Delivering Successful API Manufacturing at Scale

Bhuvaneswari Sridhar, AVP, Small Molecule Technology, Pfizer India, in an interaction with Industry Outlook, shares her insights on the development of API market, resolution of supply chain complexities, attainment of scalability, and more.

The global active pharmaceutical ingredient market size is predicted to hit USD 355.94 billion by 2030. How do you see this industry developing in India? 

The API Industry in India has been evolving and growing over the years, with a well-established pre-existing supply base for both local and global markets. Some of the major pharma companies operating in the API market are already working to increase production and capacity. Operational improvements using advanced manufacturing technologies can help to increase efficiency, which in turn may increase productivity, bringing down cost and improving sustainability.

As companies innovate and increase their competitiveness, it will be important to continue to advance manufacturing standards from a compliance and environmental sustainability perspective. This differentiation may present an advantage when being evaluated as a potential supply node for qualification in global markets. Amongst product types, the highest growth is expected in highly potent active pharmaceutical ingredients (HPAPI), such as those used in oncology therapies, because engineering/technological advancements have enabled an increase in the manufacturing of HPAPI in India.

Addressing the supply of KSMs (Key Starting Materials) will be the next challenge for the Indian API industry. KSMs are raw materials, the building blocks required for manufacturing APIs. As the API market is growing in India, the next logical step would be to build a supply chain of KSMs indigenously. Many API manufacturers are experiencing the pressure of KSM supply from abroad, pushing them to minimize risk in their supply chains through back-integration activity, whether it is in-house, through acquisitions or partnering with other organizations through vertical integration activities.

Against this backdrop, at a global level, a pro-innovation policy environment has proven to be critical to support collaboration to drive R&D and facilitate sharing of technology and information to scale up manufacturing.

Spreading API supply across multiple vendors makes the supply chain fragile, as more links in the chain increase the likelihood of problems. How can supply chain complexities be resolved?

We believe that having a supply chain that includes diversity of sourcing through the approval of multiple, competent vendors across different geographies strengthens the supply chain and ensures business continuity. A resilient API supply chain requires a robust strategy that includes a vendor system that delivers volumes needed. However, with multiple vendors a company must maintain uniformity across vendors and identify and manage potential supply chain vulnerabilities.

One mechanism to address challenges is to anticipate supply chain disruptions by using data and advanced analytics. Working with multiple stakeholders and vendors also means assessing various risks within the commodity, inflationary and geopolitical environments, and ensuring good communication channels to support navigating complexities in the supply chain is vital.

In addition, maintaining end-to-end transparency with robust change management processes, which incorporate continuous improvement, is also key to assuring supply over the lifecycle of a product. Vendors are rigorously selected, and required to maintain Pfizer standards, confirmed by ongoing change management, compliance audits, etc. At the same time, they must have an appropriate degree of flexibility in their processes for continuous improvement through shared learnings and best practices. Maintaining trust is key to building sustainable relationships.

The capability to make critical advanced intermediates in-house when required helps build more security in the latter stages of the supply chain, thus making it more resilient.

Complex APIs bring a host of new challenges for development. Size, bioavailability and stability issues are all by-products of these more complex molecules. How is the industry looking forward to meeting this issue?

Development of complex APIs requires sound theoretical models, coupled with supporting laboratory data. The industry is continuing to develop predictive models to better understand and ensure product performance attributes such as bioavailability and long-term stability. Required parameters can be understood at the beginning and any issues that may arise in the subsequent steps can be anticipated. Additionally, newer analytical tools and technologies will support both the development of process as well as the product control strategy.

New synthetic methods are a key enabler to access more complex molecules. Moreover, we can also venture into new chemical spaces with technologies such as continuous processing, which facilitates the use of reagents and reaction conditions that would not be amenable in batch manufacturing.

The more complex the molecule of API, the harder it is to scale. How do you propose to attain scalability in the API domain?

Predictive tools are essential to understand what will happen upon scale-up. We look for in-depth modelling and understanding of scale-up factors, such as computational fluid dynamics and the impact of different reactor scales and configurations. New technologies allow us to use the same (or equivalent) equipment at different stages of development (i.e., ‘scaling-out’), thus reducing the scale-up risk by mitigating changes in factors such as heat and mass transfer. A trend towards ‘digital twinning’ will facilitate assessment of scale-up issues in silico.

The areas of automation, robotics, machine learning, artificial intelligence, data-driven experimentation, modelling, predictive science, and the integration of all these facets will transform API development over the next decade.  The industry must develop the ability to predict experimental outcomes more accurately and be able to produce a greater number of experiments per unit time, with reduced human intervention, ultimately helping deliver life-saving drugs to patients at accelerated speed. Understanding the multiple facets of availability and affordability of raw materials, technological restrictions in the manufacturing process and environmental aspects is critical to deliver successful manufacturing at scale. Process modifications can be planned accordingly, which will help to scale-up.

Presently, owing to the considerable increase in the pollution threat to the environment, more and more API-producing companies have been urged to follow the greener path in order to reduce the generation of waste. How do you see this development taking place in the industry? How is Pfizer instituting greener practices in its operations?

At Pfizer, sustainable growth in alignment with our Purpose Blueprint is a key principle outlined within our Environment, Social and Governance strategy. To deliver our commitment to patients, we continually evaluate and drive improvement of our manufacturing processes. We continually evaluate ways to reduce the environmental impact of our products through resource conservation, use of in process controls, adoption of new technology to increase efficiency, application of Green Chemistry, and solvent recycling and reuse.

Through our Green Chemistry program, which is grounded in Paul Anastas and John Warner’s 12 Principles of Green Chemistry, we aim to design more efficient processes that reduce the environmental impact of our medicines throughout the product life cycle. In our manufacturing processes, we focus on selection of environmentally preferable materials, resource conservation, energy reduction and waste minimization, including resource recovery and recycling improvements. We track our progress by quantifying and reporting our greenhouse gas emissions, water use, and waste generated and diverted from disposal.

Recently, Pfizer made a public commitment to accelerate its plans to decarbonize, establishing a more ambitious goal to achieve the voluntary Net Zero Standard across our value chain by 2040.