BLA Submittal A Professional Guide

BLA Submittal for CGT: A Professional’s Guide to Success

Cell and Gene Therapy's promise to treat previously considered incurable or difficult-to-treat diseases requires successful BLA Submittals.

Innovations in healthcare and the life sciences industry continue to grow and Cell Gene Therapy (CGT) is a vivid example. CGT discovers and develops new ways to treat rare and severe diseases that were previously considered incurable. A successful Biologics License Application (BLA) submittal is vital to deliver these promising new therapies to the people who need them the most.

The Key to Unprecedented Medical Advances

What is a Biologic License Application (BLA)?

BLA is a regulatory submission to seek approval from the US Food and Drug Administration (FDA) to market and distribute a biologic product in the United States. 

Biologics are medical products derived from living organisms such as proteins, antibodies, vaccines, and cell therapies.

What are biologic products

The BLA submittal is a critical milestone in the regulatory approval process for biopharmaceuticals, biotechnology, and now cell and gene therapies to get their products to market. 

The FDA continually reviews BLA applications to determine whether a biologic product meets the required safety, efficacy, and quality standards to warrant marketing approval. The biologic product can be commercialized and distributed in the United States for the indicated use(s) only after receiving FDA approval.

It is worth noting that the BLA process is specific to the United States. In other regions, such as the European Union, a similar regulatory submission called a Marketing Authorization Application (MAA) is required to approve biologic products.

What is a BLA

Modern Science's Most Innovative and Complex Therapies

Biologic drugs represent some of modern medicine’s most innovative and complex therapies. 

Biologic drugs have saved the lives of millions of people. They are used to treat diseases including cancer, autoimmune diseases and diabetes.

Cell & Gene Therapies (CGT) revolutionized and will continue to revolutionize the way some health conditions are treated today. They promise to help treat and even cure rare and severe conditions for which there are limited, ineffective or no treatments.

Nonetheless, CGT, although a biologic product, is a new category of biologic products. This requires new technology, processes and even regulation.

Cell and Gene Therapy is personalized

For example, whereas biopharmaceuticals often follow traditional trial designs with large audiences (>1,000 patients), CGT is specialized. It requires innovative trial designs made to work with smaller sample sizes.

Because of the fundamental differences arising from CGT solutions, regulatory bodies such as the FDA, must guarantee that they provide space for innovation while ensuring public health. In the FDA commissioner Scott Gottlieb’s words:

“With each of these and with similar products, the novelty of the technology that the FDA is being asked to evaluate challenge the agency to adapt its usual approaches to product regulation in some novel ways. We need to make sure that we’re taking policy steps to enable these innovations to efficiently advance to benefit patients, while we maintain our gold standard for ensuring the safety and efficacy of new products.” (Read full communication)

Despite their great promise and innovative nature, CGT requires BLA approval.

In short, A BLA approval is a stamp of approval of regulatory compliance and a commitment to excellence in research, manufacturing, deployment of solutions, and patient health and safety.

Anatomy of the BLA: A Roadmap to Approval

A successful BLA Submittal requires a series of equally critical strategic steps. Overall, these steps cover information related to the therapy’s CMC: Chemistry, Manufacturing and Controls. The latter specifies the conditions required for effective therapy administration.

It is vital to understand that the steps and data required for approval span throughout the entire therapy life cycle. 

That is why from our point of view, a successful BLA submittal is the result of an effective team effort.

The data and documentation required for submittal require coordination among various teams. This process starts in the development phases of the therapy and continues after submission. 

These teams might evolve throughout the therapy development life cycle and include: 

  • Research & Development
  • Manufacturing, 
  • Regulatory Compliance
  • Legal. 

Understanding the Significance of a BLA​

Despite how well a product might work, no BLA means companies cannot market and commercialize their solutions. It is important to stress that regulatory compliance is not a one-time effort or checklist.

The FDA regularly audits manufacturing operations for CGT products to ensure continued public health and safety.

Failure to comply with the new and existing regulatory demands can result in a 483 Warning Letter and even a Consent Decree. In essence, failure to uphold excellence in quality and operations can result in the FDA determining that your product is not fit or reliable enough to treat patients.

