Can we slow ageing in humans? Can humans achieve immortality? These questions have piqued mankind’s curiosity since time immemorial. However, it was not until the beginning of the twentieth century that scientists actually began studying mortality curves of different cellular organisms including humans, which provided solid evidence that human lifespan can be extended in the absence of evolution. This paved the way for early studies conducted in the 1900s that focused on slowing the process of ageing instead of stopping it all together. Studies conducted by Michael Klass discovered the first set of genes posited to be involved in the process of ageing. And it was in 2009 that a breakthrough was made in the search for an anti-ageing compound and the role of rapamycin in slowing ageing was first reported. 

## Introduction to Rapamycin
Rapamycin (also known as Sirolimus) is a macrolide produced by Streptomyces hygroscopicus, which was first isolated in 1975 from the soil samples of South Pacific island of Rapa Nui. Its clinical use stems from its ability to block the mTOR pathway that controls cell growth and metabolism. 

Initially, Rapamycin was identified as an antifungal agent but later its immunosuppressive and anti-cancerous properties were established. It was only in 2009 that a study conducted by Harrison et al. demonstrated its anti-ageing property. This study has since lead to multiple studies being conducted globally to establish rapamycin's potential as an anti-ageing compound.

## Studies supporting Rapamycin’s role in anti-ageing
The TOR (target of rapamycin) pathway, which senses nutrients, contributes to cellular and organismal ageing. Invertebrates, such as yeast, nematodes, and fruit flies, have longer lifespans when the TOR signalling pathway is inhibited through genetic or pharmaceutical intervention. In many model organisms, including mice, rapamycin has been shown to increase lifespan by inhibiting this TOR pathway, with the most pronounced effects on longevity reported in females.

According to a study by Harrison et al., when rapamycin was given to 19-month-old mice, an increase in the median lifespan of 14% for females and 9% for males was observed. In a different multi-centre study, genetically heterogeneous mice were given rapamycin in food starting at the age of 9 months, and at each of the three study centres, there was an appreciable increase in life span. Female median survival increased by 18% and male median survival increased by 10%. Further, a study by Bitto et al. showed that treating 20-month-old mice with a high dose of rapamycin for only 3 months resulted in a dramatic increase in the median lifespan of both the sexes. Female median lifespan increased by 39% and male median lifespan increased by 45%. Additionally, it was also interestingly observed that changes induced by rapamycin such as those in the microbiome were not transient but persisted after rapamycin treatment was discontinued. 

Rapamycin’s conclusive role in increasing mammalian lifespan led researchers to probe the next most important question. Does rapamycin impact only lifespan or does it also potentially delay age-related diseases? Several studies conducted over the years corroborated this theory and demonstrated that rapamycin not only extended lifespan but also delayed age-related diseases such as cardiac diseases, cancer, and neural degeneration, amongst others. In a study conducted by Flynn et al., 24-month-old female mice were given rapamycin for 3 months, and health outcomes were assessed using a range of non-invasive tests. In comparison to the mice that were fed a control diet, rapamycin treatment not only reversed the age-related decline in cardiac function but also led to advantageous behavioural, skeletal, and motor changes in the test mice. It was also noted that the improvement in cardiac function persisted for 2 months after rapamycin treatment was discontinued. 

In another study, a two-year experiment was performed by Anisimov et al. using inbred mice that received rapamycin three times per week for two weeks, then a break of two weeks beginning at the age of two months. The study showed that rapamycin reduced ageing-related weight gain, lengthened life expectancy, and postponed spontaneous cancer. 

Furthermore, in a study carried out by Urfer et al., 24 healthy, middle-aged dogs were given either a placebo or a non-immunosuppressive dose of rapamycin for 10 weeks. Results revealed that when compared to dogs who received a placebo, the rapamycin-treated group experienced no clinical side effects. In the dogs treated with rapamycin, echocardiography indicated improvement in both diastolic and systolic age-related measures of heart function. 

