Key challenges for bio/pharmaceutical manufacturing 2022

Supply and demand

Even before COVID-19, the outsourcing of biopharmaceutical development and manufacturing was growing; particularly as increasing numbers of small and virtual biotechnology companies were adopting business models fully reliant on outsourcing all development and manufacturing activities.

To meet global demand for vaccine and therapeutics doses, a significant proportion of the production of COVID-19 vaccines and treatments was outsourced, with more than 230 manufacturing agreements having been publicly disclosed to date between COVID-19 vaccine and therapy developers and contract manufacturers.¹

James Choi, Executive Vice President and Chief Information & Marketing Officer and Head of Global Public Relations and Process Improvement at Samsung Biologics, explained: “The COVID-19 pandemic has been one of the greatest challenges globally for biologics manufacturing to date and has been unrelenting since its onset. As a result of the pandemic, CDMOs have seen an increasing demand to deliver drugs to market at an unprecedented speed. The requirement for regular booster vaccinations means that this need for manufacturing support will likely continue for the foreseeable future.”

Other supply challenges include COVID-19-related supply chain disruption: “With materials such as glass vials being prioritised for vaccine production, biopharma manufacturing companies have not only had to navigate supply delays due to workers isolating but also consumables shortages. Many materials required for biopharma manufacturing have seen delays of six to 12 months, as well as having a higher cost due to increased demand,” stated Bill Vincent, Founder of Genezen. He added that, due to such disruptions, it has become increasingly important for companies to predict supply with high accuracy, raise inventory levels and qualify alternative suppliers to minimise shortages.

Another supply challenge for pharma is the increasing pressure for sustainable sourcing, according to a recent report by CPhI and Baxter.² In the report, Manjit Singh, Chair of the Pharmaceutical Supply Chain Initiative (PSCI), stated: “Companies are setting out a path via their procurement policies and practices to ensure a deep understanding of the supply risk emanating from environmental issues like climate change and antimicrobial resistance (AMR), social issues like human rights and ethics, and their potential economic impacts.” According to Singh, sustainable sourcing aims to improve the ethical, environmental and social performance of suppliers, thereby mitigating any negative impacts within the supply chain. This could have a significant impact on bio/pharmaceutical manufacturing.

Novel therapeutics

According to Choi, the challenge of demand is exacerbated by another factor: the need to adapt to novel technologies, including messenger RNA (mRNA) vaccines and therapeutics.

mRNA

“Adapting to new and previously unfamiliar technologies, including mRNA, has been a substantial learning curve for many CDMOs,” commented Choi, adding that adjusting capabilities, investing in capacity and embracing these new technologies is now critical to success.

Choi explained: “The use of mRNA technologies in the production of vaccines in response to COVID-19 has demonstrated the effectiveness and potential of the technology.  The capability for mRNA to be easily edited not only makes it the ideal tool to combat viruses that can quickly mutate, but also gives it the potential to be used in the treatment of countless other diseases. This is highlighted by the fact that there were over 70 mRNA therapeutics in clinical pipelines globally as of July 2021, and there are many more assets currently in early development.³

“CDMOs must not only familiarise themselves with this technology quickly but also be fully equipped with the right capacity and capabilities, as demand for manufacturing support for mRNA products is set to increase further.”

Cell and gene therapy

mRNA is not the only key emerging therapeutic technology: 2021 has been heralded by some as the year of cell and gene therapy, with many advancements in the field. However, being such a new technology, developments in their manufacturing process is ongoing to ensure production can safely meet demand. According to Vincent, one technology set to be influential for cell and gene therapy manufacturing is the use of stable producer cell lines that can grow in suspension. Particularly important for lentiviral vector manufacturing, “having stable cell lines will eliminate the need for transient transfection as part of each production run, leading to reduced material costs while providing a more consistent product,”⁴ he commented. Additionally, Vincent said: “The ability of these cell lines to grow in suspension bioreactors will also mean that larger batch sizes can be achieved, which is essential for commercialisation.”

Vincent added that the development and adoption of stable producer cell lines is due to an anticipated challenge for the market: “As interest in cell and gene therapy grows, and the viral vector industry matures, a tightening of the regulations surrounding their manufacturing can be expected.

“Regulations are predicted to impact the use of serum in producer cell growth, as it cannot be guaranteed to be consistent in composition. Adherent 293T cells are hard to grow without foetal bovine serum (FBS) but there are currently not many serum-free media available to grow adherent cells. As a result, lentiviral vector manufacturers will need to start looking for alternative options, such as stable producer cell lines.”

Speed to market

As mentioned by Choi, speed to market now represents a significant challenge for drug developers. According to the US Food and Drug Administration (FDA)’s latest report, 74 percent (34 out of 50) of the novel drugs approved by FDA in 2021 used some form of expedited development or review pathway, specifically Fast Track Designation (36 percent, n=18), Breakthrough Therapy Designation (28 percent, n=14), Priority Review (68 percent, n=34), and/or Accelerated Approval (28 percent, n=14).⁵

“The increasing pressure for speed to market is at odds with transfer delays as projects move between sites or companies to perform subsequent processes across the supply chain. These delays have been worsened by the effects of COVID-19. The ability to obviate these delays will continue to be a pivotal criterion in selecting a manufacturing partner,” commented Choi.

