In today’s fast-paced pharmaceutical industry, efficiency plays a critical role in meeting the increasing demands for drugs and medical products. To achieve optimal efficiency, pharmaceutical manufacturers are turning to advanced automation solutions. Advanced automation encompasses cutting-edge technologies like robotics, artificial intelligence (AI), and data analytics to streamline manufacturing processes and enhance overall productivity. In this article, we will explore the significance of pharmaceutical manufacturing efficiency and delve into how advanced automation can revolutionize the industry.

Understanding Pharma Manufacturing Efficiency

Pharmaceutical manufacturing efficiency refers to the ability of a company to produce high-quality drugs and medical products with minimal resources, time, and costs. Efficiency is crucial as it directly impacts production timelines, costs, and ultimately, the availability of life-saving medications in the market. Efficient pharmaceutical manufacturing is essential to meet the growing global healthcare needs and ensure the accessibility of vital treatments to patients.

However, maintaining efficiency in the pharmaceutical industry is not without challenges. Factors such as complex processes, stringent regulations, and the need for consistent product quality pose hurdles that can hinder production optimization.

The Evolution of Advanced Automation in Pharma Manufacturing

The journey toward automation in pharmaceutical manufacturing has been a progressive one. In the past, many processes were labor-intensive and susceptible to human errors. As technology advanced, pharmaceutical companies began incorporating automation in various aspects of their operations.

The shift from manual to advanced automated systems has brought significant improvements. Robotic systems can handle repetitive tasks with precision, reducing the likelihood of errors and contamination. AI-powered algorithms optimize production schedules, making processes more efficient and responsive. Additionally, data analytics enable manufacturers to gain valuable insights, allowing them to identify areas for improvement and make data-driven decisions.

Key Components of Advanced Automation in Pharma Manufacturing

Advanced automation in pharmaceutical manufacturing relies on several key technologies. Robotics, equipped with advanced sensors and actuators, can handle tasks ranging from material handling to quality control. AI plays a crucial role in predictive maintenance, real-time monitoring, and process optimization. Data analytics utilizes vast amounts of production data to identify patterns, uncover inefficiencies, and improve overall performance.

Advantages of Implementing Advanced Automation

The implementation of advanced automation in pharmaceutical manufacturing offers numerous advantages. Firstly, it significantly boosts productivity by reducing cycle times and increasing output. Secondly, automation minimizes the risk of errors, leading to improved product quality and safety. Moreover, the automation process reduces waste, thus lowering production costs and promoting sustainable practices.

Overcoming Challenges in Adopting Advanced Automation

While advanced automation presents immense benefits, there are challenges to consider during implementation. The initial investment in automation technology may be substantial, which could deter some companies from adopting it. There may also be concerns about job displacement due to increased automation. To address these concerns, companies can invest in training and upskilling their workforce to ensure they can collaborate effectively with automated systems.

Real-Life Examples of Successful Pharma Manufacturing Automation

Several pharmaceutical companies have already successfully integrated advanced automation into their manufacturing processes. For instance, Company XYZ implemented robotic systems for material handling, resulting in a 30% reduction in production time. Another success story is Company ABC, which implemented AI algorithms to optimize their production schedules, leading to a 20% increase in overall output.

Future Trends in Pharma Manufacturing Automation

The future of pharmaceutical manufacturing automation looks promising with the emergence of new technologies. Nanotechnology may enable more precise drug delivery, while 3D printing could revolutionize the production of personalized medicines. Additionally, advanced AI systems will continue to evolve, supporting more complex and autonomous decision-making processes.

Ensuring Data Security and Regulatory Compliance

With the integration of automation comes the need for robust data security measures. Manufacturers must safeguard sensitive information to protect patients’ privacy and maintain competitive advantages. Furthermore, regulatory compliance is crucial in the pharmaceutical industry, where strict guidelines ensure the safety and efficacy of medications. Companies must adhere to these regulations while implementing advanced automation.

The Human Element in Advanced Automation

Despite the rise of advanced automation, the human element remains indispensable. Skilled workers with domain expertise are vital for overseeing and fine-tuning automated systems. Human-machine collaboration enhances the capabilities of both, leading to improved efficiency and innovative problem-solving.

Sustainability and Green Manufacturing in Pharma Automation

Beyond efficiency gains, advanced automation can contribute to sustainability and green manufacturing practices. Automated systems can optimize resource utilization, reduce energy consumption, and minimize waste generation. By adopting environmentally friendly manufacturing methods, the pharmaceutical industry can contribute to a healthier planet.

Challenges to Overcome for Widespread Adoption

While the benefits of advanced automation are evident, there are challenges that need to be addressed for widespread adoption. Companies may encounter resistance to change from employees accustomed to traditional processes. To overcome this, fostering a culture of continuous improvement and emphasizing the benefits of automation can pave the way for successful implementation.

Advanced automation is revolutionizing the pharmaceutical manufacturing landscape. By embracing cutting-edge technologies such as robotics, AI, and data analytics, companies can enhance efficiency, reduce costs, and improve product quality. The integration of automation should be viewed as an opportunity for growth, sustainability, and greater access to life-saving medications for patients worldwide.

FAQs (Frequently Asked Questions)

1. What is pharmaceutical manufacturing efficiency? Pharmaceutical manufacturing efficiency refers to a company’s ability to produce high-quality drugs and medical products with minimal resources, time, and costs.
2. How does advanced automation improve efficiency in pharma manufacturing? Advanced automation, through technologies like robotics and AI, streamlines processes, reduces errors, and optimizes production schedules, resulting in enhanced efficiency.
3. What are the benefits of implementing automation in pharmaceutical manufacturing? The benefits include increased productivity, improved product quality, cost savings, and reduced waste, leading to more sustainable manufacturing practices.
4. How can companies ensure data security when implementing automation? Companies must employ robust data security measures, encryption, and access controls to safeguard sensitive information from cyber threats.
5. What role do humans play in an automated manufacturing environment? Humans provide domain expertise, oversee automated systems, and collaborate with machines to optimize efficiency and problem-solving.

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In the fast-paced world of supply chain management, warehouse efficiency plays a pivotal role in ensuring timely and accurate order fulfillment while minimizing costs. With the rising demands of e-commerce and globalization, businesses are continually seeking innovative ways to optimize their warehouse operations. This article delves into the significance of warehouse efficiency, the challenges faced, the role of technology, and best practices to achieve maximum productivity.

Understanding Warehouse Efficiency

Defining Warehouse Efficiency

Warehouse efficiency refers to the ability of a warehouse to utilize resources effectively and deliver products to customers efficiently. It involves streamlining processes, reducing wastage, and maintaining accuracy in inventory management.

The Importance of Efficient Warehousing

Efficient warehousing is crucial for businesses to stay competitive in today’s market. It ensures swift order processing, minimizes holding costs, and enables faster response to customer demands.

Identifying Challenges in Warehouse Operations

Inventory Management

Maintaining optimal inventory levels while avoiding stockouts and overstock situations can be a complex challenge for warehouse managers.

Order Picking and Packing

Inefficient order picking and packing processes can lead to delays and errors in fulfilling customer orders.

Space Utilization

Limited warehouse space and inefficient use of available space can restrict the storage capacity and lead to operational bottlenecks.

The Role of Technology in Improving Warehouse Efficiency

Warehouse Management Systems (WMS)

A WMS provides real-time visibility into inventory levels, automates order processing, and optimizes warehouse layouts for enhanced efficiency.

Automation and Robotics

Automated systems and robotics streamline repetitive tasks, such as picking, packing, and loading, resulting in increased productivity and reduced human errors.

IoT (Internet of Things) in Warehousing

IoT sensors enable real-time tracking of inventory, monitor equipment health, and offer predictive maintenance insights.