## Future Implications
As an mTOR inhibitor, rapamycin, the first drug with demonstrable anti-ageing effect in mammals, exhibits exceptional potential for extending lifespan. Based on the studies conducted over the past 10 years, three major findings surrounding rapamycin’s role in anti-ageing have been identified. Firstly, it has been determined that rapamycin increases the lifespan of both male and female mice, which is unique because all other anti-ageing interventions are sex specific. Secondly, rapamycin is effective over a wide range of doses; it does not have a negative effect on lifespan, even at high doses. Lastly, rapamycin not only reverses many of the adverse aspects of ageing late in life but also need not be administered continuously; its effect might persist well after it is discontinued. 

Given these promising results, the imminent next step is to take rapamycin to clinical trials for use in humans. However, there is always a veritable concern around how well would the results generated in mice models translate in humans. Extensive studies, therefore, need to be conducted to determine the long-term side effects, dosage, and route of administration of rapamycin in humans before the age-old quest of increased lifespan may finally become a reality. 


large_Frame 64rethretr8.png

medium_Frame 64rethretr8.png

small_Frame 64rethretr8.png

thumbnail_Frame 64rethretr8.png

Frame 64rethretr8.png

Rapamycin-A potential anti-ageing compound?

Transplant rejection can be prevented with the use of Tacrolimus and other medications. Tacrolimus belongs to a class of drugs known as immunosuppressants. According to Joshua Diamond, MD, Associate Medical Director of Penn Medicine's Lung Transplant Program, Tacrolimus is a primary calcineurin inhibitor that has been commonly prescribed to lung transplant recipients for more than 15 years now.

Tacrolimus is currently available for administration in two forms-intravenous and oral. Having tacrolimus orally, however, has a few setbacks including limited and erratic bioavailability; multiple drug interactions; and adverse effects such as nephrotoxicity, neurotoxicity, hypertension, and onset of diabetes mellitus. 

Recently established pulmonary route of drug delivery addresses these issues and provides a more viable and safer route of administration. Pulmonary drug delivery introduces the drug in higher concentration within the lungs while reducing systemic adsorption, thereby resulting in a potentially lower incidence of adverse effects. 

A team at the University of Texas, Austin headed by Sawittree Sahakijpijarn has developed a novel formulation of Tacrolimus for pulmonary route of administration employing thin film freezing (TFF). TFF is a particle engineering technology that can alter the physiochemical properties of a drug such as particle size, surface characteristics, morphology and crystallinity. According to previous studies Tacrolimus combined with 50% w/w lactose was found to be safe and effective for treatment of lung transplant rejection in rodent models. Sahakijpijarn et al therefore used the combination of tacrolimus and lactose along with the TFF technology to develop a lyophilized powder that can be delivered to the lung using both a nebulizer and a dry powder inhaler. A pilot study was then performed by the group in human subjects to determine the efficacy and safety of this formulation. 

20 healthy volunteers were enrolled for the study. All the enrolled subjects were given a dose of the novel formulation comprising of 3 mg tacrolimus and 3 mg lactose through a nebulizer in stage 1 of the study. In stage 2, 10 out of the 20 enrolled subjects were randomly selected to take the drug of the same dosage through an inhaler.   
 
Symptoms recorded over a 24-hour period included cough, abnormal taste, shortness of breath, abnormal throat sensations and chest discomfort, with abnormal taste being the most common symptom reported during both the stages of the study. A majority of subjects enrolled for stage 2 also reported cough as a common symptom, which patients who were nebulized did not experience. This study therefore demonstrated that both the nebulization of TFF-TAC-LAC colloidal dispersion and dry powder inhalation of TFF-TAC-LAC powder were well-tolerated and safe methods for targeted drug delivery to the lung. 