Frank Kogelberg, Director of Business Development, Contract Manufacturing at Baxter, also emphasised the importance of reducing transfer delays in the report by CPhI and Baxter.²

Skilled labour shortage

Vincent highlighted: “A key factor that will continue to impact biopharma manufacturing in the next year and beyond is the limited availability of skilled labour. Although some of the problems surrounding labour shortages could be solved using automation, the fundamental issue will remain. Preparing workers for the STEM (science, technology, engineering and mathematics) industries will require further funding in the education sector – and any territory (city, state or nation) ready to solve this challenge will be poised to dominate the industry.”  

To learn more about the potential future skills shortage, read our article: The weakest link – biopharma workforce development.

Poorly soluble HPAPIs

According to Lonza CHI’s Rose Mary Casados, Senior Director of Product Management Marketing, the primary challenge facing the manufacturing industry is delivering oral solid dosage (OSD) formulations containing increasingly poorly water-soluble highly potent active pharmaceutical ingredients (HPAPIs). Casados explained: “Treating cancer remains a key area of focus for all of global pharma and continues to drive a tremendous amount of development… Many oncology products use HPAPIs and innovators, and their contract development partners have seen an increase in the number of global development projects involving HPAPIs.”

Lonza predicts that advanced formulation and manufacturing techniques for HPAPI compounds will become better understood and integrated earlier in development through 2022, with innovations in capsule materials and engineering being particularly influential. Casados stated: “Manufacturers are addressing the challenges of HPAPI drug delivery and production by integrating new formulation and drug substance processing methods including lipid-based formulations (LBFs) and amorphous solid dispersions (ASDs).

“The need to deliver HPAPI and other complex compounds now under development is contributing to a shift towards encapsulating formulations in hydroxypropyl methylcellulose (HPMC). If an API is sensitive to water and/or formulated as an ASD, HPMC capsules can help control the effects of water relative to the API and formulation stability.”

Flexibility in manufacturing

Lynn Allen, Vice President of Business Development at MedPharm Ltd, explained how the rise of drug development for orphan and rare diseases is impacting the sector, increasing the importance of flexibility in manufacturing. “As drug development becomes more specified in the target indication, so does the patient population. End markets for orphan drugs or drugs that target specific subsets of a patient population reduce the size of a market for a product. This in turn reduces the size of manufactured batch requirements,” she stated. According to Allen, these smaller batch manufacturing requirements “have led many developers to (use) mid-size and small-tier CMOs who have the scale of equipment suited to meet the demands of a smaller patient population.”

Final thoughts

By no means is this article a comprehensive review of all challenges faced by pharma and biopharma in the year to come. In fact, other concerns raised by the industry included the re-opening of EU pharmaceutical legislation this year and the continued use of virtual site inspections by regulators, which we ran out of space to cover here.

The challenges facing pharmaceutical and biopharmaceutical manufacturing in 2022 are varied, from formulation and delivery challenges to skilled labour shortages and shortened timelines. One potential solution for these hurdles is the integration of advanced technologies. According to Casados, such technologies enable drugs to be manufactured more efficiently and compliantly, and at a lower cost: “Pharma is accelerating its digital Industry 4.0 transformation in pursuit of better cGMP [current good manufacturing practice] compliance. The pressure to adopt advanced information and data technologies across the enterprise will not abate and the digitalisation trend will have significant impact on operational expenses and cost-of-goods accounting for years to come… Advanced, automated, data-controlled processes will certainly be part of the industry’s digitally enhanced future.”

References

1. GlobalData, 2021. COVID-19: Contract Pharmaceutical Development and Manufacturing Relationships. [online]. Available at: https://store.globaldata.com/report/gdps0038mar…
2. CPhI, 2021. Pharma Trends 2022. [online] CPhI, pp.6-7, 16. Available at https://www.cphi-online.com/cphi-pharma-trends-2022-report… [Accessed 10 January 2022].
3. mRNA therapeutics clinical pipeline by therapy area worldwide 2021 | Statista [Internet]. Statista. 2021 [cited 10 January 2022]. Available from: https://www.statista.com/statistics/…
4. Ferreira M, Cabral E, Coroadinha A. Progress and Perspectives in the Development of Lentiviral Vector Producer Cells. Biotechnology Journal [Internet]. 2020 [cited 10 January 2022];16(1):2000017. Available from: https://doi.org/10.1002/biot.202000017
5. FDA’s Center for Drug Evaluation and Research. Advancing Health Through Innovation: New Drug Therapy Approvals 2021 [Internet]. US Food and Drug Administration (FDA); 2022 pp. 11-12. Available from: https://www.fda.gov/drugs/new-drugs-fda-cders…