Data Analytics and Artificial Intelligence (AI)

Data-driven insights and AI-powered algorithms help warehouse managers make informed decisions, predict demand patterns, and optimize supply chain operations.

Implementing Best Practices for Enhanced Efficiency

Efficient Layout and Design

An organized and logical warehouse layout improves material flow and reduces the time taken to process orders.

Optimized Inventory Management

Regular audits, ABC analysis, and adopting just-in-time (JIT) inventory practices lead to efficient stock management.

Streamlined Order Fulfillment Process

Integrating order processing, inventory management, and shipping systems streamline the entire fulfillment process.

Employee Training and Engagement

Well-trained and motivated warehouse staff contribute significantly to improved efficiency and reduced errors.

The Benefits of Improving Warehouse Efficiency

Cost Savings

Enhanced efficiency leads to reduced operational costs, better resource utilization, and minimized waste.

Increased Productivity

Automation and streamlined processes result in higher productivity and quicker order processing.

Customer Satisfaction and Loyalty

Efficient warehousing ensures timely deliveries, leading to increased customer satisfaction and loyalty.

Overcoming Challenges and Resistance to Change

Addressing Workforce Concerns

Incorporating technology requires addressing employee concerns and providing training to adapt to new systems.

Emphasizing Long-Term Gains

Promoting the long-term benefits of efficiency improvements helps gain support for technology adoption.

Case Studies: Successful Implementation of Technology and Best Practices

Company A: Automating Order Processing

Company A achieved significant efficiency gains by implementing an automated order processing system, reducing order fulfillment time by 40%.

Company B: IoT Integration for Real-Time Inventory Tracking

By integrating IoT sensors for real-time inventory tracking, Company B improved inventory accuracy and reduced stockouts by 30%.

Company C: Data-Driven Predictive Analytics

Company C leveraged data-driven predictive analytics to optimize inventory levels, resulting in a 25% reduction in carrying costs.

Future Trends in Warehouse Efficiency

Advancements in Automation and Robotics

Advancements in automation and robotics will lead to even greater efficiency gains and reduced reliance on manual labor.

AI-Driven Warehousing

AI will revolutionize warehousing with intelligent decision-making, predictive analysis, and efficient resource allocation.

Sustainable and Green Warehouses

The future will witness the rise of environmentally conscious and sustainable warehouses, focusing on eco-friendly practices.

Conclusion

Improving warehouse efficiency is a critical component of modern supply chain management. By leveraging technology and adopting best practices, businesses can achieve higher productivity, cost savings, and customer satisfaction. Embracing these changes and staying ahead of emerging trends will enable warehouses to thrive in the dynamic business landscape.

FAQs

1. What is the significance of warehouse efficiency? Warehouse efficiency ensures timely order fulfillment and minimizes costs, contributing to overall business success.
2. How does technology enhance warehouse efficiency? Technology such as WMS, automation, IoT, and AI streamlines processes, optimizes inventory management, and improves overall productivity.
3. What are some best practices for efficient warehousing? Efficient layout and design, optimized inventory management, streamlined order fulfillment, and employee training are key best practices.
4. How can warehouse managers overcome resistance to change? Addressing workforce concerns and emphasizing the long-term benefits of efficiency improvements can help overcome resistance to change.
5. What are the future trends in warehouse efficiency? Advancements in automation, AI-driven warehousing, and sustainable practices are the future trends to watch for in warehousing.

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While the impact of COVID-19 was significant in every area of the pharmaceutical sector, some of the most pandemic’s most overlooked impacts were within the regulatory space. From study design to submissions, the virus affected every aspect of drug regulation, from trial design and co-ordination to submission of documents and filings. 

Redesigning clinical trials

The impact of COVID-19 required a more prioritised, rapid vaccine development than has ever been seen before. The need to push through an efficacious, easily manufacturable product to combat COVID affected every aspect of the pharma industry, from drug design to trials to manufacturing and regulatory affairs.

Rapid developments in the regulatory space have been critical in speeding up the clinical trial process. The need to ensure patient safety led to a decentralised, fluid approach to clinical trials, which in turn saw an uptick in ways patient data can be harvested. The urgent need for swift approvals meant that standard procedure was modified or relaxed, with regulatory applications for vaccines approved in less than a week. Overall, regulatory changes made during COVID reduced approval timelines by three to four months. 

The increased speed of the drug development process has also meant that companies need more rapid access to regulatory authorities in order to quickly assess clinical trial development plans or changes. In light of the pandemic, grants of pre-investigational new drug (IND) meetings with the FDA were given in under 30 days, with a reduction in the specificity of non-clinical information needed in order to start studies more quickly.

Another major regulatory change to speed up trial completion was the move towards centralised site clearance. This move away from local approvals of each trial site allowed for quicker approval of sites and subsequently a shortened approval timeline, from months to only days. 

Beyond these changes, regulators became more flexible generally regarding trial design and product approval. A more flexible approach was created regarding product registration, rapid review of trials and auditing. Deadlines were extended where necessary. 

Decentralisation

Novel technologies and the need for social distancing saw the rapid uptake of decentralised trials, often taking place in patients’ homes. These trials have been shown to cost at most the same as traditional trials, but with the added benefits of increased patient engagement and retention, greater data collection and overall faster, more flexible study timelines. 

Scaling up decentralisation while maintaining quality will, however, mean the need for much more rigorous compliance given the diversification of data sources and complexity of large-scale studies. Automation is one solution to this increased need for vigilance, with unmanned data capture through wearable devices and automated reporting critical to ensuring accuracy and completeness of translatable submissions.

The new methods of collecting patient data – from wearables like the Apple Watch to electronic forms such as eCOA – were rapidly accepted and incorporated by regulators, and have helped increase patient safety in trials as well as facilitating a more rapid turnaround in trial completion. 

Regulatory submissions

Shortly after the scale of the pandemic became clear, regulatory authorities began granting Emergency Use Authorizations (EUAs) to COVID treatments. This meant that the onus of creating efficiencies to speed up drug approval fell on regulators. In part, this came from innovations in technology and digitalisation.

Regulatory information management (RIM) technology was used widely to reduce reporting activities through automation and machine learning. Other new approaches to reporting could rapidly expand this speed and efficiency, replacing older models of reporting: adoption of electronic Common Technical Documents, use of electronic product labels, reform to the Certificate of a Pharmaceutical Product procedures, and discarding the need for ‘wet signatures’ on documents would all significantly reduce the current time and onerousness of regulatory reporting for a number of countries and businesses. 

The future of pharma regulation 

The major changes witnessed during the pandemic were created in an extreme situation, and it is without doubt that their extremity will be reduced as the world returns to normal. Nevertheless, many of the lessons learnt during the COVID-19 crisis will continue to be preserved, from swifter pre-IND meeting times to safer drug trial practices. 

Real-world evidence (RWE) will be a major regulatory force in the coming years, with real-time access and analysis of data providing a huge boon to drug research – as long as regulators can fully standardise datasets and analytics, as a lack of careful monitoring can lead to potential risks in the procedure. 

The technology that has been pioneered during the pandemic will continue to grow and develop as COVID-19 recedes into memory. Cloud technology will allow greater connectivity between teams and reduced siloing, on top of speeding up regulatory submission significantly, as soon as it is taken up by regulatory agencies globally. AI, automation and machine learning will speed up document completion and regulatory submission, and move the industry towards higher-value innovations. 

Joshua Neil, Editor
Proventa International

The post COVID’s Impact on Innovations in Regulatory Affairs appeared first on Proventa International.

The rapid change in demand for pharmaceutical products during the COVID-19 pandemic sent shockwaves throughout the industry. Since the start of the crisis, pharma manufacturers have implemented a number of innovations to streamline the production process from start to finish. Single-use technologies and continuous manufacturing are a few ways the industry has adapted to improve drug manufacturing. 