According to this study, inhaled Tacrolimus has similar pharmacological effects in humans as it does in animal models. The inhalation route offers the opportunity of delivering an immunosuppressant directly to the target site. Therefore, inhaled tacrolimus should be considered as the preferred future therapeutic option for patients with lung conditions requiring immunosuppression. 


large_WhatsApp Image 2022-11-17 at 3.10.50 PM.jpeg

medium_WhatsApp Image 2022-11-17 at 3.10.50 PM.jpeg

small_WhatsApp Image 2022-11-17 at 3.10.50 PM.jpeg

thumbnail_WhatsApp Image 2022-11-17 at 3.10.50 PM.jpeg

WhatsApp Image 2022-11-17 at 3.10.50 PM.jpeg

Inhalable Tacrolimus for Lung Transplant Patients to be a Reality Soon

Over the years the pharmaceutical industry has grown from small-scale manual processing with simple tools to large-scale production employing process control and automation. This trillion-dollar industry has been the slowest to adopt technological advancements such as the internet of things (IoT), artificial intelligence (AI), robotics, and advanced computing due to regulatory, technical, and technological challenges. However, with improving techno-commercial and regulatory conditions, the advent of Industry 4.0 that promises to bring to the forefront autonomous manufacturing systems with little to no human intervention is inexorable. Such advancements have the potential to transform pharmaceutical manufacturing and logistics to unprecedented efficiency and productivity. 
  

# **Brief History of Pharma Manufacturing**
The pharmaceutical industry had very humble origins stemming from herbal plant preparations using hand tools. The industrialization of these botanical, mineral, and animal-derived medicines happened only in the 19th century when hand-operated tools were transformed into industrial equipment able to crush, mill, blend, and press larger quantities of medicine. This period is often classified as Industry 1.0. 

The second industrial revolution was enabled by electricity. Early electronic machines, assembly lines, and minimal automation was employed during this period, which allowed manufacturers to control only basic parameters in their processes. 

For better quality monitoring, increased automation brought about by process analytical technology (PAT) and model-based processes called Quality by Design (QbD), led to the third industrial revolution at the onset of the 21st century. These advanced technologies provided real-time monitoring and process simulations within predefined parameters. Despite the value addition offered by these technologies, the pharmaceutical industry has been slow in adopting them. This is because a deeper understanding of processes and real-time analytics is required to maximize the potential of PAT and QbD and usher widespread implementation. Industry 4.0, the future of pharmaceutical manufacturing builds upon Industry 3.0 and its shortcomings.


# **What Industry 4.0 will look like?**
AI, IoT, and robotics all interconnected with minimal intervention of humans can be viewed as the face of Industry 4.0. Such integration can be brought about by digitization of multiple complex pieces of the pharmaceutical value chain with the help of IoT and embedded cyber-security. It will also involve the journey from simple data collection to digital maturity in which raw data captured from a manufacturing process will be converted into actionable wisdom by artificial intelligence. It is this “wisdom” that fuels the autonomous systems to self-optimize and make decisions with minimal human involvement.


# **How it can be deployed?**
Pharmaceutical manufacturing, for instance, could combine external data - including variables such as patient experience, market demand, supplier inventories, and public health emergencies - with internal data - such as energy and resource management, modeling and simulation results, and laboratory results. Such data integration and analysis can substantially streamline production capacity utilization and reduce time to market, thereby, leading to resource optimization and major cost savings.

Other areas of automation in manufacturing operations include the use of computer vision technology to replace human inspections of packaging, caps, and vials. Additionally, predictive equipment maintenance can be employed with the help of IoT and AI to reduce disturbances, risks, and production downtime. Furthermore, AI-enabled automation can be used to streamline analytical testing and ensure continuous quality assurance and data integrity across the production line. 

AI-enabled technologies can lead to optimizations in not only product manufacturing but also product development. Deep learning models can be used for process simulation during developmental stages. Furthermore, such models can be employed for optimizing different stages of drug discovery from lead generation to the prediction of pharmacokinetics and pharmacodynamics of potential drug targets.


# **Challenges in Implementation**
Industry 4.0 is the future of pharmaceutical manufacturing; however, certain regulatory, technical, and logistical challenges persist that need redressal. The lack of precedent in the industry, the costs associated with development, and the uncertainties surrounding regulatory approval have led many companies to adopt a “first to be second” approach. 

