Biologic License Application (BLA) Checklist

Under the Public Health Services Act, the Federal Food and Drug Administration (FDA) has been
given the authority, concurrent with its authority under the Food Drug and Cosmetic Act, to
regulate biologics. The FDA regulates a wide range of biologics, including, but not limited to,
vaccines, blood and blood by-products, certain monoclonal antibodies, tissue and cellular products.
Within the FDA, the Center for Biologics, as well as the Center for Drug Evaluation and Research,
can be responsible for the regulation of biologics.

Biologics are evaluated for market by the FDA through the filing of a Biologic License Application
(BLA). A BLA, although similar to a New Drug Application (NDA), has its own set of intricate
requirements. It is difficult to know whether an applicant has included all of the information
required, and provided that information in an acceptable format, under the applicable regulations.
The following checklist is intended to act as a general guide and reminder of the types of
information which must be included in a BLA, however, applicants must be cognizant that unique
and specific information will be required depending on the type of BLA (e.g., blood, vaccines).
Although it is always helpful to have legal counsel assist in a final review of the application prior
to its filing, this checklist provides a basic summary of the materials the FDA requires for each
application as set forth in the current regulations. Prior to any such filing, all applicable regulations
should be checked to ensure that there have been no material changes to the application process or
procedures.

1. Safety, Purity, Potency

 An applicant must demonstrate: (i) the product is safe, pure and potent; (ii) the facilities
for production meet the standards designed to assure that it continues to be safe, pure and
potent.

 Safety – Safety means the relative freedom from harmful effect to persons affected, directly
or indirectly, by a product when prudently administered, taking into consideration the
character of the product in relation to the condition of the recipient at the time.
 Purity – Purity means relative freedom from extraneous matter in the finished product,
whether or not harmful to the recipient or deleterious to the product. Purity includes, but
is not limited to, relative freedom from residual moisture or other volatile substances and
pyrogenic substances.

 Potency – Potency is interpreted to mean the specific ability or capacity of the product, as
indicated by appropriate laboratory tests or by adequately controlled clinical data
obtained through the administration of the product in the manner intended, to effect a given
result.
2. CBER or CDER

 An applicant must determine which division of the FDA to submit its application, as the
Center for Biologics Evaluation and Research (CBER) and the Center for Drug
Evaluation and Research (CDER) share responsibility for BLAs.

 CBER regulates: (i) allergenics; (ii) blood and blood components, including
pharmaceutical products made from blood; (iii) devices (used to safeguard blood, blood
components and cellular products from HIV, hepatitis, syphilis and other infectious agents:
reagents used to type blood; machines and related software used to collect blood and blood
components); (iv) gene therapy; (v) human tissues and cellular products; (vi) vaccines; and
(vii) xentranspalantation products (i.e. use of live animal cells, tissues or organs to treat
human diseases).

 CDER regulates: (i) monocolonal antibodies for in vivo use; (ii) proteins intended for
therapeutic use that are extracted from plants, animals or microorganisms, including
recombinant versions of these products; and (iii) other non-vaccine therapeutic
immunomodulators.

3) Archival and Review Copies of BLA

 Federal regulations require the submission of two copies of a BLA – archival and review.

 The archival copy is a complete copy of an application submission and must be bound in a
BLUE cover jacket.

 The archival copy should include a cover letter to: (i) confirm any agreements or
understandings between the FDA and the applicant; (ii) identify a contact person regarding
the application; (iii) identify the reviewing division of the FDA and the HFD number; and
(iv) convey any other important information about the application.
 The review copy is divided into six technical sections (“review sections”) and should be
submitted with each review section separately bound in a specific color: (i) Chemistry,
Manufacturing and Controls (CMC) – RED; (ii) Nonclinical Pharmacology and
Toxicology – YELLOW; (iii) Human Pharmacokinetics and Bioavailability – ORANGE;
(iv) Microbiology (if required) – WHITE; (v) Clinical Data – LIGHT BROWN; (vi)
Statistical – GREEN.
 Each review section should contain the following:
  (i) a copy of the cover letter attached to the archival copy;
 (ii) a completed (application form FDA 356h;
 (iii) a copy of the summary (defined below);
 (iv) a copy of the general index of the entire application;
 (v) an index specific to that particular review section;
 (vi) letters of reference or authorization, if appropriate; and
 (vii) patent information.

 Applicants may request supplies of the jackets (with appropriate color coding) from the
FDA or an applicant may obtain jackets from commercial sources if it meets FDA
specifications.