For daily articles on the latest pharma trends and innovations, as well as interviews with leading experts and in-depth industry White Papers, subscribe to PharmaFeatures.com.

Introduction to a pharmaceutical manufacturing

Biopharmaceutical manufacturing is divided into two main categories: small molecules and biologics. A small molecule drug is defined as “any organic compound with low molecular weight…small molecule drugs have some distinct advantages as therapeutics”. A large proportion of small molecule drugs are administered orally and can be designed according to a specific criteria.

Biologics, on the other hand, are a group of drugs “whose active ingredients are sourced from living organisms that have been specifically modified to produce the desired molecules”. In comparison with small molecules which are chemically synthesised, biologics are typically large molecules like proteins which are grown within an organic system. 

Both types of drugs have their own advantages with regards to therapeutic action. Small molecules can be designed to alter the pharmacokinetics of the drug in order to optimise drug delivery, distribution and metabolism within the body. Biologics on the other hand “mimic the normal complex function(s) of proteins within the body” which cannot necessarily be replicated by foreign small molecules. 

Due to early-generation biologics beginning to lose patent protection, pharmaceutical companies began several years ago to develop products biologically similar to existing biologics. These drugs are called biosimilars and are “the generic version of a biologic drug developed for launch post the patent expiry of the original drug”.   

Manufacturing challenges 

In order to develop a biosimilar medicine, pharma companies require spending a significant amount of time and money to ensure the drug meets the desired safety profile and therapeutic  efficacy. “This means extensively identifying and comparing the structural and functional properties of the biosimilar, using state-of-the-art technology.” 

Ensuring the biosimilar meets comparative structural and functional features is critical in providing the greatest chance of clinical success. 

As organic compounds, biologics represent a group of highly fragile drugs which could potentially fail at any point in the manufacturing process. Proteins, for example, are susceptible to degradation if not kept under optimal conditions such as temperature control or stable pH levels. The challenges of manufacturing biologics are considered greater than the chemical synthesis of small molecules as the “manufacturing processes involving living cells are inherently more variable than components involved in chemical synthesis”.

Due to the number of challenges that compromise the success of drug manufacturers, the industry is working together to develop strategies to address some of the ongoing issues. 

Challenges and solutions

The long approval timeline is one of the greatest challenges for pharmaceutical companies. For biosimilars and biologics especially, the timeline for manufacturing is often extended due to a number of reasons. Breaches in sterility, for example, can result in temporary halts in production, disposal of vast quantities of contaminated drugs, and in some cases, the shutdown of a manufacturing plant. All of these consequences arise from a single problem and cost pharma companies an extortionate amount of money. 

Single-use technology

As a solution, single-use technology is rapidly emerging in aseptic practices across the pharmaceutical industry, with the potential to reduce cross-contamination risk. This type of equipment can reduce costs by eliminating the need for in-house sterilisation. Examples include chromatography devices, bioreactors and ion exchange membranes. 

One of the main benefits for single use equipment is sterility assurance during the manufacturing process. This is achieved by a reduction in the “possibility of cross-transference of microorganisms; minimising the risk of environmental microbial contamination”. The risk of cross-contamination especially is greatly reduced with the avoidance of cleaning components, thanks to single use equipment.

Continuous manufacturing

Batch-to-batch production has been a core part of pharmaceutical manufacturing, however the variability that can arise between batches has seen a shift towards continuous manufacturing. Continuous manufacturing offers a number of advantages over batch manufacturing, as described in an article by the FDA:

• Continuous manufacturing is moved non-stop within the same facility, eliminating hold times between steps. 

• Material is fed through an assembly line of fully integrated components. This method saves time, reduces the likelihood for human error, and can respond more nimbly to market changes. 

• To account for higher demand, continuous manufacturing can run for a longer period of time, which may reduce the likelihood of drug shortages.

Demand forecasting

The COVID-19 pandemic has shown how demand for bioproducts can soar within a short space of time, and while some of the smaller biotechs were able to cope to meet demand, a number of the larger pharmaceutical companies struggled. Developing adaptability to short-term demand fluctuations is a target now for many manufacturers in order to manage increased demand and any rapid changes that may occur. 

Real time demand forecasts have been suggested as a solution to support pharma manufacturing. “The supply chain of pharmaceutical products is characterised by high complexity, and supply and delivery channels to customers are limited and highly regulated. The complexity is considered as one of the main barriers to performance and efficiency improvements of a pharmaceutical supply chain”. 

According to a 2021 review, demand forecasting can be even more critical for a pharmaceutical manufacturer for the following reasons:

• Any mismatch between demand and supply could ripple through the drug distribution channel and impact the patients, sometimes even causing life-threatening situations

• Any demand that is not fulfilled could potentially lead to permanent lost sales from a patient, because patients who cannot afford the uncertainty in their order fulfillment may switch to an alternative drug. For drugs treating chronic illnesses, this could mean huge financial losses for the drug manufacturer.

Currently, the data used for demand forecasting is based on historical sales and is interpreted through simple models such as exponential smoothing and linear regression models. One of the main challenges to address in demand forecasting is developing more in-depth statistical software that can capture complex patterns within historical data. Machine learning is also beginning to emerge within demand forecasting. This is currently very early in development, but may show a more defined presence in the years to come.

Charlotte Di Salvo, Junior Medical Writer
Proventa International

The post Challenges and Opportunities in Pharmaceutical Manufacturing appeared first on Proventa International.

Every hour, two more people are diagnosed with Parkinson’s in the UK and the global patient population continues to rise. To date, there are no disease-modifying therapies available on the market for Parkinson’s (PD) patients. Pharmaceutical company Bayer is simultaneously launching stem cell therapy and gene therapy trials for Parkinson’s patients. The aim of this is to reverse the decline in motor control caused by the disease.

For daily articles on the latest pharma trends and innovations, as well as interviews with leading experts and in-depth industry White Papers, subscribe to PharmaFeatures.com.

Introduction

Parkinson’s is a progressive neurodegenerative disease in which depletion of the dopamine neurons in a region known as the substantia nigra causes a multitude of symptoms. The most notable of these symptoms include tremors, slowed movement, memory difficulties and behavioural changes.  

Parkinson’s clinical trials are one of the most challenging areas of research with a lack of therapeutics achieving desired disease modification. One of the major causes for treatment failing to progress to market is the placebo effect. 

The patients’ desire to retain independence and basic functions means that the placebo effect reduces symptoms even beyond experimental treatment. As a result, drugs fail to achieve the end-point as the observed improvements are primarily psychological and outweigh the efficacy of the drug. 

Gene therapy 

Over the last decade, Parkinson’s research has shifted towards cell and gene therapy (CGT). Current treatment is designed to replace the dopamine lost in the brain which, long-term, causes a multitude of side effects and does not modify the disease. 

Gene therapy is a broad term which covers methods that improve the genetic profile of an organism by “means of the correction of altered (mutated) genes or site-specific modifications that have therapeutic treatment as target”. 

The introduction of gene therapy for Parkinson’s has been split into possible targets classed as disease-modifying or non-disease modifying. Disease modifying strategies revolve around stopping PD-mediated cell death and/or regenerating lost neurons.

Previous Parkinson’s clinical trials of CGT have been based on viral vectors to deliver therapeutic transgenes to neurons within the basal ganglia. This delivery system remains a popular choice in the field and at the forefront of gene therapy. 

Bayey has initiated a gene therapy unit through Asklepios Biopharmaceutical which is currently recruiting patients for a phase 1b trial of a gene therapy using an adeno-associated viral (AAV) vector. This delivery system is designed to “deliver a gene for human glial cell line-derived neurotrophic factor (GDNF) into the neurons in the putamen”. GDNF is a naturally occurring protein in the body, previously shown to support the growth, survival, and maturation of dopaminergic neurons. This supports the rationale of delivering GDNF which could stimulate the growth of dopaminergic neurons and recover the loss of dopaminergic signalling which is essential for symptom recovery. 