## Regulatory Challenges
The current regulatory framework which is based on prescriptive processes and parameters rather than performance-based regulation has prevented many pharmaceutical manufacturers from adopting new technologies. The US FDA has been working on the transition to performance-based regulation for almost a decade now and it was only in June 2021 that the draft guidelines for performance-based regulation such as those focusing on the continuous manufacturing of drug substances and products were published. A formalized framework in the near future based on these guidelines will certainly expedite the adoption of modern manufacturing technologies. 

Another major hurdle has been the burden of filing regulatory applications across multiple global jurisdictions with varying regulatory expectations, especially for new manufacturing technologies. The constitution of a single regulatory authority and universal manufacturing standards will alleviate this challenge and is therefore the need of the hour. Such harmonization will ensure that high-quality medicines are developed in the most resource-efficient manner globally. 

## Technical Challenges
Industry 4.0 officiates the need to capture, process, and retrieve large amounts of stored and real-time data to facilitate end-to-end automation of the entire manufacturing process. The challenge in handling such large datasets lies in storing them securely. Robust standards around data capture, storage, analysis, transmission, and protection are therefore required. Manufacturers might have to collaborate with third-party data centers in the future to address their growing need for data storage. 

Moreover, a smart factory requires continuous communication between the hardware and the software components. This requires extensive investment in advanced networking technology- from networking cables, sensors, machines, servers to cloud storage- all seamlessly connected for undisrupted communication. Novel, cost-effective modes of communication between networked machines that are compatible with a plug-and-play model need to be developed to enable successful industry-wide adoption in the future. 

## Logistical challenges
As manufacturers and regulators address multiple data, computing, and automation risks, Industry 4.0 approaches will also require organization-wide cultural changes for successful implementation. A new industry infrastructure based on digitized and interconnected enterprise systems requires several skills beyond those gained through the traditional disciplines of biology, chemistry, and process engineering. Skilled data scientists, computational and systems engineers, IT specialists, and AI experts will need to be hired. This might lead to a higher cost of adoption as the pharmaceutical industry will be competing with the software industry for the same small pool of talent in these areas. 

Upskilling the existing workforce, bridging knowledge gaps through extensive training programs, and interdisciplinary hiring are some of the ways through which the talent pool can be broadened and the cost of implementation can be minimized.  


# **Future Implications**
While it can be argued that much of the pharmaceutical manufacturing still operates in Industry 2.0, the importance of the efficacy brought about by Industry 3.0 and the paradigm shift in manufacturing that Industry 4.0 promises to usher cannot be undermined. Upon adoption, Industry 4.0 has the potential to dramatically increase the agility, efficiency, flexibility, and quality of the industrial production of medicines. Pharmaceutical supply chains, production processes, distribution, and inventory frameworks could all benefit significantly. 

Widespread deployment of advanced manufacturing technologies under Industry 4.0, however, requires a comprehensive regulatory framework, extensive hardware and software infrastructure integration, and highly skilled labour to fully realize the benefits of end-to-end automation. Over the coming years, there is a veritable need for different stakeholders to come together and work in tandem to make smart factories in the field of pharmaceuticals a reality.  


large_WhatsApp Image 2022-10-10 at 4.49.19 PM.jpeg

medium_WhatsApp Image 2022-10-10 at 4.49.19 PM.jpeg

small_WhatsApp Image 2022-10-10 at 4.49.19 PM.jpeg

thumbnail_WhatsApp Image 2022-10-10 at 4.49.19 PM.jpeg

WhatsApp Image 2022-10-10 at 4.49.19 PM.jpeg

Next-Gen Pharma Manufacturing: The Advent of Industry 4.0

A single course of treatment for a type of breast cancer equals 10 years of average annual wages in developing countries like India and South Africa. 75% of cancer patients in India therefore find themselves in a predicament where they can no longer continue treatment. 

