What Are the Biologics License Application Requirements?
While there are many components of a BLA submission, the primary requirements are specified in Form FDA 356h – Application to Market a New or Abbreviated New Drug or Biologic for Human Use. This form, along with the supporting application materials, data and prerequisite or supporting activities, is what the FDA uses to assess and confirm a biologic’s safety, purity and potency – its fitness for human use and consumption.
Below are the main requirements of a BLA submission.
Applicant Information: This section requires basic information about the applicant, including the name of the person or legal entity to whom the license is to be issued, contact details, and previously issued U.S. license number, if applicable.
Product/manufacturing information: Product information such as name, proprietary name, dosage form, route of administration, proposed indication for use, and proposed marketing status (e.g., prescription or over-the-counter) must be disclosed in the application. Further, manufacturing details including contact information, registration number, manufacturing steps and testing types, and inspection readiness status of the facility must also be provided.
Pre-clinical studies: The application must include detailed information regarding the chemistry of the biologic (e.g., manufacturing and controls, samples and methods validation); nonclinical pharmacology and toxicology; and human pharmacokinetics and bioavailability. Copies of important SOPs related to the chemistry, manufacturing and controls should also be included.
Clinical studies: This is a general overview of the clinical investigations of the biologic. It must include a description and analysis of each clinical pharmacology study, of each controlled clinical study of the proposed use of the biologic, a summary of the benefits and risks of the drug, and more. The application must also disclose the statistical evaluation of the clinical data.
Labeling: The application must provide the draft container label, which must include information such as the proper name of the product, manufacturer information, lot number, expiration date, recommended dose, and more. It must also provide the draft package label, including the same information as the container label and more, such as recommended storage temperature, handling instructions and inactive ingredients.
What Is the BLA Process?
The BLA submissionrequirements can differ for each product and applicable regulation (i.e., 21 CFR parts 600, 601 and 610), but the application process is generally the same, as outlined below:
- Apply for a BLA – The party responsible for the regulatory compliance of a biologic must communicate to the FDA its intention to apply for a license. This can include forming a review committee to meet with the FDA; scheduling a bioresearch monitoring inspection; and/or submitting a manufacturing validation plan, all prior to submitting the BLA itself.
- Submit a Form FDA 356h – According to the Electronic Common Technical Document (eCTD) submission requirement, a BLA must be submitted in electronic format using the current FDA fillable form and electronic signatures, unless an exemption is granted.
- Await FDA Review – The FDA reviews the BLA submission for completeness and requests any missing information from the applicant. If the information is not provided, is incomplete, or if the biologic is not ready for approval, a Refuse to File (RTF) may be issued. If the BLA is approved, the FDA will issue an approval letter authorizing the manufacturer to distribute the product.
- Implement Agreements or Commitments – If the approval letter includes any agreements or commitments, the applicant must address them according to the FDA’s requirements.
Example of Products That Need Biologics License Applications
Biologics are characterized as large, complex molecules or mixtures of molecules that are derived from or manufactured in a living system (e.g., a microorganism, or plant or animal cells), and often produced using recombinant DNA technology. In comparison, drugs are chemically synthesized by combining ingredients according to a precisely ordered process or recipe.
The term biologics applies to a wide range of substances and products with varying properties, classifications and uses, including vaccines, allergenics, blood and blood by-products, certain antibodies and proteins, tissue, cellular products and genetic therapies. They can even encompass some pharmaceutical products or devices, depending on their composition or how they are dispensed. All such products require a BLA prior to commercialization.
Due to their diversity, biologics can be regulated by either the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER). It is up to the applicant to determine which division of the FDA to submit its BLA to based on product type.
NDA vs. BLA
Like biologics, newly developed drug products must be assessed and approved by the FDA before they can be released to market. The drug equivalent to a BLA is a New Drug Application (NDA). After clinical trials have been conducted, the FDA’s CDER reviews the NDA which contains trial data and results, and other critical information about the new drug – such as manufacturing, labeling, and more – to determine its safety and efficacy for approval. Both NDAs and BLAs use Form FDA 356h.
MasterControl and Biologics License Applications
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