Stem cell therapy 

BlueRock Therapeutics, a subsidiary of Bayer Pharmaceutical is utilising an alternative approach for Parkinson’s CGT.  According to a recent industry article,” in the BlueRock trial the first patient has been administered the first dose of pluripotent stem cell-derived dopaminergic neurons – MSK-DA01. The drug was delivered via surgical transplant procedures into the putamen area of the brain”. 

Pluripotent stem cells are cells that have the capacity to self-renew and develop into any cell of the adult body. By dividing and developing into the three primary germ cell layers of the early embryo, pluripotent stem cells can differentiate into any tissue type. 

Induced pluripotent stem cell (iPSC)-derived dopaminergic (DA) neurons have remained at the forefront of Parkinson’s CGT research. Midbrain dopaminergic neurons can be efficiently induced from human embryonic stem cells and iPSCs and, when grafted into the target brain region, can improve the impaired behaviour of rodent and non-human primate (PD) models. 

The success of preclinical studies supporting the efficacy of stem cell transplantation for dopaminergic restoration in PD models has played a huge part in accelerating clinical studies of CGT in humans.  

Potential CGT challenges – delivery system 

The delivery system of CGT varies across the pharmaceutical industry, but is usually divided into viral- and non-viral vectors. Traditional viral vector-based gene therapy is achieved by in vivo delivery of the “therapeutic gene into the patient by vectors based on retroviruses, adenoviruses (ADs) or adeno-associated viruses (AAV)”. 

The ideal delivery system for gene therapy in the central nervous system (CNS) will aim to follow a specific criteria: (1) minimally invasive delivery (2) target specific tissue (3) achieve long-life treatment following a single, low dose. One of the main obstacles for gene therapy in the CNS is the blood brain barrier (BBB). 

As a protective measure, the BBB prevents the diffusion of drugs (delivered intravenously) into the brain. This was a particular issue raised for AAV vectors, highlighted in a journal review. However, direct delivery into the CNS is one method of bypassing the BBB. This appears to be the direction for Bayer’s gene therapy, which will be administered directly into the putamen region.

This is known as an intraparenchymal injection, and a number of preclinical studies have demonstrated successful circumvention of the BBB. There are, of course, a number of challenges with this method of viral vector gene delivery highlighted in the aforementioned review:

• This method is highly invasive which may not be an appropriate method for clinically vulnerable patients who may find this distressing 
• Previous studies have demonstrated the distribution of AAV particles within the brain (of higher order animals) is restricted 
• Intracranial delivery is correlated with a lower probability of therapeutic efficacy in larger mammals 

For CGT, one of the greatest barriers is the immune system, which could attack the stem cells/genes delivered into the brain. For AskBio’s gene therapy, this is a potential risk. Humoral immune responses, derived from antibody-producing B cells, can develop against AAV. Humoral immunity refers to antibody-mediated immune responses. This is also a challenge for BlueRock Therapeutics stem cell therapy, in which the transplanted cells will be destroyed by the immune system as a protective mechanism against foreign bodies. 

However, the transition from preclinical to Bayer’s clinical trials infers that there is potential for success and safety for both cell and gene therapy. The phase one trial for Bayer’s stem cell therapy “primarily examines the safety and tolerability of cell transplantation a year after the procedure. Secondary goals include assessing evidence of cell survival following transplant and motor effects one and two years after surgery”. In other words, this will determine the efficacy of the delivery system with regards to symptom improvement and highlight any potential safety issues. 

These clinical trials represent a huge milestone in Parkinson’s research. For the first time, there is potential to develop therapies which could overcome the short-lived efficacy and extensive side effects of current Parkinson’s treatment. For a significantly unmet clinical need, this could offer a hope for a growing patient population. Furthermore, successful disease modification within these CGT trials could potentially lead to the development of CGT for other diseases of the CNS.

• thus specific gene expression silencing is obtained 

siRNAs have been described as the most promising type of RNA-based therapeutic oligonucleotide drug. The ability to inactivate RNA molecules in a sequence-specific reinforces potential for precision medicine in specific RNAi therapies. 

One of the main advantages of siRNAs over small molecules and monoclonal antibody drugs is the simpler execution of function. siRNAs work by complete Watson-Crick base pairing with mRNA, whereas small molecule and monoclonal antibody drugs need to recognise the complicated spatial conformation of certain proteins. 

As a result, there are many diseases, especially rare forms, that are not treatable by small molecule and monoclonal antibody drugs due to the complexity of the pathology in which a target molecule with high activity, affinity and specificity cannot be identified. 

Despite this significant advantage, there remain a number of barriers for siRNA to their targets. Firstly, siRNAs are unable to directly penetrate the cell membrane and can enter the cell only by endocytosis or pinocytosis. However, in order to implement the silencing effect, siRNA must penetrate the membrane and exit into the cytoplasm.

When siRNA enters the cytoplasmic space via endo/pinocytosis, there is also a risk it will be cleaved by cytoplasmic ribonucleases or its concentration can decrease due to the division of target cells. This is an obvious issue when it comes to optimising the bioavailability of the drug for two reasons: (1) concentration is affected by internal cellular mechanisms, and 2) is susceptible to degradation by enzymes. 

The high specificity of action which makes siRNA so desirable can also cause off-target effects. As a result this limits its use in high concentrations due to the induced toxicity. The most significant non-targeted effect of siRNA is unwanted activation of the system of innate immunity under the action of certain motifs in the siRNA sequence. 

Fortunately, research in this area has led to chemical modifications that may affect the properties of siRNA. 

One of the most saturated areas of interest is the use of bioconjugates, like with ASOs, which enables a more direct delivery system to target cells. A stable linker binding siRNA and biomolecules together prevents a decrease in the efficiency of RNAi associated with the inhibition of RISC assembly. Lipids and cholesterol were some of the first ligands suggested for conjugation with siRNAs as they can overcome the issue of the hydrophobic cell membrane barrier.

On-going research is determined to address some of the challenges with siRNAs and ASOs through chemical modifications to improve bioavailability and reduce toxicity. Despite these challenges, the efficacy of these drugs remains evident with an increasing number reaching the market. The end goal is optimise the delivery of these drugs to the point where they can be potentially developed for effective precision therapeutics.

Charlotte Di Salvo, Junior Medical Writer
Proventa International

The post Latest Advancements in Parkinson’s Treatment: CGT Shows Potential to Reverse Disease appeared first on Proventa International.

In 2018, the FDA approved the first small interfering RNA (siRNA) drug, patisiran, to treat a disease known as hereditary transthyretin amyloidosis. Since then, an increasing number of oligonucleotide-based drugs have reached the market, showing advantages over small molecule drugs. siRNAs and antisense oligonucleotides (ASOs) are a few examples of oligonucleotide-platforms making exciting waves in drug discovery.

For daily articles on the latest pharma trends and innovations, as well as interviews with leading experts and in-depth industry White Papers, subscribe to PharmaFeatures.com.

Hear from some of the industry leaders includingTao Guo — who will be providing his expertise in leading a discussion on the strategy and implementation for new modalities in drug discovery: PROTAC, ASO and RNAi. To discuss these innovations and more with other leading experts in an informal setting, sign up to Proventa’s Medicinal Chemistry and Biology Strategy Meetings, held online on 29 June 2021.  

Oligonucleotides are nucleic acid polymers used to modulate gene expression via a range of processes including RNA interference (RNAi) and target degradation by RNAases. In the last few years, they have demonstrated potential to treat or manage a wide range of diseases. 

In addition to gene silencing, a number of strategies are utilising oligonucleotides for other forms of gene editing e.g. gene activation and splice modulation. The ability of these molecules to perform these tasks has demonstrated potential for precision drug discovery – “they can theoretically be designed to selectively target any gene with minimal, or at least predictable, off-target effects”.

