Pharmaceutical Manufacturing Facilities Research Articles

Sequential high-recovery nanofiltration and electrochemical degradation for the treatment of pharmaceutical wastewater

The presence of antibiotics in aquatic ecosystems poses a significant concern for public health and aquatic life, owing to their contribution to the proliferation of antibiotic-resistant bacteria. Effective wastewater treatment strategies are needed to ensure that discharges from pharmaceutical manufacturing facilities are adequately controlled. Here we propose the sequential use of nanofiltration (NF) for concentrating a real pharmaceutical effluent derived from azithromycin production, followed by electrochemical oxidation for thorough removal of pharmaceutical compounds. The NF membrane demonstrated its capability to concentrate wastewater at a high recovery value of 95 % and 99.7 ± 0.2 % rejection to azithromycin. The subsequent electrochemical oxidation process completely degraded azithromycin in the concentrate within 30 min and reduced total organic carbon by 95 % in 180 min. Such integrated treatment approach minimized the electrochemically-treated volume through a low-energy membrane approach and enhanced mass transfer towards the electrodes, therefore driving the process toward zero-liquid-discharge objectives. Overall, our integrated approach holds promises for cost-effective and sustainable removal of trace pharmaceutical compounds and other organics in pharmaceutical wastewater.

Isolation, identification, and characterization of resistant bacteria to antibiotics from pharmaceutical effluent and study of their antibiotic resistance.

Pharmaceutical effluents primarily enter aquatic environments through the discharge of treated and untreated wastewater from various sources, including hospitals, pharmaceutical manufacturing facilities, and households. Microbes sourced from pharmaceutical effluents such as Pseudomonas spp. pose a significant public health concern because of their high levels of resistance to multiple drugs and extreme multidrug resistance. Therefore, the present study was conducted for the isolation, identification, and molecular characterization of selected isolates from pharmaceutical effluents and also determined their antibiotic sensitivity patterns. From June 2016 to March 2017, a study was conducted on four well-known pharmaceutical companies specializing in antibiotic production in Dhaka and Gazipur. Four wastewater samples were collected from various origins and then brought to the Bacteriology laboratory for microbiological examination. Twelve pure isolates were obtained and characterized through cultural and biochemical tests while molecular identification of Pseudomonas spp. was performed using the 16S rRNA gene sequence. Twelve commercially available antibiotics were used for antibiotic sensitivity tests using Kirby-Bauer disk diffusion methods. We isolated the most predominant isolates, Pseudomonas aeruginosa (41.67%), followed by Bacillus spp. (33.33%) and Staphylococcus spp. (25%) respectively. Among 12 antibiotics, ciprofloxacin is 100% sensitive against P. aeruginosa, while the remaining 11 antibiotics are 100% resistant. Bacillus spp. showed 100% resistance to all antibiotics while 50% sensitive to vancomycin and 100% to chloramphenicol, respectively. Staphylococcus spp. was 100% resistant to all antibiotics. Our research suggested that P. aeruginosa is the reservoir of antibiotic resistance genes and spreads disease to humans from the environment. The findings of this study, i.e., the isolation, identification, and characterization of antibiotic-resistant bacteria from pharmaceutical effluent have highlighted, comprehended, and mitigated the dissemination of antibiotic resistance and opportunistic bacteria.

Environmental Monitoring and Risk Assessment of Pharmaceutical Residues Discharged from Large Livestock Complex in the Geum River Basin, South Korea

