Plant Construction & Process Technology

Opposites Attract

Blurring the Lines between Small and Large Molecule Manufacturing

19.09.2018 -

The biopharmaceutical industry has grown impressively in recent years, with its global compound growth rate (CAGR) estimated to reach 8.5% between 2018-2023, outstripping traditional new chemical entity sectors. Emerging novel drugs show huge therapeutic potential, such as antibody-drug conjugates (ADCs), checkpoint inhibitors and viral gene therapy. But as the industry grows, it may face potential issues securing an expanded supply chain.

Until recently the bio industry’s primary focus was to simply get their products to clinic as quickly as possible, with little incentive to focus on product and supply chain efficiency. However, now that the industry is experiencing greater demand and product volumes are increasing – coupled with generics and healthcare reforms – there is an increased desire to explore how overall cost of production can be lowered. It’s a mirror image of the small molecule industries maturation some 10 or 20 years earlier. As a result, innovators and bio-generic companies are exploring not only how to speed products to market, but also, how they might lower costs in the commercial phase.

Large biopharma firms now have a greater number of drugs in the pipeline, and with an increased global prevalence of biosimilars, the supply chain will come under increasing pressure. But the industry is still in its relative infancy, and some of the key factors that may allow companies to meet these demands are not yet fully matured.

Additionally, as biologics developers now are more comfortable using outsourcing providers, there is a gradual shift away from performing all production activities in-house. This is due in part to many contract development and manufacturing organizations (CDMOs) developing and investing in the skills and technologies required to make biologic drugs.

Cell Therapies: A Key Opportunity

Looking ahead, the emerging drug pipeline of advanced and newer drug classes should further fuel outsourcing. In fact, already, despite the pipeline’s infancy, there have been significant moves by several CDMOs to build facilities for the emerging cell and gene therapies. Paragon, Brammer Bio, Fujifilm, Cobra Bio, WuXi Advanced Therapies and Lonza are amongst a host of earlier adopters – the latter in fact opened the world’s largest dedicated cell and gene therapy facility in April. Cell therapies could present a key opportunity for CDMOs because the technologies and methods used to make such products are still developing.

There are clearly parallels with how outsourcing in the small molecule space has contributed to increased manufacturing efficiencies and reducing overall costs. In fact, many solid dose CDMOs now sell their services on enabling technologies for compounds that are difficult to manufacture. Over the next few years there will likely happen a “technological arms race” amongst outsourcing providers to help increase efficiencies, lower costs and decrease clinical timelines in bio.

Growing Complexity of Biologics

Another aspect that may increase the amount of work in biologics is the growing complexity of biological products. Biotech firms, especially smaller ones, may have an innovative product or idea, but lack the expertise and technology required to develop or commercialize it.

The product classes themselves are also becoming increasingly intertwined, as many advanced therapies now contain a small molecules payload, such as in ADCs; whilst in stem cell therapies, molecules are sometimes used to trigger a therapeutic response. That is without even considering the fact that small molecules themselves are growing increasingly large, and peptides are now routinely synthesized rather than fermented. Oligonucleotides are in many ways a new class altogether – not fitting into the definitions of small or large molecule.

As a result, the level of limited collaborations across both small and large molecules in recent years increased – most notably in antibody-drug-conjugates. Many in the industry now believe there are transferrable skills and lessons that can be shared between the two, particularly in areas such as staff, processing and scale-up, as well as regulation.

API producers are potentially having the most relevant and transferable skills sets. Their experiences are most similar to what a biopharma company is replicating in everyday use. For example, API synthesis is performed in solution, with materials, molecules and reactants emerging over time. Thus, the instruments used for chemical and physical measurements for API production may only need minor alterations to be useful in fermentations. Continuous chromatography, which is beginning to become more common in API work, could also be used in bioprocesses.