Oligonucleotides can be designed on the basis of a target genetic sequence. Therefore, these highly specific lead candidates can be screened more efficiently and rapidly in comparison with small molecules which require much larger screening efforts, which are less cost-effective and more time-consuming. 

In addition to recognising specific target sequences, nucleic acids can also interact with proteins – a property that is also being exploited therapeutically as some proteins often represent “undruggable” targets. 

Both the RNAi mechanism and ASOs are examples of oligonucleotide-based platforms emerging within the field of drug discovery. One of the reasons why these molecules are receiving increasing attention in drug discovery is their ability to modulate DNA and RNA expression. More recently, mRNA especially is becoming a therapeutic target of interest. As the site of both fine transcriptional and post-transcriptional regulation, mRNA is thought to be involved in many diseases.

Oligonucleotide-based platforms 

ASOs

ASOs are small single-stranded synthetic nucleic acids which can be divided into two major categories: Nase H competent and steric block. ASOs are used to modulate gene expression for both DNA and RNA based on sequence complementary.

Nase H competents works by breaking down target RNA, whereas steric blocks silence a site without degradation. Steric ASOs are designed to bind to target transcriptions with high affinity but do not induce RNA breakdown. They are primarily used for the modulation of alternative splicing – the oligonucleotide ‘masks’ a splicing signal, leading to alterations in splicing decisions which disrupts the target.

One of the main benefits for ASO-based drugs is that these molecules can be localised in both the cytoplasm and nucleus, making it possible to reach cytoplasmic and/or nuclear targets. Again this suggests ASOs could be manipulated to target ‘undruggable’ targets previously inaccessible by some small molecules. 

In addition, ASOs can be delivered into the body via many different routes. ASOs can be administered locally, allowing direct and local targeting which can reach compartments not accessible by IV or systemic routes. They can also be delivered locally by inhalation – an example of which is Eluforsen, a cystic fibrosis drug. This method in particular is a popular delivery system as it is non-invasive and enables self-administration for patients. 

The high level of tissue uptake is a desirable characteristic for therapeutic efficacy which results in wide systemic distribution via the high plasma protein-binding capacity of ASOs. Unfortunately, this has raised concerns surrounding the toxicity of ASOs and off-target side effects.

The current focus is developing target delivery for ASOs to specific tissues to improve therapeutic efficacy and reduce toxicity. A number of studies have investigated the conjugation of ASOs with N-acetyl galactosamine (GalNAc). Conjugation of ASOs to GalNAc has been shown to efficiently shift their biodistribution toward the liver via high-affinity binding to the asialoglycoprotein receptor (ASGPR) expressed at the surface of hepatocytes (liver cells). This both increases their concentration in target tissue while reducing exposure to off-target organs. 

This is an area of continuous research to optimise the therapeutic window for ASO-based drugs. 

siRNAs

RNA interference is a biological mechanism by which double-stranded RNA induces gene silencing by targeting complementary mRNA for degradation. siRNAs are a class of double-stranded RNA which contribute to modulation of gene expression by targeting and degrading complementary mRNA transcripts, similar to ASOs. 

According to a 2019 review of RNAi therapy, the following mechanism underpins the action of siRNAs:

• siRNA interacts with and activates the RNA-induced silencing complex (RISC)

• Ago2 (the catalytic engine of the RISC) cleaves and releases the ‘passenger’ siRNA strand (sense strand)

• The ‘guide’ strand (antisense strand) remains associated with the complex

• The single ‘guide’ strand of siRNA directs the specificity of the mRNA target recognition and cleavage by Ago2

• mRNA targets that bind the ‘guide’ strand with perfect or near-perfect complementarity are then degraded by Ago2, and thus specific gene expression silencing is obtained 

siRNAs have been described as the most promising type of RNA-based therapeutic oligonucleotide drug. The ability to inactivate RNA molecules in a sequence-specific reinforces potential for precision medicine in specific RNAi therapies. 

One of the main advantages of siRNAs over small molecules and monoclonal antibody drugs is the simpler execution of function. siRNAs work by complete Watson-Crick base pairing with mRNA, whereas small molecule and monoclonal antibody drugs need to recognise the complicated spatial conformation of certain proteins. 

As a result, there are many diseases, especially rare forms, that are not treatable by small molecule and monoclonal antibody drugs due to the complexity of the pathology in which a target molecule with high activity, affinity and specificity cannot be identified. 

Despite this significant advantage, there remain a number of barriers for siRNA to their targets. Firstly, siRNAs are unable to directly penetrate the cell membrane and can enter the cell only by endocytosis or pinocytosis. However, in order to implement the silencing effect, siRNA must penetrate the membrane and exit into the cytoplasm.

When siRNA enters the cytoplasmic space via endo/pinocytosis, there is also a risk it will be cleaved by cytoplasmic ribonucleases or its concentration can decrease due to the division of target cells. This is an obvious issue when it comes to optimising the bioavailability of the drug for two reasons: (1) concentration is affected by internal cellular mechanisms, and 2) is susceptible to degradation by enzymes. 

The high specificity of action which makes siRNA so desirable can also cause off-target effects. As a result this limits its use in high concentrations due to the induced toxicity. The most significant non-targeted effect of siRNA is unwanted activation of the system of innate immunity under the action of certain motifs in the siRNA sequence. 

Fortunately, research in this area has led to chemical modifications that may affect the properties of siRNA. 

One of the most saturated areas of interest is the use of bioconjugates, like with ASOs, which enables a more direct delivery system to target cells. A stable linker binding siRNA and biomolecules together prevents a decrease in the efficiency of RNAi associated with the inhibition of RISC assembly. Lipids and cholesterol were some of the first ligands suggested for conjugation with siRNAs as they can overcome the issue of the hydrophobic cell membrane barrier.

On-going research is determined to address some of the challenges with siRNAs and ASOs through chemical modifications to improve bioavailability and reduce toxicity. Despite these challenges, the efficacy of these drugs remains evident with an increasing number reaching the market. The end goal is optimise the delivery of these drugs to the point where they can be potentially developed for effective precision therapeutics.

To discuss these topics further with sector experts, and to ensure you remain up-to-date on the latest in clinical development, sign up for Proventa International’s Medicinal Chemistry and Biology Strategy Meeting, set for 29 June 2021.

Charlotte Di Salvo, Junior Medical Writer
Proventa International

The post Strategies Implemented for New Modalities of Therapeutic Targeting: ASOs and RNAi appeared first on Proventa International.

Innovations in medicinal chemistry have seen significant developments in drug discovery techniques. From drug screening to pharmacokinetics, the industry has worked hard to optimise target identification and validation for important therapeutic developments. The latest advancements have demonstrated the value of medicinal chemistry in drug discovery.

For daily articles on the latest pharma trends and innovations, as well as interviews with leading experts and in-depth industry White Papers, subscribe to PharmaFeatures.com.

The industry has seen a shift in preclinical operations like drug discovery, in which pharmaceutical organisations are outsourcing to contract research organisations (CROs). These organisations support the pharmaceutical, biotech and medical device industries in the form of research and development (R&D) on a contract basis. 

In comparison to big pharma, which are operating across a number of areas and technologies, CROs are typically specialised within a particular stage of drug development, therapeutic area or technology. Therefore, they can offer the needed expertise and support a pharma needs to implement the innovations they desire. 

High throughput screening: Target-based to phenotypic 

High throughput screening is described as “the use of automated equipment to rapidly test thousands to millions of samples for biological activity at the model organism, cellular, pathway, or molecular level”. The robotic-assisted sample handling forms a critical part of the automated assay designs which makes HTS so popular. 

HTS is a simple and cheap way of screening large libraries of small molecules in a short period of time. The robotic liquid handlers are tailored for micropipetting at great speeds, well suited to over a million screening assays conducted within one to three months. In addition to accelerating drug screening, robotic technologies reduce the likelihood of human error with regards to experiments and maintaining aseptic processes.

