IND APPLICATION TEMPLATE: CMC section

  IND APPLICATION TEMPLATE:
 CHEMISTRY, MANUFACTURING AND CONTROL INFORMATION

D.   Chemistry, Manufacturing and Control Information 1.   Introduction:
 1.1  Potential human risk(s) Indicate if 1) the chemistry of either the investigational drug substance (i.e., the active ingredient) or the investigational drug product, or 2) the manufacturing process for either the investigational drug substance or investigational drug product, presents any signals of potential human risk.  If so, discuss the signals of potential risks; to include a description of the steps proposed to monitor for such risk(s), or the reason(s) why the signals should be dismissed. 1.2  Chemistry and manufacturing: Pre-clinical versus clinical studies Describe any chemistry or manufacturing differences between the investigational drug product proposed for clinical research study use versus the investigational drug product that was used in the pre-clinical (i.e, animal) toxicology studies that formed the basis that it was safe to proceed with the clinical research study.  If there are no differences in the investigational drug product, this should be specifically stated.  If there are differences in the investigational drug product, discuss how these differences may affect the safety profile of the investigational drug product. 2.  Investigational Drug Substance: 2.1   Description of investigational drug substance
 Provide a description of the investigational drug substance (i.e., the active drug substance); including its physical, chemical (e.g., chemical name and/or structure), or biological characteristics. 2.2  Manufacturer of the investigational drug substance Provide the name and full address of the manufacturer of the investigational drug substance. Specify if the manufacture of the investigational drug substance was or was not (will or will not be) performed in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards at 21 CFR Part 211.  If so, include with the manufacturer’s address, its FDA Drug Establishment Registration Number. 2.3   Method of preparation of the investigational  drug substance
 For an investigational drug substance manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Provide a detailed flow diagram of the process for manufacture of the investigational drug substance; and incorporate a list of the components (i.e., reagents, solvents, excipients, catalysts, etc.) used in the manufacturing process.  (Note: Step-by-step procedures for, and a listing of the specifications and quantities of the components used in, the manufacture of the investigational drug substance are ordinarily not required to be included in the IND application for the initial stage of drug development; as it is assumed that the manufacturer will establish such procedures and specifications consistent with cGMP compliance.) Alternately, if the cGMP manufacturer of the investigational drug substance has submitted, or will submit, a respective Drug Master File to the FDA (or if the manufacturer has in place a FDA-accepted IND for the investigational drug substance/product), incorporate (i.e., into a referenced appendix of the IND application) a letter or written notification from the manufacturer authorizing the FDA to access its Drug Master File (or IND) in support of the chemistry, manufacturing and control information required to be submitted under this IND application. If the investigational drug product is approved by the FDA for commercial marketing, specify such and incorporate (i.e., into a referenced appendix of the IND application) the corresponding FDA-approved product labeling (i.e., product insert). For an investigational drug substance not  manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Provide a flow diagram of the process for manufacture of the investigational drug substance. Incorporate Drug Master Card(s) listing the components (i.e., reagents, solvents, excipients, catalysts, etc.) used currently in the manufacture of the investigational drug substance; to include, for each listed agent, its manufacturer or source, product specifications, and quantity used in the manufacture.  (See Example Drug Master Card.1)
 (Note: the Drug Master Card(s) may provide for alternative manufacturers of inactive components used in the manufacture of the investigational drug substance.)(Note: for novel components [i.e., non-commercially available components manufactured specifically for use in the preparation of the investigational drug substance] additional manufacturing information may need to be provided.(See Example Drug Master Card.2)
 Incorporate Drug Master Card(s) listing the step-by-step procedures used currently for the manufacture of the investigational drug substance.  (See Example Drug Master Card.1) 2.4   Acceptable limits and analytical methods use to assure the identity, strength, quality and purity of the investigational drug substance
 For an investigational drug substance manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Specify the acceptable limits of identity, strength, quality and purity that will form the basis for the release/acceptance of the investigational drug substance for its use in the preparation of the investigational drug product. Provide a brief description of the various test (i.e., analytical) methods that are (will be) used to establish that the investigational drug substance meets the defined, acceptable limits of identity, strength, quality and purity.  (Note: Validation procedures/data for the test (i.e., analytical) methods are ordinarily not required to be included in the IND application for the initial stage of drug development; as it is assumed that the manufacturer will perform such validation procedures consistent with cGMP compliance.) Provide copies of analytical data verifying that the manufacturing process results in an investigational drug substance that meets or exceeds the specified, acceptable limits of identity, strength, quality and purity. Submit a copy of the “certificate of analysis” that will form the basis for release/acceptance of the investigational drug substance for its use in the preparation of the investigational drug product.  