Key Elements in a BLA Submittal​

A successful BLA submittal hinges on four primary components:

  • Quality Control Measures: Demonstrating consistent, high-quality product outputs and robust risk management practices

  • Nonclinical Data: Assessing the drug’s safety through tests on animals and in vitro studies

  • Clinical Data: The product’s performance and safety indicators post-human trials

  • Manufacturing Information: The backbone of the BLA, detailing the production process down to the molecular level

The key elements in a BLA Submittal

Quality Control and Quality Assurance Measures

Ensuring that products applying for a BLA meet or exceed customer expectations is paramount. 

Consequently, it is essential to implement a robust quality control and assurance program. 

A Quality Control and Assurance Program involves continuous monitoring of all business aspects. It includes conducting in-depth testing at various stages of production and establishing strict standard operating procedures to maintain manufacturing and product consistency and quality. 

Compliance is a continuous process for products requiring BLA

Conducting gatekeeper assessments as early as the development phase increases the likelihood of a successful BLA submittal.

These gatekeeper assessments are performed at specific milestones to guarantee product quality. They also position the company to submit a successful BLA. Accurate documentation must be provided for every stage of the therapy’s life cycle. The documentation should highlight the consistency of operations, among other elements. 

This documentation effort allows leaders to analyze their operations and is a great opportunity to identify opportunities for business process improvements

By developing agile quality systems, companies are also becoming inspection ready. Inspection readiness is ultimately the backbone for compliance approval.

Pre-Clinical and Clinical Case Studies

Thorough pre-clinical and clinical studies are essential to submit a biologics license application (BLA). These studies serve as the foundation for proving the safety and effectiveness of a drug. 

The studies instill confidence in regulatory bodies, healthcare providers, and patients by demonstrating the efficacy of the drug through rigorous testing. Therefore, it is crucial to design and conduct comprehensive studies and thorough documentation that provide the robust evidence required to support the drug’s approval.

The BLA Submittal and Review Process

After submission, the FDA’s BLA review process typically takes a year, although variations in timelines are not unique when it comes to GCT.

This comprehensive review process examines every element of the BLA, culminating in either approval for marketing or a roadmap to revise and resubmit the application.

The process for submitting a BLA for a cell and gene therapy follows similar principles to that of other biologics. Nonetheless, you cannot replicate the exact process used for a typical biopharmaceutical or biotechnology filing. 

1. Preclinical Studies:

Once companies identify the treatment strategy in the development process, they are ready to start preclinical studies.

These preclinical studies are pretty extensive. They assess the safety, efficacy, and mechanism of action of the cell or gene therapy in laboratory settings and animal models.

These studies provide crucial data to support the rationale for human clinical trials. In the case of CGT, few and sometimes single patients for the product will increase complexity in demonstrating product efficacy and safety.

Successful pre-clinical studies are required for clinical trials involving humans.

2. Clinical Trials:

Clinical trials for cell and gene therapies are conducted in three phases. Altogether, the phased approach aims to evaluate safety, efficacy, dosing, and other parameters. 

Clinical trials involve testing the therapy in human subjects under carefully controlled conditions.

  • Phase I trials: Focus on safety and dose-finding, often involving a small number of participants.
  • Phase II trials: Assess safety and begin to explore effectiveness in larger patient populations.
  • Phase III trials: Large-scale studies designed to confirm efficacy and safety in a broader patient population.
Clinical Trial Stages

3. Manufacturing and Quality Assurance:

CGT companies have fixed budgets- especially in their early stages. Establishing robust yet cost-effective and agile manufacturing processes and quality control systems is critical to control their burn rate and ensure future compliance.

Company and financial restrictions aside, the FDA requires documentation demonstrating that the manufacturing process consistently produces high-quality products. Moreover, that these products meet their predefined specifications.

Choose the right business partners

All biologics solutions require providers and CGT is not the exception. 

For this reason, we recommend that Preclinical and Clinical stage companies choose suppliers that meet GxP requirements as early as possible. Changing suppliers can result in months of additional work and analysis. . 