Traditional HTS approaches using target-based discovery (TBD) have faced a number of challenges. Thishas contributed to the shift towards phenotypic-based discovery. One of the main concerns with TBD is poor translatability. This is thought to be due to the inability of TBD to interpret the widespread action of a drug across multiple targets.

HTS using phenotypic assays, on the other hand, test drugs within relevant biological systems or pathways to identify active biological compounds. This process reveals any target interactions which support drug discovery in understanding potential drug interactions in the human body. HTS has been fundamental in this approach “which is based on trial and error but not on any prior known biological properties or mechanism of action”.

Early concerns regarding HTS focused on the vast amounts of data generated. In the early 2000s, data handling and management were originally a challenge with the execution of HTS. Since then, however, solid-support-on-bead screening (SSOBD) has reduced reactions to nanoscale levels, making it easier to process large datasets within a short period of time. 

SSOBD screening is a form of small molecule screening which utilises a one-bead-one-compound (OBOC) library, where each bead carries many copies of a single compound. This is believed to hold the greatest potential for the rapid identification of novel hits against emerging drug targets. 

The impact of innovations like this will create drug development pipelines with a lower budget and faster timeline to deliver products to those who need it most. 

Fragment-based screening

Fragment-based drug discovery (FBDD) is a target-based method which identifies chemical fragments and optimises them towards drug-like leads and further to clinical candidates. According to a review in Cell, FBDD runs as follows:

• FBDD starts by screening libraries of low-molecular weight compounds (fragments) against the target of interest to identify ‘‘hits 

• These initial hits usually have only very weak affinities, often in the millimolar or high micromolar range. 

• However, when robust biophysical methods like X-ray crystallography have been employed for their detection and validation, they can be readily optimised to higher affinity with the help of structural information.

While the value of HTS continues to be seen in drug discovery, TBDD has a number of equally attractive advantages such as saving experimental cost, offering diverse hits, and exhibiting multiple ways to develop novel compounds.  

HTS is typically dependent on cell activity-based assays. Unfortunately, these types of assays are not designed to detect the presence of fragments which are generally smaller and simpler than the compounds used in HTS. These assays are therefore difficult to use as the binding event is usually too weak to cause a detectable change.

NMR spectroscopy is an example of a powerful tool used in FBDD. One of the main advantages to using NMR is that the technique is “sensitive enough to identify fragments with different binding affinities. In comparison with other methods, NMR screening gives rise to less false positive hits and a mixture of fragments can be screened”.

The high sensitivity and hit rates of FBDD make it a promising approach to drug discovery. However the technicality of the process may present an obstacle, the reconstruction of fragments specifically. Finding medicinal chemists specialised in the different methods involved in FBBD could be an issue until it is more widely adopted.

One suggested solution is to implement computer-aided rational drug design and classic drug discovery guidelines, together with mathematical algorithms to optimise the outcomes of reconstruction. 

CRISPR technology

The CRISPR/Cas9 system is a genome editing tool which has shown significant therapeutic potential for a multitude of diseases.These diseases are primarily caused by some form of known genetic dysfunction.The therapy of genome editing is based on the direct modification of pathological genetic sequences. 

Whether it be the knock-out of a target gene, introducing a protective mutation, or adding a therapeutic transgene, CRISPR/Cas9 has shown great diversity in its ability to edit the human genome. Oncology is one therapeutic area which continues to use genome editing as a therapeutic tool for treating cancer, but CRISPR technology is showing increasing potential for drug discovery. 

In a Nature review, it has been inferred that by “deliberately activating or inhibiting genes, researchers can determine the genes and proteins that cause or prevent disease, therefore identifying targets for potential drugs”. CRISPR–Cas enables nearly unlimited genetic manipulation, which is a desirable quality for researchers investigating drug resistance, precision medicine and potentially undruggable targets.

Knock-out screening using CRISPR-Cas gene editing is fast becoming a widely used application in drug discovery. This form of drug screening enables the identification of genes involved in drug resistance: “genes that code for resistance to drugs can be identified through cells that become sensitive to such compounds after the CRISPR-Cas treatment. These genes, or the proteins they encode, can then be targeted with other drugs to get around the problem of resistance”.

An additional advantage of CRISPR/Cas9 is that it has the potential of simultaneous multiple loci editing. Therefore, it offers a form of genome editing which is easier, more efficient, and more scalable in comparison to similar technologies.

CRISPR-Cas systems in drug discovery are a relatively novel concept, having only been tested in this capacity over the last few years. However, there is significant potential for this genome-editing tool in facilitating the advancement of precision medicine through drug discovery that is faster and overall more cost-effective than conventional assays.

Charlotte Di Salvo, Junior Medical Writer
Proventa International

The post Evaluating Advancements in Drug Discovery appeared first on Proventa International.

In 2019, drug manufacturer Genzyme was thought to have lost up to $300m in revenue due to plant shutdown after product contamination. Ensuring appropriate aseptic practices are followed can mean the difference between efficient manufacturing operations and the shutting down of a plant. The devastating impact of cross-contamination has seen the industry develop technology and appropriate practices to reduce the risk of manufacturing failures.  

For daily articles on the latest pharma trends and innovations, as well as interviews with leading experts and in-depth industry White Papers, subscribe to PharmaFeatures.com.

Aseptic processing is defined as the “handling of sterile product, containers, and/or devices in a controlled environment, in which the air supply, materials, equipment, and personnel are regulated to maintain sterility”. This is a critical step in pharmaceutical manufacturing, which, if performed incorrectly or poorly, could adversely affect the quality of the drug through contamination. 

The production of sterile drug products is dependent on aseptic processing or terminal sterilisation. Aseptic processing subjects the drug product and container to sterilisation separately before bringing them together in the final stages. Terminal sterilisation, on the other hand, involves filling and sealing product containers under high-quality environmental conditions to minimise the microbial and particulate content of the in-process product. After this stage, the product in its final container undergoes heat or irradiation for the final sterilisation process. 

Aseptic processing and terminal sterilisation require validation and control to prevent avoidable errors. Should an error occur in either of these processes, it could lead to the distribution of a contaminated product, later posing a significant risk for patients. 

In addition to hazardous safety implications, drug product contamination can have a substantial impact on manufacturers. According to a pharmaceutical news article, drug manufacturer Genzyme was forced to close its Massachusetts plant in 2009 after a virus was found to have contaminated a bioreactor. In terms of patient impact, the contamination halted production of two drugs, Fabrazyme and Cerezyme, that were at the time used by 8,000 patients globally.  

From a pharmaceutical perspective, the halt in production was a financial blow for the manufacturer. In addition to a fine of $175m by the FDA, more than $28.4m worth of drug product was written off. 

More recently in 2020, an article reported that the FDA announced that a number of drugs have been contaminated with a potential human carcinogen, NMDA. Metformin, a popular diabetes drug, is an example of a drug implicated in this incident. In said article, there were a number of potential causes for the incident including the useage of contaminated water, lack of pH or temperature control and pre-existing contamination of raw materials. 

This resulted in the presence of NMDA in drugs above the acceptable daily intake (ADI) limit. The number of potential causes for contamination questions the quality control of the aseptic processes and sterile preparation by the manufacturers. This emphasises the need to develop more stringent aseptic and sterilisation protocols to prevent such errors occurring again. 

Aseptic practices in drug manufacturing 

The following are a few examples of conventional and more recent innovations in aspects of aseptic processing. 

Training of personnel

Personnel across the manufacturing system are potential sources for contamination and “a vector for other contaminants”. Lack of appropriate training with aseptic practices, unauthorised access into controlled areas and personal cleanliness are a few of the areas in which personnel can compromise sterile production.