4. The Application Form

 Every application must be accompanied by a completed application form FDA 356h.

 The application form should be signed by the applicant, or the applicant’s attorney, agent
or other authorized official.

 If the person signing the application form does not reside or have a place of business within
the U.S., the application must contain the name and address of, and be countersigned by,
an attorney, agent or other authorized official who resides or maintains a place of business
within the U.S.

 The application form along with the cover letter, letters of authorization (if any), Index and
Summary should be packaged together and bound in a single volume. These items will
also be included with each separate review section.

 Patent information on the applicant’s drug and any patent certification with respect to the
drug should be submitted on a separate piece of paper and attached to the application
form.

5. Index

 An application must contain an index of all the elements of the application.

 For each element of the application, the index must identify the volume and page number.
 Each review section must contain an index specific to that review section.
6. Summary

 An application must contain a summary, usually between 50 to 200 pages in length (no
actual page requirements), integrating all of the information in the application and
providing a general understanding of the drug and its application.
 The summary should be written in approximately the same level of detail required for
publication in recognized scientific and medical journals.

 The summary must present the most important information about the biologic and the
conclusions to be drawn from this information, a factual summary of safety and
effectiveness data and a neutral analysis of this data, an annotated copy of the proposed
labeling, a discussion of the product’s benefits and risks, a description of the foreign
marketing history of the drug (if any) and a summary of each technical section.

7. Chemistry Section

 Chemistry, Manufacturing and Controls Section (CMC) – An application must present

chemistry, manufacturing and control information for both the drug substance
(unformulated active substance which may be subsequently formulated with excipients to
produce the drug product) and the drug product (the finished dosage from of the product).

 CMC for Drug Substance – Production of a drug substance, whether by fermentation,

cultivation, isolation or synthesis, usually starts with raw materials. The quality and purity
of the drug substance cannot be assured solely by downstream testing, but depends on
proper control of the manufacturing and synthetic process as well. The CMC for drug
substance should include the following information: (i) description and characterization;
(ii) manufacturer; (iii) method of manufacture; (iv) process controls; (v) manufacturing
consistency; (vi) drug substance specification; (vii) reprocessing; (viii) container and
closure system; and (ix) drug substance stability.

 CMC for Drug Product – This section should contain information on the final drug product
including all drug substances and excipients (inactive components) in the final product.
The CMC for drug product should include the following information: (i) composition and
characterization; (ii) manufacturer and facilities; (iii) manufacturing methods; (iv) drug
product specifications; (v) container and closure system;
(vi) microbiology; (vii) lyophilization; and (viii) drug product stability.
8. Establishment Description
 General Information – For each manufacturing location, a floor diagram should be included
in the application. In the floor diagram, and/or in an accompanying narrative, the following
information should be provided: (i) product, personnel, equipment, waste and air flow; (ii)
illustration or indication of which areas are served by each air handling unit; and (iii) air
pressure differentials between adjacent areas.

 Water System
 HVAC System

 Computer Systems

 Contamination/Cross Contamination Issues

9. Nonclinical Pharmacology and Toxicology Section

 An application should list all nonclinical studies, with volume and page numbers, in the
application’s table of contents and replicated at the beginning of this review section.

 A pharmacology/toxicology summary is required as part of the application and should

provide an integrated discussion of all pertinent findings, including interstudy and
interspecies comparisons, with appropriate cross-references to the review section.
 Data location cross-references should be included when correlations or comparisons are
made among different types of data.

 A recommended order for submission of various types of studies is: (i) Pharmacology
Studies; (ii) Acute Toxicity Studies; (iii) Multipledose Toxicity Studies; (iv) Special
Toxicity Studies; (v) Reproduction Studies; (vi) Mutagenicity Studies; and (vii)
Absorption, Distribution, Metabolism, Excretion (ADME) Studies.
 Reports of studies related to safety should contain a GLP (Good Laboratory Practice)
statement.

10. Human Pharmacokinetics and Bioavailability Section

 Typically, an application should include in the Biopharmaceutics Section studies of five
general types:

(i) Pilot or Background Studies; (ii) Bioavailability/Bioequivalence Studies; (iii)

Pharmacokinetic Studies;
(iv) Other In Vivo Studies; and (v) In Vitro Studies.

 The section should include the following information: (i) a summary of studies; (ii) a
summary of data

and overall conclusion; (iii) drug formulation: (iv) analytical methods; (v) dissolution; and (vi)
individual study reports format and other considerations.

