The Importance of a Manufacturing Strategy: Lessons Learned with Steve Lam

Commercial-scale bioprocessing is an art. Successful biopharma companies have perfected it through repetition and the implementation of new biopharma technologies. And so, manufacturing can be considered ‘easy’ compared with the trials and tribulations of drug discovery and clinical trials, particularly when product development follows well-established methodologies and a well thought-out manufacturing strategy. According to Steve Lam, Senior Vice President of Patheon’s Biologics Business, considering your manufacturing strategy early on in development pays dividends down the line – and yet it is something that many small (and large) companies fail to do. Here, Lam recounts the lessons he has learned over almost three decades in biopharma.

Applied science is the most engaging

With a degree in physical chemistry, you may have expected me to pursue a career in small-molecule drug development rather than biopharma. It all started at Argonne National Laboratories – where my dad worked. I attended an open house at the laboratory as a child; kid friendly experiments and freezing things with liquid nitrogen are very effective ways to engage children in science.  Eventually, I chose a degree in physical chemistry and in my last year of college I was preparing to do a PhD. All of my work up until that point had been in physical chemistry, but then everything changed. I was researching the base energy state of uranium, which was fascinating, but my advisor told me that it wouldn’t be applied for around 20 years or so... That horizon was too far away in my mind. So, after college, I opted to go into industry and I started my career at Armour Pharmaceuticals.  The timelines in pharma development are long too, but it is certainly very much applied and very worthwhile. Much of my career was spent at Amgen, so despite the focus on physical chemistry my career has been based around biopharmaceuticals.

A positive work atmosphere and teamwork can boost drug development

Initially, I started out in clinical manufacturing at Amgen, but over time I had the opportunity to move into various functional departments within the company. The company went through a significant transformation in a relatively small space of time – and I was excited to be able to contribute. Early on in my career, I had the opportunity to lead a quality control unit for the company. At the time, the unit was used for quality control for the majority of the company (which was smaller back then) so product samples would be sent to the unit for testing. As the company grew, it was decided that products would instead be tested where they were made. The decision created a significant need for change in the organization and I was involved in developing the leadership team in quality control. Importantly, we did this in a very positive way. We didn’t lay people off and we focused on creating a positive environment for the company.

I also had the opportunity to manage plants. One challenging project was transforming a single product, microbial commercial manufacturing plant in Colorado into a multi-product facility. It was a huge engineering project because the new product was a mammalian product – the facility also had to be multi-host. It was a big change. Eventually, I progressed into global operations planning, contract manufacturing and operations. By the time I left in 2016, I was Vice President of Operations.

One of the most fundamental lessons I learned was the importance of teamwork. The term “teamwork” is often bandied about by employers – and I’m sure everyone thinks they understand the importance of teamwork – but it is not always implemented well. From a personal point of view, I believe that teamwork is instrumental in our industry. Discovering, developing and manufacturing biologicals is a very complex undertaking and requires many different disciplines. In some pharma companies, employees work in silos, and in my experience this means that things can take a little longer – and sometimes be unsuccessful.  At Amgen, there was a team structure that brought diverse people together – and the effect was almost magical. By bringing different skillsets to teams, hurdles were usually overcome quickly. Teamwork was applied to everything, from drug discovery, through to development, and even work in the main factories. I still believe in the importance of teamwork. In today’s biopharma industry there is a need to be more nimble and flexible, which is much easier if you have a cross-functional team of experts collaborating.

Understanding what you want is the best manufacturing strategy

When it comes to commercial biopharmaceutical manufacturing, one of the key lessons I have learned was the value of really understanding your manufacturing strategy early in your product’s development lifecycle. At first, Amgen only had a handful of commercial products, which mostly used recombinant proteins. In time, the portfolio expanded and production processes began to rely on antibodies, which were more consistent and allowed for more efficient manufacturing. 

Even when working with recombinant proteins, there was always a clear view of what a product would look like once it was commercialized, and this was used to extrapolate what a product needed in terms of manufacturing. Very early on, it would be decided what indication a product would be used for, what the patient population would be, and what the final presentation would look like. This meant that other key aspects could also be addressed early on. For example, what does the unit cost need to be and how can we achieve this? What volume of drug is required? What is the best equipment and scale? If a product is expected to be a blockbuster, it provides greater confidence about implementing a 20,000-liter scale, stainless steel process. A niche product, on the other hand, may require a more flexible capacity solution. Overall, a well thought-out product and accompanying manufacturing strategy allows you to make key decisions around manufacturing with greater certainty, and better prepare your product for market.