Alternately, if the cGMP manufacturer of the investigational drug substance has submitted, or will submit, a respective Drug Master File to the FDA (or if the manufacturer has in place a FDA-accepted IND for the investigational drug substance/product), incorporate (i.e., into a referenced appendix of the IND application) a letter or written notification from the manufacturer authorizing the FDA to access its Drug Master File (or IND) in support of the chemistry, manufacturing, and control information required to be submitted under this IND application. Submit a copy of the “certificate of analysis” that will form the basis for release/acceptance of the investigational drug substance for its use in the preparation of the investigational drug product. Alternately, if the investigational drug product is approved by the FDA for commercial marketing, specify such and incorporate (i.e., into a referenced appendix of the IND application) the corresponding FDA-approved product labeling.  For an investigational drug substance not  manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Specify the acceptable limits of identity, strength, quality and purity that will form the basis for the release/acceptance of the investigational drug substance for its use in the preparation of the investigational drug product. Provide a description of the various test (i.e., analytical) methods that will be used to establish that the investigational drug substance meets the defined, acceptable limits of identity, strength, quality and purity.  Summarize the procedures that will be used to verify the correct operation of the respective analytical equipment. Provide copies of analytical data verifying that the manufacturing process results in an investigational drug substance that meets or exceeds the specified, acceptable limits of identity, strength, quality and purity. Submit a copy of the Drug Master Card(s) outlining the acceptable limits of identity, strength, quality and purity and corresponding test (i.e., analytical) methods that will form the basis for release/acceptance of the investigational drug substance for its use in the preparation of the investigational drug product.  (See Example Drug Master Card.1) 2.5   Information to support the stability of the investigational drug substance
     For an investigational drug substance manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Specify the expiry period assigned currently to the investigational drug substance.  (Note: If stability of the investigational drug substance is continuing to be studied for the purpose of extending the current assigned expiry period, indicate such and state that the assigned expiry period may be revised based on the results of the ongoing stability study.) Provide a brief description of the stability study and the test (i.e., analytical) methods that were used to monitor the stability of the investigational drug substance.  (Note: The stability study should involve storage of the investigational drug substance in the final container/closure system specified in its manufacturing process and under environmental conditions specified in the product labeling.  The extent of the test methods used to monitor the stability of the investigational drug substance should be sufficient to verify that the specified, acceptable limits of identity, strength, quality and purity are retained throughout the assigned expiry period.) (Note: There is no need to submit the actual stability study protocol.) Summarize, in tabular or graphical format, the data supporting the expiry period assigned currently to the investigational drug substance.  (Note: There is no need to submit detailed stability data.) Alternately, if the cGMP manufacturer of the investigational drug substance has submitted, or will submit, a respective Drug Master File to the FDA (or if the manufacturer has in place a FDA-accepted IND for the investigational drug substance/product), incorporate (i.e., into a referenced appendix of the IND application) a letter or written notification from the manufacturer authorizing the FDA to access its Drug Master File (or IND or NDA) in support of the chemistry, manufacturing, and control information required to be submitted under this IND application. Alternately, if the investigational drug product is approved by the FDA for commercial marketing, specify such and incorporate (i.e., into a referenced appendix of the IND application) the corresponding FDA-approved product labeling (i.e., product insert). For an investigational drug substance not manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Specify the expiry period assigned currently to the investigational drug substance.  (Note: If stability of the investigational drug substance is continuing to be studied for the purpose of extending the current assigned expiry period, indicate such and state that the assigned expiry period may be revised based on the results of the ongoing stability study.) Provide a brief description of the stability study and the test (i.e., analytical) methods that were used to monitor the stability of the investigational drug substance.  (Note: The stability study should involve storage of the investigational drug substance in the final container/closure system specified in its manufacturing process and under environmental conditions specified in the product labeling.  The extent of the test methods used to monitor the stability of the investigational drug substance should be sufficient to verify that the specified, acceptable limits of identity, strength, quality and purity are retained throughout the assigned expiry period.) (Note: There is no need to submit the actual stability study protocol.) Summarize, in tabular or graphical format, the data supporting the expiry period assigned currently to the drug substance.  (Note: There is no need to submit detailed stability data.) 3.   Investigational drug product:
         3.1  Description of the investigational drug product
 Provide a description of the of the investigational drug product (i.e., the final formulation of the investigational drug that will be used in clinical research studies) 3.2  Manufacturer of the investigational drug product Provide the name and full address of the manufacturer of the investigational drug product. Specify if the manufacture of the investigational drug product was or was not (will or will not be) performed in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards.  If so, include with the manufacturer’s address, its FDA Drug Establishment Registration Number. 3.3 Components used in the manufacture of the investigational drug product For an investigational drug product manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Provide a list of all components used in the manufacture of the investigational drug product; including both those components that are intended to appear in the final product and those components that are not intended to appear in the final product (i.e., but which were used in the manufacturing process).  For each of the inactive components, include a reference to its quality specification (e.g., USP, NF, ACS) (Note: this list may include reasonable alternatives for inactive components used in the manufacture of the investigational drug product.) Alternately, if the cGMP manufacturer of the investigational drug product has submitted, or will submit, a respective Drug Master File to the FDA (or if the manufacturer has in place a FDA-accepted IND for the investigational drug substance/product), incorporate (i.e., into a referenced appendix of the IND application) a letter or written notification from the manufacturer authorizing the FDA to access its Drug Master File (or IND) in support of the chemistry, manufacturing and control information required to be submitted under this IND application. Alternately, if the investigational drug product is approved by the FDA for commercial marketing, specify such and incorporate (i.e., into a referenced appendix of the IND application) the corresponding FDA-approved product labeling (i.e., product insert). For an investigational drug product not manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Incorporate Drug Master Card(s) listing all of the components (including the investigational drug substance) used currently in the manufacture of the investigational drug product; to include, for each listed component, its manufacturer, quality specification (e.g., USP, NF, ACS), and quantity used in the preparation.  (See Example Drug Master Card.1)
 (Note: the Drug Master Card(s) may provide for alternative manufacturers of inactive components used in the manufacture of the investigational drug product.)(Note: for novel components [i.e., non-commercially available components manufactured specifically for use in the preparation of the investigational drug product] additional manufacturing information may need to be provided.(See Example Drug Master Card.2)
 Describe the procedures (e.g., inspection of the “certificate of analysis” provided by the manufacturer, defined identity test(s)) that will be used to verify that the investigational drug substance meets acceptable standards of identity, strength, quality and purity for use in the manufacture of the investigational drug product. Describe the procedures (e.g., inspection of the product label and/or the “certificate of analysis” provided by the manufacturer) that will be used to verify that the inactive components used in the manufacture of the investigational drug product meet or exceed defined quality specifications. 3.4  Quantitative composition of the investigational drug product For an investigational drug product manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Summarize the quantitative composition of the investigational drug product.  I.e., address the quantity of the investigational drug substance and the quantities of components that are intended to appear in the investigational drug product.  (Note: For components used in the manufacture of the investigational drug product, but which are not intended to appear in the final product, describe the manufacturing processes or procedures that result in the elimination of these components.) Alternately, if the cGMP manufacturer of the investigational drug product has submitted, or will submit, a respective Drug Master File to the FDA (or if the manufacturer has in place a FDA-accepted IND for the investigational drug product), incorporate a letter or written notification from the manufacturer authorizing the FDA to access its Drug Master File (or IND) in support of the chemistry, manufacturing and control information required to be submitted under this IND application. Alternately, if the investigational drug product is approved by the FDA for commercial marketing, specify such and incorporate (i.e., into a referenced appendix of the IND application) the corresponding FDA-approved product labeling (i.e., product insert). For an investigational drug product not manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Summarize the quantitative composition of the investigational drug product.  I.e., address the quantity of the investigational drug substance and the quantities of components that are intended to appear in the investigational drug product. (Note:  For components used in the manufacture of the investigational drug product, but which are not intended to appear in the final product, describe the manufacturing processes or procedures that result in the elimination of these components.) 3.5  Method of manufacture and final packaging of the investigational drug product For an investigational drug product manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Provide a detailed flow diagram of the process for manufacture and packaging of the investigational drug product.  (Note: For sterile investigational drug products, the flow diagram should address the sterilization process.) (Note: Step-by-step procedures used for the manufacture and packaging of the investigational drug product are ordinarily not required to be included in the IND application for the initial stage of drug development; as it is assumed that the manufacturer will establish such procedures consistent with cGMP compliance.) Alternately, if the cGMP manufacturer of the investigational drug product has submitted, or will submit, a respective Drug Master File to the FDA (or if the manufacturer has in place a FDA-accepted for the investigational drug product), incorporate a letter or written notification from the manufacturer authorizing the FDA to access its Drug Master File (or IND) in support of the chemistry, manufacturing and control information required to be submitted under this IND application. Alternately, if the investigational drug product is approved by the FDA for commercial marketing, specify such and incorporate (i.e., into a referenced appendix of the IND application) the corresponding FDA-approved product labeling (i.e., product insert). For an investigational drug product not manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Incorporate Drug Master Card(s) listing the step-by-step procedures used currently for the preparation and packaging of the investigational drug product; to include, for sterile investigational drug  products, the procedures for sterilization of the product.  (See Example Drug Master Card.1)
