As a result of an early 2020 change in the Public Health Service Act definition of a “biological product,” it now includes “protein,” defined as “any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size.”  Under this new definition, 89 products that were originally registered with FDA under a New Drug Application (NDA) are now biologicals, effective March 23, 2020. They will now be covered by Biologics License Applications (BLAs).

The FDA March 2020 transition from NDAs to BLAs introduced several changes to the NDA holders that were switched to BLAs:

  • Need for upfront process validation in the BLA
  • More scrutiny of process microbiology
  • A new CMC review office

In addition, under the BLA framework the rules about referencing Master Files are more restrictive than with NDAs.

The FDA document “Preliminary List of Approved NDAs for Biological Products That Will Be Deemed to be BLAs on March 23, 2020 (current as of December 31, 2019)” is available here.

At the ISPE Biopharmaceutical Manufacturing Virtual Conference in early June, FDA Center for Drug Evaluation and Research (CDER) Office of Product Quality (OPQ) Office of Pharmaceutical Manufacturing Assessment (OPMA) Senior Scientific Advisor Patricia Hughes gave a regulatory perspective on the changing biomanufacturing landscape including the implications of the PHS Act definition change. 

In addition, she discussed regulatory and guidance updates, including some of the changes that are being implemented on the pre-license inspections, as well as some new approaches to biomanufacturing and FDA’s view of the future of microbial testing methods. These points are covered in Part II of this article series. 

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Confronting Regulatory Challenges

Hughes explained that some of the challenges FDA is facing include, “persistent and widespread drug shortages due to deficiencies in pharmaceutical quality and manufacturing, specifically due to outdated manufacturing technologies, facilities, and equipment.  A survey of the product defects and recalls indicated that between 2013 and 2017, 62% of the drug shortages were attributable to quality issues and 63% of them were for sterile injectables.”

A second challenge the agency is facing is that “there has been rapid expansion of the manufacturing of complex biological products and fragmented supply chains across the globe with complex site transfers and processes.  This has limited the ability to increase production and provide market supply and demand, resulting in many drug shortages.”

In addition, the market has increased for biologics.  The coronavirus pandemic has created new pressures in the manufacturing arena requiring very rapid scale ups and site transfers of either promising drugs that may be used in the pandemic or shifting needs, shifting drugs into other sites to make room for the current pandemic.

As a result, FDA has been updating the regulatory landscape to meet some of these changes. Hughes addressed a few of the regulatory changes that have happened very recently.

89 NDAs Now BLAs

In early 2020, the Public Health Service Act was amended to include a new definition of biological products and as such to include a series of products that were deemed to be biologics.  The FDASIA law of 2012 also amended the Food, Drug, and Cosmetic Act to include the ability of FDA to do a records review in advance or in lieu of an inspection, and this has affected the inspection program (Figure 1).

Figure 1 Changing Regulatory Landscape
FIGURE 1 | Changing Regulatory Landscape

The agency also has proposed changes to the 21 CFR 600 regulations to include biosimilars—the pathway for biosimilar approval.  For 601.12 there have been some proposed regulations to clarify the use of master files.

In addition to that, FDA has issued guidance documents on the emerging technology program, which is intended to help manufacturers promote innovation and modernization.

A new guidance document also was issued in December 2018 on the ‘deemed to be a license’ products that are now regulated under the Biologics Licensing Application (BLA) program.

And there is a new guidance released in February 2019 on continuous manufacturing, Quality Considerations for Continuous Manufacturing.

The Public Health Service Act amendment in March 2020 clarified the statutory framework for the deemed products—that is the insulins, etc. that were previously approved under the NDA program.  The definition for what is a biological product is new—previously it only included proteins that were derived from biological systems, but the new definition includes synthetic polypeptides.

The biologics previously approved under section 505 of the Food, Drug, and Cosmetic Act have now had their NDAs converted to BLAs. And this impacts a large group of protein products and includes products that are especially important:

  • All insulins
  • Insulin analogs
  • Human growth hormone
  • Pancreatic enzymes
  • Reproductive hormones

There is also an associated guidance document regarding these ‘deemed biological products.’  This is a huge category of products that have now entered the biological arena.

Proposed changes to 21 CFR 601.2 impact the referencing of master files in BLAs and the role of master files in a BLA.  The transition products or the “deemed biological products” that were approved as NDA products were able to cross-reference master files for their drug substance, drug substance intermediate, or drug product. 

There are specifically 89 applications that are deemed to be BLAs now that were NDA products.  And 17 of these 89 products incorporated master file references.  They referenced seven master files.

They will be allowed to continue to reference those.  But any new BLA that is approved will not be able to cross-reference a master file for drug substance, drug substance intermediate, or drug product. For other than those elements, master files can be used.  For example, for containers and closures. NDAs will be able to cross-reference a master file.

