AN OVERVIEW OF PHARMACEUTICAL AND BIOLOGICAL PRODUCT QUALITY CONTROL

Quality control (QC) is a procedure or set of procedures intended to ensure that a manufactured product or performed service adheres to a defined set of quality criteria or meets the requirements of the client or customer. QC is similar to, but not identical with, quality assurance (QA). There are various quality control parameters and guidelines which ensure us to deliver a slandered and contamination free product in the market. These quality control procedure and guidelines ensure the product development in the global slandered. In past years the role of quality control is increased in pharmaceutical and biotechnology industry. The maintenance of product quality is maintained by these procedure and guideline. Here we give a analytical description about why quality control procedures are important in the field of pharmaceutical and biological product manufacturing and what are the similarity between these procedures in both industries. Key words- QC,Pharmaceutical products,Biological product

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

The utility of immune function monitoring in predicting clinical outcomes in cirrhosis and following liver transplantation

© 2015 Dr. Siddharth SoodBackground: Transplantation is a life-saving procedure offered to thousands of people around the world each year. In most cases, lifelong suppression of the recipient’s immune system is required to prevent allorecognition and organ rejection. However, immunosuppressive medications have significant side effects that are now responsible for much of the post-transplant morbidity and mortality. Balancing the risks of over and under immunosuppression is key to patient management, but without an objective marker of immune function, clinical events remain common. QuantiFERON-Monitor (QFM) is a net immune function biomarker that measures IFNγ after stimulation of whole blood with an innate and adaptive immune stimulant. It is potentially accessible as it is based on the same laboratory platform as the readily available QuantiFERON-gold assay. The studies within this thesis represent the first translational clinical studies evaluating this assay. Methods: A cross-sectional pilot study compared QFM in healthy controls with patients before and after liver transplantation. Subsequent studies focused on immune function biomarkers and correlation with clinical events both before and after transplantation. In a cirrhotic transplant-waitlisted population, the QFM assay was performed and patients prospectively monitored for infection prior to transplant. This was followed by a prospective observational post-transplant cohort study in which QFM was taken longitudinally to assess for clinical events including infection and rejection based on pre-defined criteria. The same cohort was monitored for cytomegalovirus (CMV) reactivation with a CMV-specific T-cell assay, to evaluate the potential for more specialised immune monitoring. A small subgroup of controls and rejectors were compared for pre-transplant cytokine production using an enhanced sensitivity bead array and flow cytometry. Results: The pilot study confirmed that QFM could discriminate between populations known to be immunosuppressed. Compared with healthy controls, lower QFM was seen in patients following transplantation when on immunosuppression. QFM did not vary by age, gender or disease aetiology. In the cohort of cirrhotic patients, low QFM was associated with the risk of infection prior to transplant. This risk was also demonstrated after transplantation, where a low QFM at one week was significantly associated with risk of infection, but not rejection. Conversely, a high week 1 QFM was significantly associated with rejection, but not infection. Based on the selected optimal cut-offs, approximately 70% of all transplant patients were identified as being over- or under-suppressed. The risk of post-transplant rejection was further heightened in patients who had lower pre-transplant baseline pro-inflammatory cytokine production. QFM was not associated with risk of CMV reactivation. However, a CMV-specific immune function assay was significantly associated with CMV in patients inappropriately classified as low-risk based on current standard of care. Conclusions: Without an objective marker of immune function, clinical events remain exceedingly common following liver transplantation. The studies within this thesis represent the first translational studies involving QFM - a net immune function biomarker which benefits from being accessible, rapid and comprising both innate and adaptive immune stimulants. Future individualisation and optimisation of immunosuppression based on immune monitoring could fundamentally alter the way patients are monitored and treated following transplantation

Development of inhaled PLGA encapsulated Ivermectin for the treatment of SARS-CoV-2

OBJECTIVE: SARS-CoV-2 is a global threat to public health because of its high rate of infection causing fatalities. The arrival of vaccines has provided relief, but newer strains of SARS-CoV-2 are difficult to contain. As such, there is an urgent need to repurpose FDA-approved drugs with proven activity against COVID-19 as therapeutics to prevent proliferation of the virus. Recently, we reported that ivermectin (IVM) inhibited 3-chymotrypsin-like protease (3CLpro), an enzyme vital to SARS-CoV-2 replication, with a half-maximal inhibitory concentration (IC50) of 21μM. However, when taken orally, under 2 μM of IVM reaches the lungs, which is less than the IC50 against 3CLpro. Hence, site-specific delivery of IVM to the lungs will yield better results. We propose to develop an inhaled form of IVM and indocyanine green (ICG) encapsulated Poly(lactic-co-glycolic acid) (PLGA) to deliver IVM to the respiratory tract. METHODS: We hypothesize that once the formulation is delivered, the presence of ICG will enable in vivo imaging of the nanoparticles, and IVM will inhibit 3CLpro to prevent viral replication. Particle size and morphology of the synthesized particles will be characterized via particle size analyzer and Scanning Electron Microscope (SEM). Fourier Transform Infrared (FTIR), Thermogravimetric Analysis, and Differential Scanning Calorimeter will be used to confirm the presence of IVM in the nanoparticles and the amount of IVM in the nanoparticles will be quantified using high-performance liquid chromatography (HPLC). The Aerodynamic Particle Size Distribution Profiles tests (APSD) will be used to investigate their deposition profile. The nanoparticles were synthesized via double emulsion method with 0.3% polyvinyl alcohol as surfactant. RESULTS: Particle size analysis revealed that PLGA, PLGA-ICG, and PLGA-IVM-ICG were 100, 160, and 175 nm, respectively, and SEM confirmed their spherical morphology. FTIR validated the presence of IVM in the nanoparticles, and, once completely analyzed, they will be characterized in vitro and in vivo. Finally, in vitro assays have shown approximately 60% inhibition of our formulations against the enzyme. CONCLUSION: In summary, our data suggests that these formulations will act as a successful drug delivery mechanism to deliver IVM directly to the lungs. Furthermore, the efficacy of this system in vitro has shown that there is a need for in vivo trials in the future

Sarcoidosis manifesting as massive splenomegaly: a rare occurrence.