Potential of a Cross Industry Collaboration

Beyond APIs there are potential benefits in exploring overall manufacturing methodologies. Whilst large molecule companies have only recently begun to generate their own optimization data, the small molecule industry has been around for 50 years, streamlining its supply chain to establish the best practices. Even if their production modes are distinct, there are certainly experiences of the small molecule industry that could pave the way for biopharma’s own supply chain to flourish.

Addressing this issue directly, the 15th Annual Survey on Biopharmaceutical Manufacturing Production and Capacity, conducted by BioPlan Associates, asked 120 industry experts several questions about the potential integration.

The result of the study has shown that the most prominent areas where respondents believe they could learn from small molecule firms were:

  • Process control (33%)
  • Quality management (30%)
  • Training operators and technicians (29%)

These top three areas are not particularly surprising since they address current good manufacturing process (GMP) practices, which are consistent across both the large and small molecule industries.

Other areas of potential crossover identified in the survey include scale-up or process development, clean room operations, regulatory compliance, and automation/process control, where just under a quarter of respondents believed that large molecule manufacturing could benefit from small molecule expertise. This indicates that a collaboration between the two industries could lead to greater production levels, with better quality and at a lower cost (see figure for full data).

Large molecule manufacturers could also benefit in the future from the use of continuous bioprocessing. Although continuous methodologies have entered the small molecule space and are currently refined, biologics has not adopted it to the same degree. This may be due to the fact that continuous bioprocessing is more difficult because fermentation processes are one of the key requirements, which are restrictive for time, temperature and other factors. This means the drug formation rate may be limited and not allow for a continuous flow.

Whilst there is a lot that the large molecule industry can learn from its small molecule counterpart, there is still plenty to gain on the small molecule side of a collaboration between the two. As small molecule pharma manufacturers have established their best practices over the past 50 years, the industry tends to be risk averse and does not easily adopt new technologies; even though technologies such as continuous processing could lower costs over time.

Biopharma as an industry has been more adept at adopting new methods – such as single use technologies, which reduce the need for scale up, as well as complicated weighing and dispense steps, and cleaning validation.

If these two industries could learn from one another’s strengths they will have the capability to manage and even streamline the complex supply chains and development timelines in order to meet greater demand and reduce the overall costs.


Even though this trend is in an early stage, the industry is gradually moving towards a new era where pharmaceutical and biopharmaceutical manufacturing are no longer viewed as distinct entities – with workforces, regulatory pathways and new technologies working more closely together. In particular, the biopharma supply chain is becoming increasingly complicated, and managing these intricacies will be key to maintaining the industry’s growth. Biopharma industry experts agree there are clear opportunities to learn from small molecule firms in refining their supply chain as well as finding new staff. However, what is interesting, is that in the small molecules space experts argue they may in fact have even more knowledge to pass on to the counterparts in bio. Finally, with novel processes and methodologies now being tested in bio, the small molecule space should explore how these newer approaches are being introduced into a highly-regulated space.

In terms of contract manufacturing, the fastest growth is now coming from bio CDMOs, with newer companies introducing contract cell and gene therapy services over the next 5-years – thus, supply chain learnings and skills from small molecule experts should be in increasingly high demand. Another approach to differentiate and achieve growth for smaller bio CDMOs is novel technologies that accelerate production and lower costs. Big pharma has already partnered with a number of smaller biotechs for anything from AI technologies to 3D micro-organoid modelling and bio process improvements – the latter is where there will likely be a new “arms race” for the best technologies amongst outsourcing providers. Big pharma will also seek to mirror its approach in the small molecule industry, and mitigate supply chain risk, by seeking to partner with several CDMOs in both development and commercialization of its most profitable new targets.

There are clearly short-term supply chain efficiencies to be learned from the small molecules sector, coupled with PAT and scale-up process improvements from the API space. But the willingness to take a long-term view and incorporate modern technologies – that may come with short term regulatory hurdles – is clearly something that bio is embracing much faster than its older compatriot.

This article is based on a whitepaper published by bioLIVE & CPhI Pharma Insights. The original publication is available at