Now that I am working at Patheon, a leading contract development and manufacturing organization (CDMO), I understand more than ever why early product and process knowledge is so important. All too often, companies – particular those at an early stage – have not thought about commercial manufacturing needs and whether their early-stage process is ultimately the best method for their product – or whether it will work on a large scale. For small, early-stage companies, funding is usually limited, which means they are often rushing to generate results in time to receive more funding. These companies are often so driven by results that they overlook key opportunities to stop and evaluate decisions that will guide and facilitate commercial manufacturing. The danger is that a company will make it to Phase III, and then suddenly realize that a crucial processing change is needed, which will impact timelines – and increase costs.

For some customers, we have been forced to backtrack and evaluate whether their processes are well understood. How do the process attributes affect the quality attributes? Are those well-defined? If there are gaps, they need to be filled to help ease the regulatory and commercialization process.

It’s good to have a new perspective

Amgen was a fantastic company to work for, and I am particularly proud that I was able to see the company grow so much. In time, I found myself interested in returning to a smaller, startup environment because I missed the entrepreneurial, all-hands-on-deck atmosphere. And that’s why I ultimately joined Patheon in February 2016. I find it exhilarating to be working with so many different clients and have responsibility for the four sites that manufacture biologic drug substance, as well as process development.

Successful, established companies tend to find manufacturing relatively straightforward because they have gained experience along the way. When I first started at Amgen, some of the plants were running at low run-rates and there weren’t many commercial products. As the pipeline developed, the run rate increased and the company became much better at manufacturing because of repetition – processes began to run consistently and all products began to follow similar commercialization pathways. The company also implemented the right processes, systems and training to operate at a high capacity utilization and avoid errors. At Patheon, I work with companies of all shapes and sizes, including start-ups and virtual companies. Projects can arrive in very different stages – some are very advanced and have been well thought-out, others are very early stage, and some are advanced but still missing crucial process development.  Overall, you gain a perspective that you just can’t see in a big biopharma company – and it’s very rewarding to optimize so many different processes and aid with product development.

New technologies can lead to better processes

The biopharma industry has changed significantly since I first started out and it’s been exciting to have a front row seat. Over the last 20 years, there have been real changes in cell culture titers, particularly for antibodies. When I first started, 1 gram per liter was considered a good titer, but today companies are regularly pushing 4 or 5 grams per liter. The changing titers, as well as product indications and demand, have led to some big changes in upstream bioprocessing; most significantly, companies no longer need huge, 20,000 liter bioreactors because a 2,000 liter bioreactor can get the job done. Downstream processes, however, are still very large and there are questions about how these can be reduced. I’ve seen some exciting work in this area, including innovations in membrane technology, harvesting technology, and continuous processing. These advances have been taking shape for many years, but the serious developments were placed on the backburner while the industry was chasing titers. Now that we have titer, it’s time to look at the bottlenecks downstream, and to examine how to break them.

New technologies are emerging all the time to help facilitate bioprocessing, but some companies appear oblivious... As part of a manufacturing strategy, it’s important to review new technologies. If you haven’t thought about your manufacturing strategy early enough, then the tendency is to try and use a platform process. Platform processes have their advantages (easy to implement), but users also lose the opportunities for greater efficiencies and economies offered by state-of-the-art processing technologies. If you have a product that is expected to be a blockbuster, then big stainless steel tanks will give the lowest unit costs. If you have a niche product with uncertain future demand, then stainless steel can be risky – single-use technologies and multiplexing are usually worth considering. Single use and other flexible technologies can also be an effective bridging strategy while you try to better understand demand for your product. In some cases, companies adopt a first generation process, with the aim of introducing second and third generation processes as time goes on – and gradually improving the process.

Science isn’t an issue, but cash is

Manufacturing is a very repetitive process and the more you do it, the better you get. Scientifically, we now know a lot about manufacturing and bioprocessing, and if a company is struggling with a problem then there are many external experts and CDMOs that they can turn to. Science is also advancing in terms of drug discovery. We are seeing an exciting transition to the cell therapy space with CAR-T technologies and gene therapies, and conversations are moving from therapies to cures.

Science and manufacturing prowess continue to advance, but the industry is struggling in terms of funding – a significant problem for early-stage companies – and the cost of medicines. These are the challenges of today but also the future. What happens when medicines are developed that people cannot pay for? The new, groundbreaking treatments coming through the pipelines come with high costs, but it will be a onetime upfront cost, as opposed to ongoing therapy, which may require daily pills or weekly injections, as well as medical interventions and hospitalization. It is a public policy challenge – and how the situation plays out will affect the future of our industry. While we cannot directly address this in a manufacturing strategy, we can focus on making high quality products in the most efficient manner possible.