Derivation of process control strategy for biosimilar: Is it different from the way a control strategy is derived for a novel biologic?

Quality based development (QbD) has become the preferred choice for developing manufacturing process for any biologic drug. A proponent for this approach has been the US Food and Drug Association (FDA). Recently, the first QbD applications have been successfully filed with FDA. Biosimilars have also gained popularity in the recent past. Development of these drugs are very different from the way a novel biologic is developed. In the last five years, many companies around the world have started working on Biosimilars of which some companies have been able to successfully develop and get approvals for Biosimilars in both FDA and European Medicenes agency (EMA). Application of QbD for a Novel and a Biosimilar drug is quite different. By nature of the requirement for developing a Biosimilar, quality of the ‘reference product’ against which the biosimilar is being developed is considered while making decisions during process development. Though the same concepts applies for a novel drug, the target quality profile is not as defined as one can write for a Biosimilar. This is because product quality information regarding the reference product is well-known and can be thoroughly analyzed and characterized. While the targets can be easily derived for a Biosimilar, deriving a process control strategy is tough. Critical Process Parameter (CPP) is defined as a process parameter that has significant impact on the safety and efficacy of the drug. While this definition for CPP is applicable for a Bisomilar also, another aspect which requires consideration for a Biosimilar drug is the impact of process parameters on ‘fingerprint biosimilarity’. Hence the classification of process parameters as those that are critical and those that are not is not as straight forward like for a Novel drug. Derivation of acceptance range for these parameters also is different – The acceptance range for CPPs when compared to that for a novel biologic is generally found to be narrow. This is because the desired range for the outputs (such as aggregates, glycan, charge, size variants etc.) is narrow owing to the product quality ranges observed for the reference product and not just the levels of the outputs which has an effect on safety and efficacy. These subtle differences make deriving the process control strategy for a Bisomilar different from a novel biologic. In this presentation, a detailed overview of scale down model qualification, process characterization experiments, and the control strategy for Biosimilar manufacturing processes is provided. A case study will be presented which showcases some of these concepts of deriving control strategy as how it is applied for a Biosimilar process

Cystic lymphangioma of the breast in an infant successfully managed with intralesional bleomycin: a case report with relevant review of the literature

Cystic hygromas, also known as lymphangiomas, are unusual congenital malformations of the lymphatic system and commonly involve the head and neck region or axilla. Involvement of other sites such as breasts is very rare. The preferred mode of treatment for lymphangioma of the breast in adults or children is surgery. We report a case of breast lymphangioma in a 3-month-old male child, which was managed successfully by intralesional bleomycin.Keywords: breast, bleomycin, intralesional sclerosing agent, macrocystic lymphangiom

DNA vaccination for rabies: Evaluation of preclinical safety and toxicology

AbstractThe worldwide incidence of rabies and high rates of therapy failure, despite availability of effective vaccines indicate the need for timely and improved prophylactic approaches. DNA vaccination based on optimized formulation of lysosome-targeted glycoprotein of the rabies virus provides potential platform for preventing and controlling rabies. As per the pre-clinical requirements, listed in guidelines of Schedule Y, FDA and that of The European Agency for evaluation of Medicinal Products; we evaluated the acute (single dose – 14days) using three dosing levels, that is, the therapeutic (1×), average (5×) and high dose (10×) intramuscular toxicity in the rodent model Swiss Albino mice. Furthermore, the chronic intramuscular toxicity (repeated dose – 43days with another 14days for satellite groups) was investigated using broad dosing levels ranging from low (7×), mid (14×) to high (28×) in Wistar rats. A range of parameters including physical, physiological, clinical, immunological, hematological along with histopathology profiles of target organs was monitored to assess the impact of vaccination. There were no observational adverse effects despite high dose administration of the DNA vaccine formulation. Thus, this study indicates the safety of next generation of vaccines as well as highlights their potential application

Divergent evolution of Corynebacterium diphtheriae in India: An update from National Diphtheria Surveillance network.

Diphtheria is caused by a toxigenic bacterium Corynebacterium diphtheria which is being an emerging pathogen in India. Since diphtheria morbidity and mortality continues to be high in the country, the present study aimed to study the molecular epidemiology of C. diphtheriae strains from India. A total of 441 diphtheria suspected specimens collected as part of the surveillance programme between 2015 and 2020 were studied. All the isolates were confirmed as C. diphtheriae with standard biochemical tests, ELEK's test, and real-time PCR. Antimicrobial susceptibility testing for the subset of isolates showed intermediate susceptibility to penicillin and complete susceptible to erythromycin and cefotaxime. Isolates were characterized using multi locus sequence typing method. MLST analysis for the 216 C. diphtheriae isolates revealed major diversity among the sequence types. A total of 34 STs were assigned with majority of the isolates belonged to ST466 (30%). The second most common ST identified was ST405 that was present in 14% of the isolates. The international clone ST50 was also seen. The identified STs were grouped into 8 different clonal complexes (CC). The majority belongs to CC5 followed by CC466, CC574 and CC209, however a single non-toxigenic strain belongs to CC42. This epidemiological analysis revealed the emergence of novel STs and the clones with better dissemination properties. This study has also provided information on the circulating strains of C. diphtheriae among the different regions of India. The molecular data generated through surveillance system can be utilized for further actions in concern

Effect of Electromagnetic Field on Antimicrobial Activity and Novel Antimicrobial Compounds

The objective of this study is to determine the antimicrobial activity of the essential oils and effect of electromagnetic field on the activity. To find out antimicrobial activity of essential oils (Thyme, Clove, Lavender), against test organisms disc diffusion assay was performed. MIC of all essential oils were determined under electromagnetic field and non-electromagnetic field. Both studies confirmed the antimicrobial activity of oils and effect of electromagnetic field. However, time killing experiment was conducted to calculate rate of inhibition for essential oils, lavender oil and thyme oil showed higher rate as compared to that of clove oil. This study provides evidence to antimicrobial activity of essential oils, and also confirmed the effect of electromagnetic field on the activity. The proposed mechanism for antimicrobial activity is inhibition of metabolic enzymes which has supported with Analytical Profile Identification (API 20NE)

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication