The push to expedite COVID-19 vaccines over the past year has led the biopharmaceutical industry to try novel strategies to accelerate product development and manufacturing. To compress discovery, development, and manufacturing into several months rather than a typical multiple-year effort has meant reexamining nearly every aspect of the process — including facilities required to house the work.

Successful COVID-19 vaccine development undoubtedly will change biomanufacturing strategy forever. Previously, current good manufacturing practice (CGMP) manufacturing options were twofold:

• building facilities and related infrastructure and expertise internally
• outsourcing GMP manufacturing to third parties such as contract development and manufacturing organizations (CMOs/CDMOs).

Now a growing number of early stage companies are considering a novel hybrid approach to leasing cleanroom space, with related infrastructure and expertise provided as a service. This model eliminates facility build-out lead times, shifts the burden of facility maintenance, and prevents the need to share intellectual property (IP) with third parties. Flexibility and control afforded by a hybrid strategy give developers the autonomy to make process changes quickly and eliminate potential technology transfer delays and failures (inherent risks in outsourcing).

Two Years from Procurement to Readiness
In plotting out a timeline to scale up a biomanufacturing facility, the rule of thumb is that procurement, construction, and qualification typically take two years to as many as five years — or more (1). Some new technologies are shortening that to 18 months. Building CGMP expertise and capabilities in areas beyond biomanufacturing — e.g., materials management, facility/asset management, and supply-chain logistics — can be time consuming, as well.

An added hurdle is the need to develop capabilities and expertise in GMPs and quality management systems. That adds to the already long timelines for achieving CGMP readiness. The situation is exacerbated further for novel therapeutics such as cell and gene therapies, personalized drugs, and microbiome processes that require nontraditional chemistry, manufacturing, and controls (CMC). Thus, many businesses turn to outsourcing most of the “heavy lifting.” But when it comes to manufacturing advanced therapies such as messenger RNA (mRNA), oligonucleotides, and microbiome technologies, CMOs/CDMOs face their own challenges related to capacity and capability.

Waiting Lists and IP Concerns
Outsourcing has become such a popular recourse in biopharmaceutical development and manufacturing that CMOs/CDMOs are getting overwhelmed. In a recent report, Bourne Partners notes that demand has stretched the average waiting time for outsourced capacity “from 16 to 24 months” (2). In fact, the report continues, customers are “buying slots in production queues years in advance.” The contract-service industry is responding to its capacity challenge by bringing new facilities online, but the report points out that “any new capacity will be quickly absorbed by existing product backlog.”

Some service providers might have space but lack expertise or equipment to develop manufacturing solutions for new product modalities. And those that do have the capability might introduce their own challenges for product developers to overcome.

IP, Expertise, and Speed to Market: Most CMOs/CDMOs require access to a product sponsor’s IP before they can embark on product development, manufacturing, or delivery. That can present a particularly daunting challenge for early stage companies that count intellectual property as their only true asset. Technology transfer can bring significant delays and bottlenecks as clients and providers exchange not only IP, but also science and process knowledge.

Let’s not minimize the problem of insufficient expertise. Rapid technology innovation in the biopharmaceutical industry can leave many CDMOs behind. Significant investments made over the past decade could be nearly obsolete technology already. When service providers do have new technology, they yet could lack the in-house talent and expertise required to work with a broad range of complex therapies. And even when they do seek to specialize, talent has been difficult to find and hire in the competitive CDMO market, which is marked by a generally high rate of employee turnover.

Early stage biopharmaceutical companies typically make their own changes as they develop and refine their own manufacturing processes. Optimization may lead to retraining, which adds even more time to the overall development process and delays the progress of a product to market.

In the pharmaceutical industry, developers succeed or fail based on speed to clinic and speed to market. It’s important, therefore, to reduce as many unnecessary complications as possible — including technology transfer time. This is a good reason to keep IP and knowledge in house.

Taken together, the realities of facility construction/retrofit timelines, outsourcing challenges, and IP protectiveness have led some biopharmaceutical entrepreneurs to embrace a hybrid model. This middle ground is occupied by multiproduct, tenanted facilities with customized support functions provided as a service, including materials management, asset management, training, information technology (IT) support, and so on.

Facilities As a Service
Apart from regionalized technology incubators, the concept of flexible manufacturing facilities with customized support services is relatively new to the biopharmaceutical industry. The ideal clients for such facilities are early stage companies beginning the transition into human clinical trials. Such companies typically are moving from research and development to GMP for the first time — or have been outsourcing early phase CGMP manufacturing. The challenge for those companies is that most have not been through such processes before. Many bioentrepreneurs find that safe and efficient product and process development require considerable knowledge and expertise outside of their comfort zone.

When that’s an issue, it’s important to acknowledge that not all hybrid-manufacturing providers are the same. Some lease only the cleanroom space itself — no more, no less. But that is just a small piece of the puzzle required for early stage companies trying to come to grips with the requirements of biopharmaceutical manufacturing and delivery.

A key advantage of hybrid options that include both customized cleanroom space and support services is that they enable product sponsors to keep much of their own experience and IP in house. That’s especially significant for young companies counting IP as their principal business asset.

Speed to clinic is important particularly for the “fail-fast” attitude that pervades today’s biopharmaceutical development and commercialization ecosystem. Drug manufacturing takes time, effort, and money — so if a molecule is destined to fail, then it’s better for everyone if that happens sooner rather than later. Failing fast means being able to use the same IP in another way by pivoting to another program.

It Doesn’t Need to Last Forever: Early stage companies aren’t likely to need such flexible, hybrid options throughout their life cycles. Such companies also need an infrastructure in place for phase-appropriate GMP programs and related quality management systems that help them accelerate their products into clinical testing.

As a product progresses through the clinical phases, its sponsor will “graduate” from a hybrid facility either to later-phase CMO/CDMO support or to its own manufacturing site. Knowledge gained through appropriate support in the early stages will be critically important as such companies move on, eventually becoming larger scale biomanufacturers of their own commercial-batch products.

Changes to biopharmaceutical development brought about by the race for effective COVID-19 vaccines can provide a roadmap for what the industry will look like in the future. Traditional ways of manufacturing therapies and vaccines have become outmoded because of obstacles related to design–construction–qualification timelines and the simple fact that demand is outstripping capacity in the CMO/CDMO marketplace. A middle ground of using facilities that provide cleanrooms and ancillary CGMP services has emerged as a new manufacturing option. This new strategy can enable companies to grow quickly with the support that they need to help them eventually outgrow the service offering and move on to bigger and better things.

References
1 Setting Up a Pharmaceutical Manufacturing Process and Supply Chain: A Complex and Lengthy Undertaking. Pharmaceutical Research and Manufacturers of America: Washington, DC, 2021; https://www.phrma.org/-/media/Project/PhRMA/PhRMA-Org/PhRMA-Org/PDF/S-U/Setting-Up-A-Pharmaceutical-Manufacturing-Process-and-Supply-Chain-A-Complex-and-Lengthy-Undertaking.pdf.

2 Market Insight: Biopharmaceutical CDMOs Analysis Update. Bourne Partners: Charlotte, NC, August 2019; https://bourne-partners.com/wp-content/uploads/2019/08/Biopharmaceutical-CDMOs-Market-Update.pdf.

Ravi Samavedam is president and chief operating officer of
Azzur Cleanrooms on Demand, 411 Waverley Oaks Road, Suite 126, Waltham, MA 02452; 1-781-893-1251; https://azzur.com/services/cleanrooms-on-demand.