Beyond FDA approval: The next big hurdle for COVID-19 drug and vaccine development could be scale

While the FDA has stated they will work to approve or authorize new products to address COVID-19 as quickly as possible, approval is not the only barrier companies need to consider. Companies are already grappling with the need to scale up the production of experimental treatments faster than ever, and need to consider the regulatory hurdles to doing so.

 

To contact the author of this analysis, please email Lily Rosenfield (lrosenfield@agencyiq.com)


To contact the editor of this analysis, please email Alec Gaffney (agaffney@agencyiq.com)

Executive IQ Brief

  • How things work now: During clinical testing, most drug products are made in relatively small batches. Once approved, companies may wish to expand their production capacity to make greater quantities of a product, or make other changes such as making a product at a new facility. These changes are referred to as Scale-Up and Post-Approval Changes (SUPAC). All manufacturing changes require the company to notify the FDA, while certain changes also require prior FDA approval.
  • What’s new: As companies seek to bring new treatments to market for COVID-19 as quickly as possible, many are now trying to think about how to rapidly scale up production of their products both before and after potential approval. Some are scaling up production to meet demand for their product under Expanded Access, while others are trying building out additional capacity in anticipation of eventual approval. Without these efforts, any approved treatment or vaccine likely won’t be available in sufficient quantity for months or even years after approval.
  • Impact: Scaling up pre-approval requires extensive resources and capital, and may not be feasible for some companies working to develop new products to fight the virus. Two resources will be critical: Capital and partnerships. Life sciences companies should give thought to how they can rapidly expand production capacity to meet demand, while also thinking about models which might allow them to scale down production based on the number of new COVID-19 patients, the emergence of more effective treatments, or the use of a vaccine product.

Regulatory Background

After a company receives FDA approval for a product, they may have a need to make changes to their product or the manner in which it is made. For example, a company may wish to increase the number of units they produce, or make operational changes to their manufacturing site to make it more efficient or to replace outdated equipment.

 

Many of these post-approval changes affect the components and composition of the drug itself, the manufacturing site(s) at which it is made, the manufacturing processes that produce the product, the specifications of the drug product, the drug’s container closure system, or the way in which the drug is labeled.

 

Whenever a post-approval change is made the company must notify the FDA. The type of notification required is dependent on the type of change. According to the FDA, a “major change” which “has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product” requires the submission of a supplemental application and FDA approval prior to distribution with the change in place.

 

The supplement is called a Prior Approval Supplement (PAS). While the review process associated with a PAS is extensive, it can be expedited for public health reasons.

 

Changes that have a “moderate potential to have an adverse effect on the identity, strength, purity, or potency” of a drug constitute a “moderate change.” These require notification through either a Changes Being Effected in 30 Days (CBE-30) or Changes Being Effected (CBE) supplement.

 

The CBE and CBE-30 supplements operate more like a notification of a change to the agency, with the CBE-30 providing a 30-day window between the notification and the changes being implemented. The FDA can stop a manufacturer from continuing to distribute the product if it disapproves.

 

Minor changes that have very small potential to impact the identity, strength, quality, purity, or potency of a drug in an adverse way can be described in a sponsor’s next Annual Report to the FDA.

 

Manufacturing at Scale

Some changes are made immediately after approval is granted in order to scale up production operations to meet commercial demand for a product. These changes in batch size are separated into Level 1 and Level 2 changes based on the factor by which a sponsor wants to multiply its production.

  • Level 1 changes: A change in batch size, up to and including a factor of 10 times the size of the pilot batch or biobatch. These types of changes can be included in an annual report.
  • Level 2 changes: A change in batch size beyond a factor of ten times the size of the pilot/biobatch. This requires a CBE supplement.

 

Both Level 1 and Level 2 changes are applicable if the equipment used to produce the test batch(es) is of the same design and operating principles, if the batches are manufactured in full compliance with current good manufacturing practices (CGMPs), and if the same standard operating procedures (SOP’s) and controls are used on the test batch(es) and on the full-scale production batch(es).

 

While the FDA’s Scale-up and Post-Approval Changes (SUPAC) guidance describes various changes companies make and their reporting requirements, it is relatively dated, with most documents having been published in the late 90s. Since technology in the manufacturing and production process has advanced, including the advent of continuous manufacturing techniques, some practices described are out of date.

 

Scale-up processes may look different depending on the dosage form or route of administration of the drug. Typically biopharmaceuticals have been more challenging to scale up than solid-dosage drugs due to the complexity of their manufacture. 

 

Regardless, the process of getting a drug product to a patient does not end at approval. The post-approval process can be strenuous, expensive, and time consuming and quickly interfere with the ability to serve patients quickly.

 

Regulatory Context

While the FDA has stated its intention to review products intended to treat, detect, and prevent COVID-19 as quickly as possible, companies still face significant hurdles to making these products available to patients quickly.