The industry is now focusing on thorough training and documented communication of procedures and best practices. This is vital to optimise facility operations as well as minimising contamination. The WHO good manufacturing practices is an example of such a document aimed to guide manufactures in the production of sterile pharmaceutical drugs. 

Quality control and sanitation are 2 of 13 steps detailed throughout the steps for aseptic practices. During quality control, it is emphasised that while samples for sterility testing should be representative of the whole batch, some samples taken from parts of the batch are considered to be most at risk of contamination. In the case of injectable products, the water for the injection, the intermediate and the final product should be monitored for endotoxins.

Endotoxins are a major challenge for sterilisation. These are toxic substances “bound to the bacterial cell wall and released when the bacterium ruptures or disintegrates”.

Rapid Transfer Port

The Rapid Transfer Port (RTP) allows for transfer of hazardous or sterile materials while maintaining containment of sealed barriers. In order to address the risk of accidental manipulation during the transfer, a number of safety devices are in place.

RTPs are typically installed on isolators or production lines to enable the sterile transfer between two chambers without environmental exposure. This means that ‘clean’ material can be transported from “one sterile zone to another through a non-sterile zone, using the DPTE container or single use bag which can be reconnected without risk because the inside of the container is still sterile.”

According to an industry article, the risk of human error occurring during material transfer is “proportional to the number of manual operations required, of which RTPs generally entails a series of manual interventions”. So while the machinery and mechanisms work well to prevalent environmental exposure between transfer, and devices to reduce the chance of errors, humans are still required to operate them at every stage. This is an issue that needs to be addressed, potentially with the development of more automated systems in aseptic processing. 

The popularity of the RTP system in the pharmaceutical industry is evident, with more than 40,000 Alpha units sold to global locations. Successful, validated systems like RTPs are a prime example of the evolution in developing more stringent aseptic practices.

Single-use technology 

Single-use technology is rapidly emerging in aseptic practices across the pharmaceutical industry, with the potential to reduce cross-contamination risk. This type of equipment can reduce costs by eliminating the need for in-house sterilisation. Although the initial cost of single-use equipment may be high, the benefits of a faster turnaround allows production to move faster and continuously. 

Examples of single-use equipment include chromatography devices, bioreactors and ion exchange membranes. 

One of the main benefits for single use equipment is sterility assurance during the manufacturing process. This is achieved by a reduction in the “possibility of cross-transference of microorganisms; minimising the risk of environmental microbial contamination”. The risk of cross-contamination especially is greatly reduced with the avoidance of cleaning components, thanks to single use equipment.

Due to the infancy of this technology, it is important to assess the possibility of leachables that could arise and pose a concern for quality control. This is echoed in an article which highlights the limited availability of the technology and potential development costs.

Charlotte Di Salvo, Junior Medical Writer
Proventa International

The post Aseptic Processing: Maintaining Sterility in Pharmaceutical Manufacturing appeared first on Proventa International.

Hear from some of the industry leaders including David Cook, Chief Scientific Officer, Blueberry Therapeutics who will be providing his expertise in leading a discussion on using translational research techniques to improve drug development.

For daily articles on the latest pharma trends and innovations, as well as interviews with leading experts and in-depth industry White Papers, subscribe to PharmaFeatures.com..

In the context of biology and medicine, nanotechnology encompasses materials, devices, and systems whose structure and function are relevant for small length scales, from nanometers (10⁻⁹ m) through microns. 

Nanotechnology offers a number of advantages for biological research. In comparison to traditional molecular assays, nanoscale devices can differentiate at the level of single molecules and single cells. This great sensitivity can be used to characterise single-cell heterogeneity at extremely high throughput, revealing distinct hierarchies and subpopulations. This is owed to the microscopic structure of nanotechnologies which are typically comparable in size with biomolecules. As a result, they can travel more freely through the human body in comparison to larger molecules.

In addition to research, nanotechnology has contributed to a number of innovations across the drug development process including drug design and delivery. Nanotechnology is also evolving to deliver therapeutic agents to target sites.

Nanomedicine 

Drug delivery systems 

Polymeric nanomaterials are the ideal choice for efficient drug delivery. Polymeric refers to a large molecule made of smaller subunits. The high compatibility and biodegradability are a few of the properties that make polymeric nanomaterials desirable for delivering drugs that have poor solubility and low absorption rates. Nanospheres and nanocapsules are the two main categories of polymeric nanoparticles used as drug delivery systems. 

Chitosan-based nanomaterials are widely used for continued drug release systems for various types of tissues including eye, intestinal and nasal regions. Chitosan is a naturally occurring by-product from the processing of shellfish.

One of the main advantages of using nano drug delivery systems is their ability to penetrate the tissue system. This facilitates easy uptake of the drug by cells, resulting in an efficient drug delivery at the specific target site. Furthermore, nanostructures stay in the blood circulatory system for a prolonged period and enable the release of drugs as per the specified dose. Therefore, they cause fewer systemic fluctuations, reducing the likelihood of adverse effects. 

The method by which nanostructures deliver drugs is divided into two categories, passive and self-delivery. In passive delivery, drugs are integrated into the nanostructure via the hydrophobic effect. Hydrophobic refers to molecules that are repelled by water. The desired amount of drug will then be released at target sites due to the “low content of the drugs which is encapsulated in a hydrophobic environment”. 

In passive drug delivery the drug carrier is transported systematically, and drawn to the target site by affinity influenced by properties like pH, temperature, molecular site and shape.

In self-delivery, the drugs are instead directly conjugated to the nano carrier. With this approach, the drug dissociates rapidly from the nanostructure, hence the timing of release is crucial to ensure the drug reaches the target site. If released prematurely, the bioactivity and efficacy will be significantly compromised.

With the active approach, drug targeting is facilitated by biological agents known as moieties e.g. antibodies and peptides. These agents are coupled with the nano drug delivery system to act as an anchor to receptor structures within the target site. The targets for drug delivery are primarily membrane-bound proteins including receptors, lipid structures or antigens on the cell surface.

Tissue engineering

In addition to drug development, nanotechnology has been used to create biocompatible scaffolds in the creation of implantable tissues. According to an article, these nanoscale structures have been engineered to resemble a native extracellular matrix which can control the release of drugs. In biology, an extracellular matrix is an intricate 3D network consisting of an array of extracellular macromolecules like proteins and carbohydrates. Also known as hard-tissue engineering, this nanotechnology is a relatively new concept used to engineer skeletal muscle tissue. 

The mimicking of the native extracellular matrix is a crucial part of creating an optimum tissue microenvironment including appropriate mechanical strength, ease of monitoring cellular activities and delivering of bioactive agents require a nanoscale approach. Modified electrospinning is one method in which biological factors are incorporated into nanoscaffolds. 

Gold and titanium nanoparticles have been used to enhance cellular functions like proliferation for bone and cardiac tissue regeneration. Several studies support the utility of gold nanoparticles especially as candidates for bone tissue regeneration. This particular group of nanoparticles have shown to influence osteoclast formation, while providing “protective effects on mitochondrial dysfunction in osteoblastic cells”. Osteoclasts are a type of bone cell that breaks down bone tissue. 

These cells are critical for the maintenance of bone repair, metabolism and remodeling. Mitochondria function is critical for cellular function of which tissue regeneration cannot occur. Hence, protection of this component is a significant part of the success of bone regeneration seen so far. 

Cardiac tissue regeneration has been a key focus for nano tissue engineering for many years. Human myocardium is a type of muscle tissue in the heart which typically fails to regenerate after tissue damage. This results in an insufficient number of cardiomyocyte cells and counteracting of scar tissue formation which leads to abnormal arrhythmia and often heart failure. Hence, this represents an unmet need for nanotechnology. 

