Early Clinical Trials with Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information

Status: Draft

Date: September 2010

Organization: Center for Biologics Evaluation and Research (CBER)

Target Audience: Drug sponsors submitting Investigational New Drug Applications (INDs) for early clinical trials with live biotherapeutic products (LBPs)

Laws and Regulations Referenced: 
21 CFR 312.2 (a) & (b): Investigational New Drug Applications (INDs) are required for drugs undergoing approval for marketing except those that are already approved for sale and are not seeking new indications or any significant changes to labeling, dosing, route of administration, or advertising of the product.

21 CFR 312.23: Covers required IND content and format.

21 CFR 312.23(a)(1): Sponsors must submit a cover sheet with their IND application.

21 CFR 312.23(a)(7) and 312.23(a)(7)(ii): Covers chemistry, manufacturing, and control (CMC) information (varies according to the scope of the clinical trial).

21 CFR 312.23(a)(7)(iv): INDs must include (a) a description of a drug substance including physical, chemical, and biological characteristics, the name and address of its manufacturer, methods of preparation, and information on stability; (b) a list of all components of the drug products (including reasonable alternatives for inactive compounds) used in the manufacture of the product; (c) a brief description of composition, manufacture, and control of placebos used in the trial; (d) a copy of all labels and labeling to be provided to trial investigators; and (e) a claim for categorical exclusion from the need for environmental analysis or environmental impact statement.

21 CFR 312.23(a)(8): Sponsors must provide adequate pharmacology and toxicology information about an investigational drug, including animal and in vitro studies.

21 CFR 312.3(b): Provides definitions of terms relevant to IND submissions.

21 CFR 312.140(a)(3): INDs for biological products regulated by CBER should be submitted to: Document Control Center (HFM-99), CBER/FDA, 1401 Rockville Pike, Suite 200N, Rockville, Maryland 20852-1448.

21 CFR section 600.3(h)(1): A “virus” is defined as a product containing living cause of an infectious disease.

21 CFR 610.13(a)(1): Each lot of dried biologic drug product must be tested for residual moisture and must not exceed established limits.

21 USC 321(g)(1): A “drug” is defined as a substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of a disease in humans or other animals. Claims made about the ability of a substance to act as a drug must be truthful and not misleading.

42 USC 262: Covers regulation of biological products.

42 U.S.C. 262(i): A biological product is defined as a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.

42 U.S.C. 262(j)
and Section 505 of the Federal Food, Drug, and Cosmetic Act: Interstate commerce of any new drug requires approval from FDA.

501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 351(a)(2)(B)): The manufacture, processing, packing, and holding of a drug must conform to current good manufacturing practices. Otherwise, the drug is considered to be adulterated.


  • Clinical trials: Studies of new drugs or treatments in humans. Also known as Phase 2, 3, and 4 trials. Conducted after non-clinical trials. Requires IND approval from FDA.
  • Live biotherapeutic product (LBP): A virus, therapeutic serum, toxin, antitoxin, blood, blood component or derivative, allergenic product, protein, or analogous product that contains live microorganisms (such as bacteria) and is used to prevent, treat, or cure a disease or condition in humans. This does not include vaccines.
  • Investigational New Drug Application (IND): An application submitted by a sponsor to FDA seeking approval to test a new drug or treatment in humans. Includes data from non-clinical trials.
  • In vitro: Translated literally as “within glass.” In drug development this refers to laboratory tests conducted in test tubes or culture dishes, or otherwise outside any living organism.
  • Non-clinical trials: Studies of new drugs or treatments either in vitro or in animals to determine basic safety information. Often referred to as “Phase 1” studies, they are conducted before trials in humans (Phase 2, 3, and 4 clinical trials) can begin.
  • Sponsor: An individual or organization (often a pharmaceutical company) that takes responsibility for and initiates clinical trials. The sponsor submits applications to FDA including INDs.

Live biotherapeutic products (LBPs) vary widely in where they are sourced, how they have been modified for medical use, what they are used for, how they act in the body, how doses are measured, and how they are administered to patients. As such, clinical trials meant to evaluate whether LBPs can prevent, treat, or cure diseases in humans involve collecting a wide range of types of data. This means the content of Investigational New Drug Applications (INDs) for LBPs are also diverse.

This is a challenge to sponsors of new LBPs because there is no model application they can reference while preparing an IND. Inexperience with LBP filings or in interacting with the Center for Biologics Evaluation and Research (CBER) and US Food and Drug Administration (FDA) compounds the problem.