11. Microbiology Section (necessary only for submissions to CDER and if anti-infective
agent)

 The application should include a technical section describing: (i) the biochemical basis of
the drug’s action on physiology; (ii) the antimicrobial spectrum of the drug, including
results of in vitro preclinical studies demonstrating concentrations of the drug required for
effective use; (iii) any known mechanisms of resistance to the drug including results of any
known epidemiologic studies demonstrating prevalence of resistance factors; and (iv)
clinical microbiology laboratory methods needed to evaluate effective use of the drug.

12. Clinical Data Section

 The application should generally describe the clinical investigations of the drug, including
the following:

(i) a description and analysis of each clinical pharmacology study of the drug; (ii) a description
and analysis of each controlled clinical study pertinent to a proposed use of the drug, including the
protocol and a description of the statistical analyses used to evaluate the study; (iii) a description
of each uncontrolled clinical study, a summary of the results and brief statement explaining why
the study is classified as uncontrolled; (iv) a description and analysis of any other data or
information relevant to an evaluation of the safety and effectiveness of the drug product obtained
by the applicant from any source including information derived from clinical investigations,
commercial marketing experience, reports in the scientific literature and unpublished scientific
papers; (v) an integrated summary of the data demonstrating substantial evidence of effectiveness
for the claimed indications; (vi) a summary and updates of safety information; (vii) a description
and analysis of studies or information related to abuse of the drug; (viii) an integrated summary of
the benefits and risks of the drug;

13. Statistical Section

  The application should include a statistical evaluation of clinical data, including the
following: (i) information concerning the description and analysis of each controlled
clinical study, and the documentation and supporting statistical analyses used in evaluating
the controlled clinical studies; (ii) information concerning a summary of information about
the safety of the drug product, and the documentation and supporting statistical analyses
used in evaluating the safety information.

14. Case Report Forms and Tabulations

 An applicant should submit case reports for: (i) all patients who died during a clinical study;
and (ii) patients who did not complete a study because of any adverse event, whether or
not the adverse event is considered drug related by the investigator or sponsor, including
patients receiving reference drugs or placebo.

 An applicant must submit case report tabulations for individual patients for: (i) the initial
clinical pharmacology studies; (ii) the adequate and well-controlled clinical studies; and
(iii) the safety data.

15. Labeling

 Container Label – The container label should include: (i) the proper name of the product;
(ii) the name, address and license number of the manufacturer; (iii) the lot number or other
lot identification; (iv) the expiration date; (v) the recommended individual dose, for
multiple dose containers; (vi) the statement “Rx only” for prescription biologicals; and (vii)
if a Medication Guide is required, then a statement instructing the authorized dispenser to
provide a Medication Guide to each patient to whom the drug is dispensed.
 Package Label – The package label should include: (i) the proper name of the product; (ii)
the name, address and license number of the manufacturer; (iii) the lot number or other
lot identification; (iv) the expiration date; (v) the preservative used and its concentration,
or if no preservative is a safety factor, the words “no preservative”; (vi) the number of
containers, if more than one; (vii) the amount of product in the container expressed as
number of doses, volume, units of potency, weight, equivalent volume or such combination
of the foregoing as needed for an accurate description of the contents, whichever is
applicable; (viii) the recommended storage temperature; (ix) the words “Shake Well,” “Do
Not Freeze” or the equivalent, as well as other instructions, when indicated by the character
of the product; (x) the recommended individual dose if the enclosed container(s) is a
multiple-dose container; (xi) the route of administration recommended, or reference to such
directions in an enclosed circular; (xii) known sensitizing substances, or reference to an
enclosed circular containing appropriate information; (xiii) the type and calculated amount
 of antibiotics added during manufacture; (xiv) the inactive ingredients when a safety factor;
(xv) the adjuvant; (xvi) the source of the product when a factor in safe administration; (xvii)
the identity of each microorganism used in manufacture, and, where applicable, the
production medium and the method of inactivation

16. Patent Information

 An applicant must submit information on each patent that claims the drug or a method of
using the drug that is the subject of the BLA and with respect to which a claim of patent
infringement could reasonably be asserted.
An applicant must submit basic information about each patent, including the following: (i)
patent number and the date on which the patent will expire; (ii) type of patent; (iii) name of patent
owner; (iv) if the patent owner or applicant does not reside or have a place of business within the
U.S., the name of the agent of the patent owner or applicant who resides or maintains a place of
business within the U.S. authorized to receive notice of patent certification.