This study aims to collect water samples from two tributaries within the Geum River basin in South Korea, where large-scale livestock complexes are located, to quantify the measured environmental concentration (MEC) of pharmaceutical residues using a multiresidue analytical method developed with liquid chromatography–tandem mass spectrometry (LC-MS/MS), and to evaluate the environmental risks posed by the detected pharmaceuticals to aquatic organisms. The water samples were collected at a total of 17 points, including up-, middle-, and downstream of the Seoksong and Nonsan-Gangkyoung streams connected to the Geum River, from October 2018 to March 2019. A multiresidue analytical method using LC-MS/MS was developed to quantify 49 pharmaceuticals with hydrophilic lipophilic balance using solid phase extraction. The recovery rates varied between 67.23% and 136.98%, while the limits of quantification were from 3.99 to 46.32 ng/L. Ecotoxicological information on acute and chronic effect endpoints (e.g., EC50, NOEC, etc.) was obtained from the U.S. EPA ECOTOX Knowledgebase. Considering the worst-case scenario, the lowest observed effect endpoint (mainly NOEC) of the most sensitive species was selected, and predicted no effect concentration (PNEC) values were calculated by dividing the endpoint by an assessment factor (AF). The mean, minimum, and maximum MECs of pharmaceuticals were divided by PNECs to calculate risk quotient (RQ). Caffeine was detected in all sampling sites with a detection frequency of 100%. High levels of pharmaceuticals (9.212 μg/L of sulfathiazole, 8.479 μg/L of acetaminophen, and 5.885 μg/L of florfenicol) were detected. The RQ values exceeded 1 and reached up to 84.79 (high risk category) for acetaminophen, and were between 0.11 and 0.83 (moderate risk) for carbamazepine, etc. The RQs for the rest of the 15 substances were below 1 (low risk). In the future, further studies should be conducted to monitor other micropollutants, including industrial chemicals, pesticides, etc., at different locations of the Geum River basin, including livestock farms, pharmaceutical manufacturing facilities, wastewater treatment plants, and other facilities, for long-term period.

Exploration and evaluation of modular concepts for the design of full-scale pharmaceutical manufacturing facilities.

The design of biopharmaceutical processes is predominantly driven by the domain of experimental process design. This approach can be further improved by combining multiple domain information such as experiments, unit models, and flowsheet models. Approaches consisting of methods and flowsheet models provide the framework for exploring, analyzing, and ultimately evaluating the combinatorial space of all possible designs within the molecule-to-manufacturing value chain. In recent years, modular process designs are of interest in the pharmaceutical industry because of the shift toward multiproduct, mutiprocess processes. Therefore, a systematic approach for how to evaluate the utilization of the modular plug-n-play concept provides metrics that can propel modular design from a viable design alternative to the selected alternative for full-scale manufacturing. The objective of this paper is to present such an in silico approach for the evaluation of modular designs. The approach is presented as a systematic method and then, is exemplified through the manufacture of an active pharmaceutical ingredient (API). The application of the method shows how to transition from a typical design-for-purpose design alternative to a modular design through the utilization of data, modeling, simulation, and uncertainty/sensitivity analyses for quantification of various selection metrics such as process robustness and flexibility.

Occurrence and Ecological Risk Assessment of Pharmaceutical Residues in Effluents from Pharmaceutical Manufacturing Facilities in Kumasi, Ghana

Occurrence and Ecological Risk Assessment of Pharmaceutical Residues in Effluents from Pharmaceutical Manufacturing Facilities in Kumasi, Ghana

Design, Development, and Validation of a Culture-Independent Nucleic Acid Diagnostics Method for the Rapid Detection and Quantification of the Burkholderia cepacia Complex in Water with an Equivalence to ISO/TS 12869:2019.

In the wake of a series of outbreaks of finished pharmaceutical product-related Burkholderia cepacia complex (Bcc) human infections worldwide, the United States Food and Drug Administration (FDA) in 2017, and subsequently in 2021, issued advisory notifications to the pharmaceutical industry for stringent Bcc testing requirements for pharmaceutical manufacturing processes and for finished pharmaceutical products prior to release to the marketplace. The advisory notifications highlight non-sterile aqueous finished pharmaceutical products as being a major culprit associated with many of these human infection events. As such, there has been a significant number of Bcc-contaminated finished product recalls resulting in company revenue losses, delayed finished product release, finished product shortages for patients, and manufacturing plant shutdowns coupled with company reputational damage. With many of the finished product recall events, pharmaceutical grade water and/or manufacturing facility water distribution systems were identified as the primary origin source of Bcc contamination. Testing and monitoring regimes currently employed to identify Bcc contamination of water associated with pharmaceutical manufacturing are often limited by costly, laborious, lengthy, and nonspecific traditional microbial culture-based methodologies. Presently FDA approved, European Conformity (CE) marked, and International Organization for Standardization (ISO) standard microbial culture-independent rapid, quantitative, specific, and sensitive nucleic acid diagnostics (NAD) methodologies are now gaining greater widespread acceptance in their routine usage in testing laboratories. Here we present the development of a rapid (<4 hours from sample in to result out) single test culture-independent Bcc NAD method, incorporating a quantitative real-time polymerase chain reaction (qPCR) assay. This method can be used for the detection and simultaneous identification of all 24 Bcc species currently assigned, directly from water samples. This culture-independent Bcc NAD method is validated to the testing method equivalent of the ISO/TS 12869:2019 standard, which is a widely used rapid culture-independent NAD method for detecting Gram-negative Legionella species in water.