This Guidance helps sponsors correctly prepare and submit the Chemistry, Manufacturing, and Control (CMC) section of the IND. The advice in the Guidance is meant to reduce the risk of having an application denied due to avoidable mistakes in its preparation.

Before a new drug can be tested in humans, the FDA must approve an IND from the drug’s sponsor. Sponsors submit the IND when they feel they have enough positive data from non-clinical trials (ie, in vitro and animal testing) to justify clinical trials in humans.

The IND is a complex document with many parts, and the data collected during non-clinical trials of new LBPs is widely varied. To help sponsors navigate the IND preparation and submission process, CBER uses the Guidance to give advice on what should be included in the CMC section.

First and foremost, communication with CBER is critical. Pre-IND meetings can help sponsors understand what data to include in their applications and how to present it. These meetings can also help everyone involved anticipate each milestone in the process. Second, applicants are urged to avoid delays by mailing the completed IND in triplicate to the correct address at CBER. Electronic submissions are also possible and are addressed in a separate guidance.

In terms of CMC information, sponsors should start by reading the guidance on Current Good Manufacturing Process (CGMP). Detailed information on the LBP is required including the source and strain, the name and address for the manufacturer, a complete list of active and inactive ingredients, a description of the conditions where the LBP is manufactured, and a plan for preventing contamination from other substances or microbes.

Finally, the Guidance summarizes advice on presenting non-clinical and clinical data.

Sponsors who fail to follow requirements for submitting CMC information in INDs risk having their application denied by the FDA. These unnecessary errors are costly to sponsors and can delay the availability of new drugs. This Guidance is needed to give advice to sponsors who have never worked with CBER, are new to applications involving LBPs, or who simply want to increase their chances of a successful submission.

Resulting Recommendations:

Administrative and Regulatory Procedures

Chemistry, Manufacturing, and Control (CMC) Information

  • Current good manufacturing practices for investigational drugs vary by clinical trial phase. Refer to Guidance for Industry: CGMP for Phase 1 Investigational Drugs.
  • Include a description of the live biotherapeutic product (LBP) with its biological name and strain designations, original source, and documentation of any modifications made.
  • Characterize the LBP (species and strain at a minimum) and include a description of acceptable limits and analytic methods used to assure its identity, strength, quality, and purity. Report actual laboratory data and quantitative information in a table rather than a written summary.
  • Provide the name and address of the manufacturer of the drug plus a comprehensive list of other products that are manufactured or manipulated on the same premises. If there is any possibility of contamination from the sharing of equipment, proximity of production, or extraneous microorganisms, indicate how the equipment will be cleaned between the manufacture of different products. A floor diagram is recommended.
  • Provide a list of all materials used to produce the drug, a flow chart of the manufacturing process, a detailed description of the cell banking procedures, descriptions of how cells are grown and harvested, descriptions of how the drug is purified, and a description of how the drug is sampled and tested during production.
  • Include preliminary specifications and tests for the drug, including assays for identity, purity, microbial contamination, potency, stability, etc.
  • Describe all necessary ingredients, both active and inactive, used in the manufacture of the drug. Include the names and addresses of the manufacturers.

Non-Clinical Information

  • Submit adequate data from pharmacological and toxicological studies in laboratory animals or in vitro to justify evaluation of the LBP in human trials.
  • Consult with CBER to determine how much non-clinical data is considered necessary and adequate.

Clinical Information

  • If submitting third party data from clinical trials involving the same LBP, be sure to obtain all relevant study reports, records, data listings, and documentation of statistical analyses so conclusions can be verified. Be sure to account for final disposition of all trial participants because missing data due to a large number of dropouts, withdrawals, or protocol violations weakens the analysis and conclusions.
  • Define diseases and criteria for milestones (worsening, relapse, improvement) of the disease that are relevant to the population being studied. Refer to the International Conference on Harmonisation (ICH) guidance documents for Efficacy, Joint Safety/Efficacy, Quality, and Safety for information on clinical studies in different populations.

The Guidance helps make the requirements of CBER and FDA more transparent to sponsors of LBPs. Sponsors are therefore less likely to have INDs denied due to avoidable mistakes in the preparation of the application. As a result, costs associated with preparing and submitting INDs are decreased and new drugs that are shown to be suitable for the treatment, cure, and prevention of diseases can be made available faster and more efficiently.

For more information on this issue, contact the Kulkarni Law Firm.