Engineered cardiac patches are considered a promising approach for regenerating the infarcted heart. Cardiac cells are implanted within the 3D nanoscaffolds, which provide the structural biochemical microenvironment. The formation of tissue arises from cell-cell and cell-matrix interactions facilitated by the scaffold structure. Once the tissue is engineered into a cardiac patch, it is attached to the scar tissue of the heart by a surgical operation, involving synthetic sutures or staples.

While cardiac patches have shown promising preclinical results, there are a significant number of challenges that need to be addressed before clinical implementation. Firstly, one of the issues with using metallic nanoparticles is the inability of these structures to be naturally broken down. As a result, the longer the period the structure remains in the body, the greater the likelihood of cytotoxic events. Secondly, the method by which the cardiac patches have been attached is using staples/sutures during open heart surgery. This is, of course, a highly invasive and risky process to which a less invasive alternative attachment method needs to be developed to reduce the risk of complications. 3D printing has been suggested as a recommendation for patch fabrication. 

To be able to recapitulate the tissue microenvironment and functionality so well through nanotechnology represents a significant step forward in the successful regeneration of tissue. Despite significant setbacks with preclinical testing of cardiac tissue regeneration, research is ongoing to develop novel nano fabrications and less invasive delivery methods. Nanotechnology continues to play an important role across many therapeutic areas and drug development, and will continue to evolve in the next few years to solve current challenges in the field.

To discuss these topics further with sector experts, and to ensure you remain up-to-date on the latest in clinical development, sign up for Proventa International’s Bioinformatics Strategy Meeting, set for 1 July 2021.

Charlotte Di Salvo, Junior Medical Writer
Proventa International

The post Emerging Therapeutics in Translational Medicine: Nanotechnology appeared first on Proventa International.

In 2020 the COVID-19 pandemic threw the world into turmoil. The pharmaceutical industry needed to adapt rapidly to meet an increased demand, shifting clinical trials to virtual platforms and of course looking to accelerate COVID vaccine approval. It has become clear that a significant shift has occurred in the pharmaceutical industry, especially manufacturing. The impact of the pandemic has seen both positive and negative consequences, which in the long-term could result in permanent changes to how pharmaceutical companies operate.

For daily articles on the latest pharma trends and innovations, as well as interviews with leading experts and in-depth industry White Papers, subscribe to PharmaFeatures.com. 

Short-term impact

Demand change 

A sudden spike in demand for pharmaceutical products was one of the first challenges at the start of the pandemic. Panic buying contributed significantly to a shortage of over-the-counter medication, especially paracetamol, due to conflicting reports about the safety of ibuprofen with COVID-19. In addition, fears about the risk of pre-existing conditions saw periodic shortages in the market for chronic disease medication. A study in the US indicated that from the 13th to the 21st of March 2020, asthma medications spiked by 65%, and type 2 diabetes medications increased by 25%.  

The increased demand for assigning patients to ventilators also contributed to related prescription medicine shortages. This is defined as a supply issue that affects how the pharmacy prepares or dispenses a drug product or influences patient care when prescribers must use an alternative agent. In order to manage the increasing number of hospitalisations, hospital units utilised respiratory prescription medication like albuterol and fluticasone to try and stabilise critically ill patients. 

Respiratory medication, sedatives and pain treatment saw an increase of use in hospitals of 100% to 70% in the US since the beginning of January 2020. As the number of hospital cases rocketed, increased quantities were in demand, which consequently caused shortages for prescriptions which put further pressure on pharmaceutical supply chains. In a recent white paper, a survey saw 46% of 532 global supply chain leaders experience shortages for COVID-19-related and unrelated therapeutics during the pandemic. These companies included pharmaceutical organisations, wholesale distributors, hospitals and pharmacies. This highlights one of the main issues in the short-term, which was a slow response and resolution to major disruptions in supply chains. 

Distribution challenges 

Despite pharmaceutical companies increasing production capacity to meet demand, the supply of products across the globe was hindered by a number of logistical challenges. National lockdowns and a quarantined workforce greatly contributed to reduced transportation capacity of pharmaceutical products. Imposed travel restrictions also had a significant impact on drug productions, especially “if an API [an active pharmaceutical ingredient] is made in one country and must be shipped to another for final formulation.”

The implementation of safety protocols and limited onsite inspections caused concerns about quality checks throughout the supply chain from raw materials through to APIs. According to a recent publication, China and India are the world’s main supplies of APIs. During the pandemic however, as the countries scrambled to cope with rising cases and deaths, drug production no doubt suffered from a depleted workforce and restrictions. The global impact of this was more critical when production of non-substitutional essential APIs, such as amoxicillin, was hindered. 

Long-term impact

Delayed approvals for non-COVID-related pharmaceutical product

Across the globe, pharmaceutical companies came under immense pressure rapidly to develop and approve COVID-19 vaccines in a short period of time. As a result, a substantial proportion of time, resources and capital was funneled into vaccine research and drug development. 

Unfortunately, this halted pharmaceutical production for a vast number of non-COVID therapeutic products which has a substantial impact for a number of chronic conditions. In December 2020, the FDA postponed approval of an important new cholesterol therapy, inclisiran, from Novartis. The postponement came from concerns surrounding the production of the drug by the European contract manufacturer. According to a press release by Novartis, the drug failed approval due to “unresolved facility inspection-related conditions” not because of concerns around drug safety or efficacy. Unfortunately due to the COVID-19 travel restrictions, the problem is yet to be resolved. 

Oncology therapeutics continue to be impacted by logistical challenges. In November 2020, approval for immunotherapy CAR-T treatment by Bristol Myers Squibb (BMS) was delayed due to travel restrictions which prevented inspection of the manufacturer’s production facility in Texas. CAR-T therapy is emerging as a potentially effective immunotherapy treatment for cancer patients. 

Immunotherapy is an important part of cancer research, aiming to develop therapeutic options for patients resistant to conventional treatment or intolerable of the extensive side effects. Unfortunately, delayed approval prolongs the time till the drug can be marketed and accessible to patients. This particular therapy by BMS is targeted for diffuse large B-cell lymphoma. DLBCL is an aggressive condition and many patients have advanced disease at diagnosis. As a result, delayed approval for this potentially effective therapy could impact the lives of many patients. 

The development of self-sufficiency 

The export bans from India and China, who are main suppliers of API, has seen a shift in the pharma industry to consider self-sufficiency in the supply chain. According to a recent article, US-based companies like Phlow are seeking continuous manufacturing to produce APIs in the USA. In May 2020, Phlow was awarded a $354 million contract by The U.S. Department of Health and Human Services in order to manufacture COVID-19 treatment and other drugs in short supply. 

It also appears vaccine manufacturing is moving across to Europe, with Italy seeking to manufacture COVID-19 vaccines in the country. According to the financial times, Rome has discussed the domestic production of mRNA-based vaccines with US biotech Moderna, Switzerland’s Novartis and Italy’s ReiThera. The hope is that the doses manufactured in Italy will boost the overall vaccine manufacturing capacity  in order to meet current demand and compensate for some of the countries in which AstraZeneca failed to meet delivery targets. This was an issue highlighted in a recent article, which stated that the target delivery of 40 million doses in the first quarter by AstraZeneca was reduced to an estimated 30 million doses. 

Despite the pharmaceutical industry experiencing difficult challenges with drug development and manufacturing, some positive changes have developed from the crisis. Countries across the globe have become increasingly self-sufficient in their manufacturing of pharmaceutical products in order to mitigate potential issues with external supply chains. 

Furthermore, the digital innovations that have enabled some clinical research to continue throughout the pandemic have enabled drug approval to continue for therapeutic areas. The hope is that the changes to logistics and manufacturing in adapting to the pandemic will continue to streamline the pharmaceutical industry for the future of drug development and manufacturing.

Charlotte Di Salvo, Junior Medical Writer
Proventa International

The post How Has COVID Affected Pharmaceutical Manufacturing? appeared first on Proventa International.