Regulatory Compliance of Small-Scale Pharmaceutical manufacturing facilities in Addis Ababa, Ethiopia

Background: there is growing concern that medicines supplied to most of the developing countries are of substandard quality. Along with the establishment of strong regulatory systems for ensuring compliance and regulatory law enforcement, manufacturing facilities need to work to implement dependable systems at each stage of the production process to ensure the safety, efficacy, and quality of their products. Objective: the aim of this study was to assess the level of compliance with regulatory requirements by small-scale pharmaceutical manufacturing facilities in Addis Ababa, Ethiopia.&#x0D; Material &amp; Method: A cross-sectional observational study was conducted using a structured questionnaire and checklist to assess the level of compliance of small-scale local pharmaceutical manufacturing facilities to regulatory requirements and also to identify the challenges faced by the manufacturing facilities.&#x0D; Result: This study indicated that the overall implementation status of regulatory requirements in the local small-scale pharmaceutical manufacturing companies is far below the minimum standard set by WHO and the national regulatory authority. Basic on specific regulatory requirement elements compliance: requirements related to QA were 26.9, requirements related to personnel qualification were 38.1, requirements related to Quality control were 25.9, and requirements related to sanitation and hygiene were 15.3. Of the total regulatory requirements, only 26.1% were found to be implemented. Major challenges faced by the local small-scale pharmaceutical manufacturing industry for the implementation of regulatory requirements were: human resource capacity constraints, limited investment, limited support from Governments and other stakeholders, and poor infrastructure.&#x0D; Conclusion: The study demonstrated that level of regulatory requirements implementation in the local small-scale pharmaceutical manufacturers is far below the minimum standard set by the national regulatory authority. Important gaps were reported particularly in materials management, production operations, quality control, and sanitation and hygiene.

Environmental Monitoring in a Pharmaceutical Manufacturing Facility Using a Culture Independent Approach

Strict microbial control is required in manufacturing facilities to ensure the quality of pharmaceuticals and foods. Environmental microbial monitoring plays a fundamental role in reducing the risk of microbial contamination. Appropriate microbial control requires an understanding of abundance and community structures of microbes in the target environment. However, most of these microbes are not culturable using conventional methods. In this study, we determined the number of microbial particles and assessed the environmental microbiome in a pharmaceutical manufacturing facility, using high-throughput sequencing of rRNA gene fragments. Our results provide fundamental data for the evaluation and control of microbes in the pharmaceutical and food industries.

A constraint programming model for makespan minimisation in batch manufacturing pharmaceutical facilities

This work introduces a constraint programming (CP) model to minimise the makespan of a large scheduling problem in batch pharmaceutical manufacturing facilities. The model included campaign-manufacturing, sequence-dependent changeover, forbidden product-equipment assignment, non-working periods, limited renewable resources, finite intermediate/non-intermediate storage policies and preemptive and non-preemptive operations. The model was tested by scheduling two real examples. Each example consisted of two cases. Case A used the actual number of workers per shift. Case B involved reorganising the shift pattern of the workers. The results from the model were qualitatively validated and compared with the baseline schedules. The makespan of the first example decreased by 24.35% for case 1.A and 38.63% for case 1.B. The second example reported a 2.17% decrease in makespan for case 2.A and 16.67% decrease for case 2.B. This demonstrates the success of the proposed model as a simulation tool to identify the manufacturing bottlenecks by running what-if scenarios.