The definition for what is a biological product is new

The amendment allows BLAs to incorporate by Master File reference information other than drug substance, drug substance intermediate, or drug product.  It also allows IND applications to incorporate by Master File reference any information for product subject to licensure under the PHS Act.

It will not allow BLAs to incorporate by Master File Reference information on the drug substance, drug substance intermediate and drug product.

Physical Inspection Not Necessary?

One of the characteristics of BLA approval is based on an integrated assessment of product and facility standards.  This is listed in the Public Health Service Act, section 351 A to C, which also applies to biosimilars.

It very clearly states that the biological product would be approved on the basis that a product is pure and potent and that the facility meets the standards designed to assure that the product is safe, pure, and potent and that the applicant consents to inspection.

In 2012 when FDASIA was approved, it provided the agency with a legal option to perform a records review that was previously not available.  And this was amended to the Food, Drug, and Cosmetic Act section 704a.

How does this affect the BLA pre-license inspections?  “As you know, every time a BLA was submitted to the agency, there was always an associated pre-license inspection,” Hughes explained.  “But with FDASIA, if the agency can derive sufficient information to conclude from a records-based inspection that the establishment meets applicable requirements to ensure the continued safety, purity, and potency of the biological product, then the agency would be able to license the product without a physical inspection.  This is a major change in the landscape.  And it has come about as a result of the pandemic that there has been new thought about how to meet the obligations of inspections.”

Any new BLA that is approved will not be able to cross-reference a master file for drug substance, drug substance intermediate, or drug product

Waivers for a physical inspection may be granted if similar information can be derived from a records-based inspection as would be derived from a physical inspection.  Also, the establishment needs to meet applicable GMP standards.  An inspection would not be waived, if for example a new facility or building is proposed, or there are significant GMP deficiencies had been reported in previous inspections, where significant processes and scale-up changes are proposed.

How does this affect future prelicense inspections?  “FDA has been limited by the number of inspections that it can conduct during the current pandemic due to travel restrictions,” Hughes said.  “And that has really focused our concern about which inspections can be conducted based on record reviews.”

If a decision has been made to request relevant records and other information from an applicant in advance or in lieu of a facility inspection to support the application of approval, “this will allow for better resource utilization, both in industry and the FDA. And this is all due to the pandemic. I think this is a new shift and it will help manage and allow for the approval of applications.”

New Approaches to Biomanufacturing

What are the new changes and approaches to biomanufacturing?

The Emerging Technology Program was established in 2014 to allow for industry to meet with FDA and to identify problems that would prevent the approval of more modern and advanced manufacturing methodologies or analytical methods.

The intent was to try to resolve issues before an application submission to facilitate innovation.  And this program has worked very well. It is highly active now.  This is something that is a good mechanism for being able to address some of the challenges that we are facing and hopefully to try to resolve some of these.  [Author’s Note: David Doleski Encourages Industry To Participate In FDA’s Emerging Technology Efforts.]

The biologics field is rapidly expanding globally.  And the biopharmaceuticals are extremely expensive due in part to the complexity of the product and processing facilities.  Scale-up and site transfers are difficult.  The whole supply chain is fragmented across the globe.  And it is particularly challenging from a regulatory oversight perspective.

“The supply chain is also susceptible to disruptions and unacceptable shortages and recalls as is evidenced by the recalls and the shortages that FDA is dealing with on a constant basis,” Hughes emphasized.

New Biomanufacturing Developments

Now there are players that have limited experience in biological products entering the market, especially with either the new modalities or the deemed biologics, Hughes pointed out.  “Many new players with limited experience with biological products appear inflexible and have complex and inefficient scale-up and site transfers.  And in addition to all of that, the virus pandemic is highlighting the urgency of really trying to increase manufacturing flexibility, speed, scale up, and site transfers to supply chain reliability. It is really causing major disruptions in the whole biomanufacturing field.”

She noted that the industry “has a dire need for implementation of new methods and new testing technologies.  Some of the drivers of these that we are seeing include new modalities with usable alternative cell lines.  We have seen and we have approved some process intensification coupled with more continuous and streamlined methods of biomanufacturing.”

There are many new methods and new advances in the pipeline.  Some have been approved, some are going to be presented to the FDA as it meets with industry through the ETT programs and IND programs.

The agency is seeing an increasing use of closed single-use systems, which should facilitate site transfers and scale-up while maintaining process control because of the similarities of the systems.

It is also beginning to see some use of rapid methods for continuous process monitoring and real-time release, “which is good,” Hughes commented.  “We are also seeing more integrated process automation.”

In Part II of this story, Hughes discusses FDA’s vision for the future of biomanufacturing facilities and equipment, the challenges of single-use-systems, emerging new modalities, the promise of continuous manufacturing, and the future of microbial test methods including those for endotoxins and pyrogens.

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