How to prepare early for regulatory submissions from IND to BLA

Bringing a new cell and gene therapy (CGT) to market is a complex journey, and one that requires rigorous testing and adherence to safety and regulatory standards. At BioLife Solutions, we have supported many drug manufacturers as they prepare for Investigational New Drug (IND) and Biologics License Application (BLA) submissions. We have learned over the years that early preparation for IND and BLA submissions may save time and rounds of questioning with regulatory bodies.

As we continue to assist drug manufacturers at various stages within the clinical trial process, we thought it would be helpful to summarize the different preparation steps and how we support our partners.

The drug development process begins with a commercial Investigational New Drug (IND) application, which allows manufacturers to conduct clinical trials. The IND submission includes details about the drug’s formulation, manufacturing process, and planned clinical studies. According to the U.S. Food and Drug Administration (FDA), here is a list of required documentation that must be included with every application:

• Form FDA 1571: Primary IND application form.

• Form FDA 1572: Statement signed by the investigator detailing their qualifications and agreement to conduct the study.

• Form FDA 3674: Certification that the study is registered on ClinicalTrials.gov.

• Cover Letter: A summary of the IND application, including the drug name, intended indication, study design, and sponsor information.

• Preclinical Data: Results from animal studies evaluating the drug’s safety and pharmacology.

• Clinical Protocol: Detailed plan for the clinical trial, including patient selection criteria, study procedures, and data collection methods.

• Information and data on the drug’s chemistry, manufacturing, and controls (CMC).

Often, therapy developers rely on manufacturers of critical components and supplies to provide critical information to the CMC section related to manufacturing processes, testing, verification, and validation of those materials. A good partner is required to successfully navigate assembly of a robust CMC package.

Once submitted, regulatory agencies have 30 days to review IND applications, request additional information, and respond with their first round of questions. Depending on how thoroughly the company can answer the questions, the IND submission could go through additional rounds of questioning. Then, the application is either allowed or put on clinical hold. This application review timeline is completely controlled by the FDA.

When sufficient evidence of safety and efficacy is collected, drug manufacturers submit a licensing application (BLA in the US) to regulatory agencies to request permission to introduce, or deliver for introduction, a biologic product into instate commerce ( 21 CFR 601.2 ).

• A BLA provides the FDA with extensive data demonstrating that a biologic product is safe, pure, and potent. This application details the product’s safety, efficacy, pharmacology, clinical trial results, manufacturing process, and labeling. Essentially, it ensures that the biologic meets stringent quality and regulatory standards before reaching patients.

• The information included in a BLA includes chemistry and composition, pharmacology, preclinical and clinical study data, manufacturing procedures, labeling, and potential risks.

Again, critical information to support CMC may be available only from the supplier of materials thus requiring good communication between the therapy developer and their partners.

Many regulatory agencies have published guidance for how a developer should evaluate GMP controls throughout development. 2,5 For the IND application, the amount of information required is typically lower than that expected at subsequent regulatory filings. At the early stages however, using materials that have a demonstrated history of successful use in clinical-stage and commercial-stage therapies, provides a high level of assurance that regulatory expectations can be met, reducing the risk of elongated regulatory review timelines. For BLA, fully compliant Good Manufacturing Practices (GMP) are expected requiring significant information about the materials and components used during manufacturing.

As you develop your organization’s bioproduction process, please consider how your supplier partners address the following:

• Are the starting materials used high-quality and GMP-compatible?

• What are the quality specifications for raw materials used in the manufacturing process?

• How are raw materials sourced, received, inspected, and stored to maintain their quality?

• Do suppliers have a robust quality system in place to ensure consistent raw material quality?

• How are environmental controls implemented?

• How are manufacturing processes controlled and monitored?

• Is the process effective, with repeatable results every time?

• What process controls are in place for monitoring equipment, documentation and recordkeeping, and batch record reviews?

• Do is quality risk management addressed?

• How are complaints and feedback managed?

• How are deviations managed and controlled?

• How are personnel are trained?

A Master File contains proprietary information about raw materials, including quality attributes, manufacturing information, and formulation details. Where available, Regulatory agencies use Master Files to verify that excipients and process materials meet safety and quality requirements.

At BioLife Solutions, we maintain Master Files with the FDA for the following product families:

• CryoStor® cryopreservation media

• HypoThermosol® FRS biopreservation media

• Stemulate® human platelet lysate

• nLiven PR™ human platelet lysate

• T-Liven PR™ human platelet lysate

• CellSeal® Cryogenic Vials for closed-system fluid transfer and storage

If a drug manufacturer is using any of these products in their process, they may reference our Master File by requesting a Letter of Authorization (LOA) from BioLife Solutions. This allows BioLife to share confidential information and streamline questioning the regulatory agency may have around our products.

While the FDA accepts Master Files as part of the BLA process, European regulatory agencies do not. Instead, agencies will request detailed documentation and may require additional clarifications. BioLife Solutions supports global regulatory submissions by providing the necessary quality and compliance information for our customers.

If you are a drug manufacturer and need to reference one of our Master Files, visit the BioLife Solutions Knowledge Center and submit a Master File Letter Request form . Our regulatory team will ensure you have the documentation needed to support your IND or BLA submission.

At BioLife Solutions, we are committed to supporting you through every stage of the drug development process, ensuring that your therapies have the best chance of success.

• S. Food and Drug Administration. (n.d.). Biologics License Applications (BLA) Process (CBER). FDA. Retrieved February 11, 2025, from https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/biologics-license-applications-bla-process-cber

• S. Food and Drug Administration. (n.d.). Current Good Manufacturing Practice (CGMP) Regulations. FDA. Retrieved February 11, 2025, from https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practice-cgmp-regulations

• S. Food and Drug Administration. (n.d.). Development & Approval Process (CBER). FDA. Retrieved February 11, 2025, from https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber

• S. Food and Drug Administration. (n.d.). Drug Master Files (DMFs). FDA. Retrieved February 11, 2025, from https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs

• S. Food and Drug Administration. (n.d.). Guidance for Industry: CGMP for Phase 1 Investigational Drugs. FDA. Retrieved February 11, 2025, from https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-cgmp-phase-1-investigational-drugs

• S. Food and Drug Administration. (n.d.). Guidance for Industry: Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications. FDA. Retrieved February 11, 2025, from https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-providing-regulatory-submissions-electronic-format-certain-human-pharmaceutical

• S. Food and Drug Administration. (n.d.). IND Application Procedures: Overview. FDA. Retrieved February 11, 2025, from https://www.fda.gov/drugs/investigational-new-drug-ind-application/ind-application-procedures-overview

• S. Food and Drug Administration. (n.d.). Investigational New Drug (IND) Application. FDA. Retrieved February 11, 2025, from https://www.fda.gov/drugs/types-applications/investigational-new-drug-ind-application