Fluidization characterization in the ConSigma 25 dryer via process data – A method of advanced quality assurance in continuous manufacturing

Wet granulation lines in pharmaceutical manufacturing facilities typically comprise a dryer that removes the excess moisture content after wet granulation. In this study, a semi-continuous dryer installed in the ConsiGma 25 wet granulation line was investigated. The goal was to highlight specific characteristics of this type of dryer, utilizing the available process data and the corresponding data obtained via material characterization. This paper addresses typical effects and issues associated with the dryer’s setup and operation (e.g., unexpected cell temperature profiles, the effects of air flow and temperature on the granule properties, variations in the granule moisture between the dryer cells). Since in many situations the liquid-to-solid ratio is based on the properties of granules after the granulation step, the selection of inlet air flow rate and the inlet air temperature of the dryer as well as the overall line throughput (affecting the cell fill level in the dryer) are of particular interest from a practical point of view. This paper discusses these issues and provides suggestions on how to address them when setting up the process. A novel approach for characterizing the fluidization inside the dryer by means of quantifying the “smoothness” of the temperature profile is proposed. The paper should be viewed as a hands-on guideline, which highlights possible pitfalls during the process setup and offers solutions.

Accommodating clinical trials and other externally manufactured cellular therapy products: challenges, lessons learned and creative solutions

Background aimsThe Division of Transfusion Medicine and Cellular Therapy at New York-Presbyterian/Columbia University Irving Medical Center (NYPH-CUIMC) comprises the immunohematology laboratory and blood bank (transfusion service), hemotherapy/apheresis and the cellular therapy laboratory (CTL). The CTL processes and stores hematopoietic progenitor cells for bone marrow transplantation from all currently acceptable sources, including bone marrow, peripheral blood and umbilical cord blood. The laboratory provides services for the pediatric and adult blood and marrow transplant programs at both NYPH-CUIMC and the Morgan Stanley Children's Hospital of New York-Presbyterian. The laboratory processes and stores approximately 200 cellular therapy products per year, and the division participates in numerous clinical trials within the institution and with external pharmaceutical manufacturing facilities. As a licensed tissue bank, commercial chimeric antigen receptor T-cell products and other cellular-based therapies that are approved by the US Food and Drug Administration (FDA) are routed through the CTL for storage, processing, coordination of transportation, chain of custody and, eventually, thaw and distribution. Currently, we are distributing four such products from Kite Pharma, Novartis and Bristol Meyers Squid. In comparison to the amount of work, we employ a small staff of only four full-time clinical laboratory technologists, one technical specialist, one quality and operations manager and one medical director. In recent years, the growing use of the hematology/oncology service and the introduction of new immunotherapies have put significant pressure on our division to accommodate and scale up operations. Accompanying this growth is a mounting administrative burden and upsurge in regulatory and protocol-specific oversight. The purpose of this article is to share lessons learned and creative solutions to help better accommodate the surge in development of novel cellular therapies. MethodsTo handle this increase in demand, the CTL worked to standardize administrative procedures, implement comprehensive document control solutions, digitize data collection and implement lean design concepts to increase effectiveness and mitigate risk. ResultsDistribution of a standard operating procedure for clinical trial management improved the “on-boarding” process and allowed the laboratory to have more influence in the decision-making process. Implementation of digital workflows and a comprehensive document control system allowed for improved organization of critical documents and proved to be flexible enough to accommodate various protocol-specific requirements. Introduction of visual ques and reorganization of the workspace facilitated better organization, mitigated risk and assisted the laboratory in maintaining regulatory compliance. ConclusionsBetter-defined, structured and controlled laboratory processes helped laboratory management implement new clinical trials and track critical data. Implementing digital solutions using widely available tools like Microsoft SharePoint has proven to be a very secure, low-cost and flexible solution to keeping us “up-to-date” and inspection-ready.

Implementing Project Portfolio Management at Pharmaceutical Manufacturing Facilities

Pharmaceutical manufacturing facilities are complex entities that are heavily regulated by health authorities. Manufacturing sites are challenged by increased production costs, tight regulations, and heavy competition. Without a disciplined and organized management of initiatives, projects end up being terminated due to poor performance or misalignment with strategy. This study examines different types of project needs at regulated manufacturing facilities and determines how the project portfolio management processes aids the manufacturing facilities in screening and selecting projects that aid in achieving the organization's strategic goals. Moreover, the study finds not one set of criteria can fit all projects in pharmaceutical manufacturing facilities. As a result, segregation of projects into different categories and then applying funds allocation ratio and the pre-screening criteria is proposed. Finally, the study contributes new logic inputs to the screening process within the body of the program and portfolio management.