Although not required, selecting a GxP-compliant supplier reduces risk as you progress with your clinical trials. Making this decision early on will also position your company for a more efficient and seamless scale-up process.

Remember that the BLA requires detailed information on the manufacturing process. This includes data on your suppliers which includes details regarding:

  • cell sourcing, 
  • vector production (if applicable), 
  • genetic modification procedures, 
  • cell expansion or culture, 
  • purification, 
  • final formulation, 
  • and others (as applicable)

GxP Compliance can lead to cost-savings and cost-avoidance

GxP compliance is a set of guidelines and regulations related to the various aspects of production, testing, and distribution of pharmaceuticals, biotechnology, medical devices, and other products associated with the healthcare and life sciences industry. 

Achieving compliance may result in investing in electronic systems, additional documentation, and operational controls that are not vital at the early stages of product development. Nonetheless, the standardization and best practices of GxP may result in both cost savings and cost avoidance for your organization in the long run. 

Even when full GxP compliance is not mandatory you can start to adopt key guidelines to make your operations more robust. Ensuring your research, operations, and quality teams prioritize compliance typically results in stronger documentation and better execution of processes. This focus and mindset will streamline your BLA submittal process.

4. BLA Preparation:

Compiling BLA documentation involves organizing and submitting all relevant data and information related to the cell or gene therapy product. 

This data includes:

  • preclinical data
  • clinical trial results
  • manufacturing and quality control data
  • pharmacology and toxicology studies
  • information on the proposed labeling, packaging, and distribution plan

We know the FDA will release new guidelines sometime in 2024-25. These guidelines will likely focus more on quantitative data and a risk-mitigation approach in treatment development. 

Although a challenge for CGT companies, this approach aims to increase long-term public health and safety. In the words of LaSalle Group‘s Chief Quality Officer, “BLA Submittals are a matter of integrity and trust.” 

In her 2024 presentation at the Bioprocessing and Development (BPD) symposium, Amador highlighted that CGTs (and all Life Science companies) “[must] Keep in mind that all information [included in the BLA submittal] must be based on scientific knowledge. Relevant and accurate clinical and stability data from throughout the product life cycle is foundational and vital to success.”

Carmen Amador at NCRAF on BLA Submittals

5. BLA Regulatory Submission:

BLAs are submitted to the FDA’s Center for Biologics Evaluation and Research (CBER) or the Office of Tissues and Advanced Therapies (OTAT), depending on the nature of the therapy.

Submit form FDA 356h

Applicants must submit a FDA Form 356h to the document control center to CBER- a division of the FDA that specifically handles biologics. Form FDA  356h is an application to market a new drug, biologic, or antibiotic drug for use in humans.

Both paper and electronic submissions are acceptable. However, as with New Drug Applications (NDA), an electronic Common Technical Document (eCTD) can be used to submit a biologics license application. 

Be prepared for Regulatory Roadblocks

Ensuring you are well-prepared to handle potential regulatory hurdles is crucial to keeping the BLA process on track. 

Maintaining transparent communication channels with regulatory agencies, proactively addressing feedback and suggestions, and quickly adapting to unforeseen changes are essential. By taking these steps, you can stay on top of regulatory requirements and help to ensure a smooth and successful BLA process.

6. FDA Review:

The BLA revision process includes assessments by interdisciplinary teams of regulatory scientists, clinicians, pharmacologists, statisticians, and manufacturing experts.

The FDA may request additional information or clarification during the review process.

7. Advisory Committee Meeting (if applicable):

In some cases, the FDA may convene an advisory committee meeting to solicit expert opinions on the safety and efficacy of the therapy. These meetings provide additional insights and recommendations to the FDA.

8. BLA Approval or Response:

Based on the review, the FDA will issue a decision to either approve the BLA, request additional information (e.g., post-marketing studies), or issue a complete response letter outlining deficiencies that need to be addressed before approval.