**“Even with insurance coverage, patients living with cancer in many countries have reported financial stress, to the extent that they may lower the treatment dose, partially fill prescriptions or even forego treatment altogether.”**- WHO report on cancer drug pricing 

Cancer drug pricing and access to cancer medicines thereby remain much debated topics globally. According to a study conducted by WHO, the per capita expenditure on cancer drugs has been 2 to 8 folds higher than the global per-capita expenditure on health. 

The ubiquitous problem of cancer drug unaffordability is often attributed to factors such as high R&D cost of drug development, complex manufacturing process, expensive raw materials, amongst others. 

At Raspa, our goal is to reduce the cost of cancer treatment by manufacturing quality cancer active components also known as Active Pharmaceutical Ingredients at lower costs. We believe that process and productivity optimization and value-based innovation at each stage of the supply chain can bring about major cost reductions. Enhanced shop-floor testing and data monitoring through laboratory information management systems coupled with blockchain for supply chain traceability and transparency are some of the automation efforts that Raspa aims to undertake to improve productivity.  

Furthermore, we are undertaking extensive R&D efforts within the field of process optimization to help us realise our goal. The use of genetic and metabolic engineering followed by process simulations on Artificial Intelligence based platforms are some of the ways through which we aim to improve product yields while reducing costs.

At Raspa, we truly believe that affordable healthcare where each and every cancer patient has access to treatment should be the foundational goal of a sustainable, value-based pharmaceutical company. This is the very goal that we have set out to meet.


large_color-2174052.png

medium_color-2174052.png

small_color-2174052.png

thumbnail_color-2174052.png

color-2174052.png

Cancer Drug Unaffordability: A global problem

*Joan, an industry veteran with more than 30 years of experience, is the former Managing Director of Novartis Spain. Over the years, he has also worked for the likes of Bayer, Boehringer Ingelheim and Sandoz Pharma as Medical Director and Head of R&D and is currently working as the Director of Innovation at the Barcelona Institute of Global Health.*

*An MD in medicine, a lawyer, and a management major, Joan has many feathers in his cap. He has also served as an advisor to many prominent government and private organizations including serving as a member of the Research and Development Advisory Board to the Department of Health of the Government of Catalonia, Spain.*

**Q1. What according to you is the biggest challenge facing the pharmaceutical industry today?**

Meet the needs for preventive and therapeutic solutions of the population at global scale though efficient and high-quality products and services, with a focus on medical needs but also with a strong focus on equity to achieve health for all.

**Q2. What excites you the most about Raspa?**

Raspa is an important step in the right direction to improve the global equity in the provision of high-quality treatments to patients with serious medical needs.

**Q3. How do you think Raspa’s vision aligns with your own personal vision in bringing about a change within the pharmaceutical industry?**

Traditionally many pharma companies have had such a huge margin that the efficiency has not been addressed to the extent of other industries. Raspa intends to produce generic and generic plus top-quality drugs at much adjusted prices due to cutting edge innovation in production and development and also through innovative solutions by combining pharma technologies with others such as digital and medical devices technologies. 

**Q4. How do you envision healthcare evolving over the coming 10 years especially within the field of oncology?**

Oncology is the main interest of Raspa and it is really one of the areas with the highest medical need and also an area where the drug prices (amazingly enough including many generics and biosimilars) are more outrageous, to the point that some oncologists speak about the “ finantial toxicity” of cancer drugs that are accessible only to a tiny proportion of patients and in many cases imply the bankrupcy of the whole family.

I believe that this situation is simply unacceptable and that the pressure from the patients  and also from an increasing proportion of oncologists will introduce significant changes by moving towards a predictive, preventive, personalized, and participatory medicine and that therapies will be made accessible to an ever increasing proportion of patients. Companies like Raspa will definetively become key to drive this much needed progress.


Healthcare solution
for the future

Pipeline

Conventional API

R&D

Our Insights

Join Us.
To Make Healthcare More Affordable.

Healthcare solutionfor the future

Pipeline

Conventional API

R&D

Our Insights

Join Us.To Make Healthcare More Affordable.

Healthcare solution
for the future

Join Us.
To Make Healthcare More Affordable.