PQ Forum #21 - Validation Initiation Document Template

Validation documents are key documents in a pharmaceutical manufacturing facility. Validation documents must be carefully written for internal and external review including audit by regulatory inspectors; they may be accessed numerous times during a product lifetime. The most frequently reviewed validation documents are Stage 2 Process Performance...

PQ Forum #21 - Validation Initiation Document Template

Validation documents are key documents in a pharmaceutical manufacturing facility. Validation documents must be carefully written for internal and external review including audit by regulatory inspectors; they may be accessed numerous times during a product lifetime. The most frequently reviewed validation documents are Stage 2 Process Performance Qualification documents.

The Impact of COVID-19 on the Efficiency of Packing Lines in Pharmaceutical Manufacturing Sites in Egypt

Corona Virus Disease COVID-19 has significantly impacted the pharmaceutical manufacturing sector. Production Efficiency in pharmaceutical facilities is questionable to withstand the drastic conditions under which the drug manufacturing supply chains are. Overall Equipment Effectiveness (OEE) is a primary indicator of efficiency. The aim of this review is to demonstrate a comprehensive overview on the factors impacting OEE and how they are affected by COVID-19.&#x0D; &#x0D; This review was done on a multinational pharmaceutical manufacturing facility in Egypt. In order to better understand the business model under study and have clearer vision on the impact of COVID-19 on each aspect of it, the business anatomy model &amp;lsquo;9 Elements&amp;rsquo; by Elsafty (2018) was used. The time horizon of this study is 2020 to understand the impact of the COVID-19 pandemic on the pharmaceutical manufacturing performance.&#x0D; &#x0D; The pandemic led to increase the pharmaceutical products demand which subsequently put a pressure on supply planners to alter the production scheduling. COVID-19 unraveled the weaknesses in the supply chains and the overreliance on materials suppliers of one source. This had a direct impact on the supply of materials and spare parts. Production efficiency has also been impacted by the health conditions of workers and operators might been community infected. Lack of high-skilled workers leads to decrease in the productivity due to the inability to manage and solve problems the right way and independently. Materials and finished goods quality are questionable in such situation. Introduction of counterfeit and falsified materials is a predictable side effect.&#x0D; &#x0D; It is concluded that OEE is affected by COVID-19 that moderates the inputs of OEE; availability, performance and quality. The pandemic has an impact (positive or negative) on the top losses of a machine efficiency.

Applying Lean Six Sigma Methodology to a Pharmaceutical Manufacturing Facility: A Case Study

This research examines a case study on the implementation of an effective approach to advanced Lean Six Sigma problem-solving within a pharmaceutical manufacturing site which manufactures acetaminophen (paracetamol containing pain relief) tablets. Though this study was completed in a single manufacturing company, the implementation of this study delivers important application and results that can be deployed in other such manufacturing companies. The manufacturing site faced backlogs in customer orders due to increased demand. Increased demand is due to brand popularity and recognition, product efficacy and a COVID 19 pandemic that intensified the demand for pain relief tablets in an already very busy site. With increased demand, to ensure timely deliveries, customer satisfaction and minimize delays, sources of site productivity losses and wastes needed to be analyzed and reduced or eliminated. Manufacturing Packaging line downtime was identified as one area of concern. The goal of the research was to introduce a problem-solving technique to reduce downtime within a manufacturing site without affecting the production required to fulfil customer demand while increasing product quality. The research utilized an integrated LSS methodology which identifies, stratifies and effectively eliminates non-value adding (waste) activities, by following a 7-step customized problem-solving methodology which resulted in complete elimination of the issue under investigation and savings of just under half a million dollars. The learnings are being deployed and leveraged worldwide across the pharmaceutical organizations parent site and sister sites. The presented results demonstrated that Lean Six Sigma methodology and tools are effective for accurate root causing of problems and enablers of implementation of continuous improvement.