Sarcoidosis is a multisystemic granulomatous disease of unknown origin occurring worldwide and affecting people of all races and ages. This disease manifests most frequently with bilateral hilar lymphadenopathy, pulmonary infiltrates, and skin and ocular lesions. Granulomatous inflammation of the spleen is common in patients with sarcoidosis, but splenic enlargement is unusual and massive splenomegaly quite rare. Splenomegaly is usually homogeneous, but multiple low-attenuating nodular lesions are occasionally seen and easily mistaken for lymphoma, metastases, or infections such as tuberculosis. We describe an unusual case of sarcoidosis in a woman who presented with massive splenomegaly with extensive nodularity that cleared completely with corticosteroid therapy

Late presentation of congenital urachal sinus in a middle aged male complicated by an umbilical abscess: A case report

Urachus or the median umbilical ligament is a fibrous strand connecting umbilicus to bladder, representing embryologic remnant of cloaca and allantois. Urachal anomalies are infrequent in adult population. Moreover they have a different course in adults than pediatric age group in which they are more common, frequently involute and have a benign course. These remnants are prone to infection and development of malignancy. A proper diagnostic workup by clinical and imaging tools is required. We present a case report of a urachal sinus complicated with abscess in an adult with brief review of the literature

INTERLEUKIN-6 - 174G/C POLYMORPHISM IN NON-ALCOHOLIC FATTY LIVER DISEASE - PREVALENCE AND METABOLIC CHARACTERISTICS

The C allele of rs1800795 single nucleotide polymorphism (SNP), or `-174G/C`, in the promotor of Interleukin-6 (IL-6) gene is associated with an increased rate of metabolic risk, insulin resistance (IR) and diabetes (1), especially in the Caucasian populations. However, Asian populations are almost monomorphic for the G allele, which is also associated with obesity comorbidities and diabetes in this population. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome with IR the driving factor in its development. The aim of this study was to determine prevalence of IL-6 - 174G/C polymorphism in patients with NAFLD and to investigate the differences in metabolic phenotype between genotype groups. This cross-sectional analysis included 28 participants with NAFLD. Anthropometric, body composition, biochemistry and homeostatic model of assessment of insulin resistance (HOMA-IR) were recorded. Patients underwent magnetic resonance spectroscopy to determine intrahepatic lipids (IHL). Polymorphisms were genotyped by Fitgenes Limited. Forty-three per cent of patients with NAFLD were CC homozygote or GC heterozygote and 57% GG homozygote carriers. The C+ genotype consisted of 75% Caucasian and 25% non-Caucasian, in contrast to 25% Caucasian and 75% non-Caucasian for GG. Prevalence of diabetes was higher in C+ allele carriers compared to G homozygotes (67% vs. 31%, respectively). Subjects with the C+ genotype compared to GG had significantly greater waist circumference (114.4±22.4 cm vs. 100.2±10.6 cm), hip circumference (118.4±21.4 cm vs. 102.4±7.7 cm), fat mass (44.7±8.4% vs. 35.9±5.4%) and high-sensitivity C-reactive protein (5.3±3.6 vs. 2.8±2.6 mg/L), (p<0.05). C+ carriers also displayed higher plasma insulin concentrations, HOMA-IR and IHL, albeit non-significantly. Conclusion: Although numbers are small, results highlight that IL-6 - 174C variant is associated with Caucasian ethnicity, prevalence of diabetes, and greater anthropometry and body composition measurements in NAFLD. We envisage that these differences will be more apparent as patient numbers increase

Acoustic radiation force impulse accuracy and the impact of hepatic steatosis on liver fibrosis staging

Introduction The accuracy of Acoustic Radiation Force Impulse (ARFI) imaging has been validated in the setting of hepatitis C, however, the accuracy in the setting of fatty liver disease (FLD) has been less well‐established. The aim of this study was to assess the accuracy of ARFI in the setting of hepatic steatosis. Methods Patients with biopsy proven or sonographically diagnosed liver steatosis were assessed for ARFI trends including: inter‐operator concordance, interquartile range, ARFI failure rate, relationship between ARFI velocity and steatosis severity, and concordance between biopsy and ARFI fibrosis scores. Results Three hundred and forty‐nine patients were assessed (53 ‘biopsy’ cohort and 296 ‘ultrasound’ cohort), with 28 patients having biopsy on the same day as ARFI. Low stages of fibrosis (F0/1) were over‐estimated by ARFI in 62% of cases with biopsy correlation (n = 16, P < 0.001), with ARFI offering increased accuracy in regard to higher‐stage fibrosis (14/15 cases, 93%). In both the biopsy and ultrasound cohorts the failure rate and median inter‐quartile range increased with increasing steatosis, and the inter‐operator concordance remained good across all liver steatosis severities. Conclusion In the setting of steatosis, ARFI is very sensitive in detecting, and accurate in diagnosing, higher stages of fibrosis regardless of steatosis severity. It tends to overestimate the fibrosis category in lower stages of fibrosis. The present study does not show conclusively if the presence of steatosis or its severity independently alters ARFI measurements