary columns has been obtained.

Validatibility of a capillary isoelectric focusing method for impurity quantitation.

A strategy is presented for examining the validatability of a capillary isoelectric focusing (cIEF) method, intended for quantitation of product-related impurities in a protein drug substance, according to guidelines published by the International Conference on Harmonization (ICH). The results of this study demonstrate the suitability of cIEF as an analytical method for the quantitation of two product-related impurities in a protein drug substance: a monodeamidated degradation product and an aggregated form of the parent molecule. A range of impurity levels was generated by spiking the isolated impurity species, into a representative production lot of the drug substance. Six impurity spike levels (0.5-12% impurity for deamidated species and 0.5-8% impurity for aggregated species) were analyzed in triplicate. Measurement of impurity peak area percent in the spiked samples provided the data for computing specificity, accuracy, precision, linearity and limit of quantitation (LOQ) for the impurities. Accuracy, defined as the agreement of peak area percent for impurity species with the theoretical impurity percentage from the spike ratio, was 85-96% for the deamidated species and 73-97% for the aggregated species. A linear relationship was found between the measured area percent and the theoretical percent impurity for both impurity species (coefficient of determination, r2=0.9994 for deamidated species and =0.9827 for aggregated species). Precision (repeatability) studies demonstrated a low relative standard deviation (RSD) value (<6%) at all spike levels for both impurity species. Intermediate precision and reproducibility were evaluated by simulating many of the multivariable testing conditions expected during the life cycle of an analytical method, such as multiple equipment and laboratories. Repeated analyses of the drug substance under these varied conditions, yielded RSD values of <20%, for both impurity species. The LOQ, defined as the lowest impurity level where both accuracy and precision were achieved, was assigned at the 0.5% impurity level for both impurity species. This work illustrates a successful strategy in applying the ICH validation guidelines for impurity analytical methods to a cIEF method. Moreover, the data demonstrate the ability of cIEF to be used reliably as an analytical method for impurity quantitation.

Electrosmotic mobility and conductivity in columns for capillary electrochromatography.

Columns employed so far in capillary electrochromatography (CEC) contain both a packed and an open segment with concomitant changes of the electric field strength and the flow velocity at the interface of the two segments in such duplex columns. To take this into account in measuring, processing, and interpreting CEC data, a framework is presented for the evaluation of the conductivity ratio and the interstitial electrosmotic flow (EOF) mobility and their usage as tools for characterizing CEC columns. This is illustrated by experimental data obtained from measurement of the current and the EOF in capillary columns packed with different stationary phases. The current data yielded the ratio of the conductivities of the packed and open segments that has been shown to be useful for the evaluation of the porosity and tortuosity. It is assumed that these important packing characteristics are the same for the flow of current and for the flow of the bulk mobile phase in the CEC column. The EOF mobility in such duplex columns is defined in two different ways. The apparent mobility, which is widely reported at present, is obtained from the length of packed segment, the migration time, and the overall electric field strength. On the other hand, the actual mobility is obtained after taking into account the porosity and tortuosity of the packing as well. Thus, the actual mobility is made independent of the porosity and tortuosity and therefore can be useful to estimate the zeta potential for characterizing the packing surface. Measurements of both the apparent and actual electrosmotic mobilities for a number of different columns have shown that the apparent and actual mobilities are significantly different in their magnitude. For this reason, it is recommended that, instead of the apparent EOF mobility, the actual mobility is used for the characterization of the packing in CEC columns.

Cyclodextrins as selectivity enhancers in capillary zone electrophoresis of proteins.

The selectivity in the capillary zone electrophoresis (CZE) of a variety of acidic and basic proteins including alpha-chymotrypsinogen A, cytochrome c, lysozyme, ribonuclease A, ovalbumin, and beta-lactoglobulins A and B, was altered by adding 6-monodeoxy-6-monoamino-beta-cyclodextrin or carboxymethylated beta-cyclodextrin to the electrophoretic medium of aqueous 50 mM sodium phosphate, pH 2.5. On the other hand, no significant improvement was obtained in the separation upon addition of heptakis (2,6-di-O-methyl)-beta-cyclodextrin. Whereas protein adsorption on the wall of raw silica capillaries was significant in the absence of cyclodextrin, by addition of beta-cyclodextrin or its derivatives to the background electrolyte, wall adsorption was reduced with concomitant enhancement of the recovery. The results confirm that in various separation techniques, particularly those which employ microcolumns, certain cyclodextrin additives can be useful selectivity enhancers not only in the separation of small sample molecules but also in that of proteins.