Suspension of Fine Particles in Air and their Removal by Ventilation in an Indoor Environment as a Model of a Pharmaceutical Manufacturing Facility

Suspension of Fine Particles in Air and their Removal by Ventilation in an Indoor Environment as a Model of a Pharmaceutical Manufacturing Facility

Opportunities, Constraints and Critical Supports for Achieving Sustainable Local Pharmaceutical Manufacturing in Africa: With a Focus on the Role of Finance, Final Report

The Open Society Foundations Public Health Program commissioned an interdisciplinary team to examine the extent to which gaps in financing are an obstacle to more robust local production of pharmaceutical products (including diagnostics, vaccines and treatments (DVT)) and personal protective equipment (PPE) with focus on Africa. The Report is posted here. The Executive Summary and an Addenda compilation (which includes 3 supplemental research reports) are posted along with the Report at the website of Nova Worldwide Consulting.The overall findings of the study are that gaps in financing pose a constraint on the localization of pharmaceutical production in Africa. The gaps are not mainly due to a lack of financial capital in global financial markets that might be deployed for this purpose. The main problems are associated with the market environment in the sense that sustainable business operations require adequate demand, and market demand for pharmaceutical products in Africa is limited by various factors. In addition, comparatively weak infrastructure (recognizing variation among countries) makes it difficult to compete with large efficient foreign suppliers that are bolstered by foreign government support. Potential investors appear to perceive relatively high risks associated with investing in pharmaceutical manufacturing in Africa.Transforming political engagement:The COVID-19 pandemic may serve as adequate impetus to transform local production of pharmaceuticals into a governmental priority. Government commitment at a high level is required to engage the financial levers that will support localization of production.Sustainable business models:Particularly outside the vaccine sector, successfully operating a pharmaceutical manufacturing facility means addressing a market with sufficient demand to generate revenue and profits. Alternatively, or as a supplement, governments may provide direct subsidies, guaranteed offtake agreements, tax credits, local production pricing premiums, and other measures to substitute for market demand. These forms of support are commonly used for “infant industries”, and there should be plans to withdraw such support once a business has achieved sustainability.The social impact investor market:African governments should consider a program to encourage sovereign wealth funds and other financial asset managers to invest in local production on the African continent as a way to accomplish important social goals. To facilitate this objective, there should be some type of backstop or guarantee of the social impact investments within reasonable parameters. The African Development Bank may be helpful in establishing mechanisms for this purpose.Opportunities for advocacy:There is substantial room for advocacy by civil society to move Africa toward greater self-sufficiency in the production of pharmaceutical products. At the high level of political commitment, government authorities should be persuaded to prioritize local production of pharmaceuticals as a matter of public health security, engaging the financial levers to support such a commitment. At the level of industrial policy, the African Union should be encouraged to engage in concrete planning for regional pharmaceutical production hubs, and associated infrastructure and centers of technical expertise. Whether in conjunction with that, or separately, procurement authorities should be encouraged to form regional pooled procurement mechanisms to aggregate demand, allow for more effective bargaining with suppliers, and support regional hub manufacturers.Support for effective implementation of the African Continental Free Trade Area in terms of reducing barriers to intra-Africa trade in pharmaceutical products would improve the market situation. Similarly, continuing support for efforts to integrate the African regional regulatory structure for pharmaceutical products would accelerate access to medicines. Establishment of a library of available drug master files for reference by manufacturers would significantly lower barriers to manufacturer market entry.Foundations should be encouraged to develop a transparent platform which could provide information to African manufacturers with respect to opportunities for financing and expertise for pursuing their objectives.

Cross contamination control strategy in multiproduct pharmaceutical manufacturing facilities

Cross contamination control strategy in multiproduct pharmaceutical manufacturing facilities

Critical Electrical Design: Creating a Master Plan for a Research Campus

This article discusses the process of developing an electrical system master plan and utility upgrade for a large pharmaceutical research, manufacturing, and office facility. The ultimate goal for the site is to develop a more sustainable, resilient, and flexible campus. In this article, the team outlines the procedure for developing a list of project drivers, moves through the three design options established by the design and construction team, and discusses the development of an implementation plan that includes designing the utility switchgear, the paralleling gear, and the sequence of operation for the new systems.