9. Post-Approval Commitments and Monitoring:

Following approval, the sponsor may be required to fulfill post-marketing commitments. These commitments may include conducting additional studies to monitor the long-term safety and effectiveness of implementing risk evaluation and mitigation strategies (REMS). 

Long Term Follow Up (LTFU) has been implemented as a standard practice following the 2020 LTFU FDA Industry Guidance with the goal “to understand and mitigate the risk of a delayed adverse event.”

Sustaining Excellence Post BLA Approval

Gaining approval from the FDA’s Biologics License Application (BLA) process is significant for any company. However, it is crucial to understand that compliance needs to be understood as a continuum.

Committing to ongoing compliance and surveillance is essential to ensure the product is safe and effective post-approval. 

This requires continuous monitoring and evaluation of the product’s performance and implementing any necessary changes to maintain its quality and safety standards. 

By upholding these post-approval requirements, companies can sustain their product’s reputation and integrity while providing patients with safe and effective treatments. 

Technological Advances and the BLA Process

Cell Gene Therapy is a complex, ever-changing industry characterized by cutting-edge technological advancements and groundbreaking scientific research. 

To achieve success in the future, companies need to stay informed and up to date with the latest innovations in this rapidly evolving field. Failure to do so could result in missed opportunities to improve patient’s lives, lost market share, and, ultimately, limited success in the highly competitive biopharmaceutical arena.

One of the changes our team has been addressing is the focus of the FDA on a planned, risk-based approach, as previously mentioned. As the industry continues to grow, we expect CGT companies to develop a risk assessment and strategy for risk mitigation even before the start of clinical investigations.

The Role of Technological Innovation

Within scientific innovation and evolution, there has also been a new wave of technologies to help make these solutions viable and financially accessible.

Artificial intelligence is one of them. Artificial intelligence (AI) plays an increasingly significant role in various aspects of the FDA’s Biologics License Application (BLA) approval process, offering opportunities to enhance efficiency, accuracy, and decision-making. 

AI algorithms can analyze large volumes of preclinical and clinical study data, including safety and efficacy data, patient outcomes, and adverse events. 

Overall, AI holds significant promise for transforming the FDA BLA approval process by augmenting human expertise, improving efficiency, and enhancing the quality and safety of biologic products brought to market. Among other applications, it is currently being used to streamline the analysis of clinical trial data. This application reduces lead times and can enhance accuracy. 

Similarly, blockchain technology promises to ensure the integrity of the supply chain, providing an added layer of security and transparency. 

These developments pave the way for a new era of biopharmaceutical research and development that holds immense promise.

Final Thoughts: The Regulatory Professional’s Call to Action

Global Regulatory Landscapes

The biopharmaceutical industry is subject to rigorous regulatory requirements that differ across different global markets. Compliance with these regulations is crucial for the success of biopharmaceutical companies. 

Recently, there has been a push for harmonization of these regulations, with efforts underway to create a uniform set of global practices. This move towards harmonization is changing the way biopharmaceutical companies navigate regulatory requirements.

The same rigor and trends can be expected for CGT. Scientists should expect agencies to continue to learn about the products, technologies, and innovations. This new knowledge is bound to inform future communications and guidelines.


The BLA process indicates the dedication of regulatory professionals, compliance officers, and biopharmaceutical companies to the highest levels of integrity and public health. 

On the one hand, the mission of CGT companies is to deliver efficient treatments to address life-threatening conditions. Conversely, regulatory bodies must ensure that those treatments are safe, effective and consider potential risks.

Navigating the complex process of a BLA submittal requires a proactive and collaborative approach from the earliest stages of the Development Phase.

A robust BLA submittal strategy ensures critical milestones are met and preemptively addresses potential challenges. 

Success hinges on the commitment of a cohesive team dedicated to upholding established guidelines and fostering open communication. 

Seeking support from consultants can be a strategic investment for your organization. External players help avoid groupthink. They can also help integrate cross-industry benchmarks and best practices into your submission process. 

By thoroughly understanding the intricacies and possibilities of approval, CGT professionals can pave the way for a future full of innovative and life-changing biological products. Most importantly, they will be better equipped to deliver innovative therapies to the patients who need them the most.



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