 

While the FDA may approve a new drug product, it may not be available commercially to all patients who desire access for months due to the scale of demand. Companies who develop vaccines for SARS-CoV-2 may need to make hundreds of millions of doses just to meet US demand, for example. The speed at which scale-up would need to occur is also likely to be far faster than normal. Generally, scale-up operations may not occur until Phase 3 clinical trials are underway, and scale-up might take years to complete (such as the construction of a new manufacturing facility). For COVID-19, some companies are trying to accelerate the scale-up process as much as possible, and have already started despite products being in early-stage testing.

 

In response to this pressure, some companies may look to have a much larger number of manufacturing sites and partners to effectively scale their manufacturing operations. For example Eli Lilly and AbCellera announced a partnership in March which would utilize AbCellera’s pandemic response platform and Eli Lilly’s development, manufacturing and distribution capabilities in order to develop a COVID-19 treatment. 

 

As Eli Lilly noted in the statement, “while typically a new therapeutic antibody program might take years to get in the clinic, our goal with AbCellera is to be testing potential new therapies in patients within the next four months.”

 

GlaxosmithKline (GSK) is working with several companies, including Sanofi, Vir Biotechnology, Dynavax, and Innovax to allow them to use its vaccine adjuvant in manufacturing and testing.

 

Other partnerships aim to tackle manufacturing of new treatments regionally. Vir Biotechnology and WuXi Biologics announced an agreement to develop a COVID treatment together, and, if approved, WuXi will have the rights to manufacture in China, while Vir will take over in other markets worldwide.

 

While scaling up usually requires working with a handful of parties for different aspects of manufacturing (active pharmaceutical ingredients, excipients, etc.), COVID product manufacturing may require multiple partners for each individual piece to meet product demand.

 

Even with agreements between some of the biggest multinational life sciences companies, it could be difficult to meet demand in the short time frame.

 

What’s New

Some companies are tackling timing issues by scaling up even before receiving FDA approval, also known as “at-risk” manufacturing.

 

While this is unusual in the industry, multiple organizations are deploying this tactic due to the pandemic. This forces companies to go “at-risk” in their manufacturing, meaning that they are producing their product to meet current demand with no guarantee it will be approved and make it to market.

 

For example, Johnson & Johnson stated on March 30th that it is “moving on an accelerated timeline toward Phase I human clinical trials […] and scaling up in parallel to this testing.” By scaling up in tandem with the various clinical trial phases and producing the vaccine at risk, J&J aims to generate more than one billion doses.

 

In order to achieve such a feat, the company is expanding manufacturing capacity around the globe by establishing capabilities. This tactic is costly—and risky. The company notes this will be a $1 billion effort split between J&J and the Biomedical Advanced Research and Development Authority (BARDA). If the product isn’t shown to be effective or isn’t approved, that investment could mostly be for naught.

 

However, even with that funding and scale-up efforts, the earliest the vaccine would likely be ready is the beginning of 2021 through FDA’s Emergency Use Authorization, J&J wrote.

 

Gilead Sciences is also ramping up producting of its experimental anti-viral, remdesivir. Gilead CEO Daniel O’Day said the company “made the decision to invest and scale up regardless” of potential challenges. The company intends to manufacture more than a million treatment courses by the end of the year.

 

Pre-approval scale-up is likely to require two key ingredients: Capital and partnerships. The capacity needed for creating products to fight a global pandemic cannot be achieved quickly with the manufacturing capacity of just one company. 

 

Similarly, few companies are likely to be able to make up-front, pre-approval investments in manufacturing without sufficient capital, especially if that capital may not provide a return on investment.

 

What’s Next

For many organizations, post-approval scale up will still be the status quo for bringing products to patients. Even so, this process will still require more partnering and investment than typically required in order to meet demand.

 

This demand is also likely to emerge even before approval. Companies like Gilead have already seen massive demand for access to their drug through the FDA’s Expanded Access program. Other companies are likely to face similar demands for access.

 

Even as companies race to expand capacity, they are just as likely to need to anticipate highly variable demand. A company making a COVID-19 therapeutic, for example, might face substantial short-term demand for the product, but see that demand dissipate as the number of new cases decreases, as vaccines reach that market, or as more effective treatments are discovered. The need for flexibility could incentivize the use of contract manufacturing or partnerships to meet that demand.

 

Several key regulatory questions remain. For example, will partnering organizations need to submit to a pre-approval site inspection by the FDA? Will companies allow their partners to manufacture a product as an authorized generic, or waive patent rights and require them to file as a generic drug? If many companies are manufacturing a product, is there potential for manufacturing variability that leads to differences in safety or efficacy? How soon will the FDA be able to review Prior Approval Supplements, or might it waive certain requirements entirely?

 

To date, the FDA has not offered guidance on these questions, and the life sciences industry may need them answered quickly.

 

Life sciences companies have already been advancing through development phases in record time to product products for COVID-19. The next challenge will be expediting scale-up processes so they can reach patients in record time as well.

 

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