 3.6  Acceptable limits and analytical methods use to assure the identity, strength, quality and purity of the investigational drug product For an investigational drug product manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Specify the acceptable limits of identity, strength, quality and purity that will form the basis for the release of the investigational drug product for human use. Provide a brief description of the various test (i.e., analytical) methods that will be used to establish that the investigational drug product meets the defined, acceptable limits of identity, strength, quality and purity. (Note: The test [i.e., analytical] methods that should be submitted will vary according the dosage form of the investigational drug product.  For example, for sterile products, the sterility and bacterial endotoxin (i.e., pyrogen) test methods should be submitted.) (Note: Validation procedures/data for the test [i.e., analytical] methods are ordinarily not required to be included in the IND application for the initial stage of drug development; as it is assumed that the manufacturer will perform such validation procedures consistent with cGMP compliance.) Provide copies of analytical data verifying that the manufacturing process results in an investigational drug product that meets or exceeds the specified, acceptable limits of identity, strength, quality and purity. Alternately, if the cGMP manufacturer of the investigational drug product has submitted, or will submit, a respective Drug Master File to the FDA (or if the manufacturer has in place a FDA-accepted IND for the investigational drug product), incorporate (i.e., into a referenced appendix of the IND application) a letter or written notification from the manufacturer authorizing the FDA to access its Drug Master File (or IND) in support of the chemistry, manufacturing, and control information required to be submitted under this IND application. Alternately, if the investigational drug product is approved by the FDA for commercial marketing, specify such and incorporate (i.e., into a referenced appendix of the IND application) the corresponding FDA-approved product labeling. Submit a copy of the “certificate of analysis” that will form the basis for release/acceptance of the investigational drug product for use in the clinical research study. For an investigational drug product not  manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Specify the acceptable limits of identity, strength, quality and purity that will form the basis for the release of the investigational drug product for use in the clinical research study. Provide a description of the various test (i.e., analytical) methods that will be used to establish that the investigational drug product meets the defined, acceptable limits of identity, strength, quality and purity.  Summarize the procedures that will be used to verify the correct operation of the respective analytical equipment. (Note: The test (i.e., analytical) methods that should be submitted will vary according the dosage form of the investigational drug product.  For example, for sterile products, the sterility and bacterial endotoxin (i.e., pyrogen) test methods should be submitted.) Provide copies of analytical data verifying that the manufacturing process results in an investigational drug product that meets or exceeds the specified, acceptable limits of identity, strength, quality and purity. Submit a copy of the Drug Master Card(s) outlining the acceptable limits of identity, strength, quality and purity and corresponding test (i.e., analytical) methods that will form the basis for release of the investigational drug product for human use.  (See Example Drug Master Card.1)
 3.7  Information to support the stability of the investigational drug product For an investigational drug substance manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Specify the expiry period assigned currently to the investigational drug product.  (Note: If stability of the investigational drug substance is continuing to be studied for the purpose of extending the current assigned expiry period, indicate such and state that the assigned expiry period may be revised based on the results of the ongoing stability study.) Provide a brief description of the stability study and the test (i.e., analytical) methods that were used to monitor the stability of the investigational drug product.  (Note: The stability study should involve storage of the investigational drug product in the final container/closure system specified in its manufacturing process and under environmental conditions specified in the product labeling.  The extent of the test methods used to monitor the stability of the investigational drug product should be sufficient to verify that the specified, acceptable limits of identity, strength, quality and purity are retained throughout the assigned expiry period.) (Note: There is no need to submit the actual stability study protocol.) Summarize, in tabular or graphical format, the data supporting the expiry period assigned currently to the investigational drug product.  (Note: There is no need to submit detailed stability data.) Alternately, if the cGMP manufacturer of the investigational drug product has submitted, or will submit, a respective Drug Master File to the FDA (or if the manufacturer has in place a FDA-accepted IND for the investigational drug substance/product), incorporate (i.e., into a referenced appendix of the IND application) a letter or written notification from the manufacturer authorizing the FDA to access its Drug Master File (or IND or NDA) in support of the chemistry, manufacturing, and control information required to be submitted under this IND application. Alternately, if the investigational drug product is approved by the FDA for commercial marketing, specify such and incorporate (i.e., into a referenced appendix of the IND application) the corresponding FDA-approved product labeling (i.e., product insert). For an investigational drug substance not manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Specify the expiry period assigned currently to the investigational drug product.  (Note: If stability of the investigational drug product is continuing to be studied for the purpose of extending the current assigned expiry period, indicate such and state that the assigned expiry period may be revised based on the results of the ongoing stability study.) Provide a brief description of the stability study and the test (i.e., analytical) methods that were used to monitor the stability of the investigational drug product.  (Note: The stability study should involve storage of the investigational drug product  in the final container/closure system specified in its manufacturing process and under environmental conditions specified in the product labeling.  The extent of the test methods used to monitor the stability of the investigational drug product should be sufficient to verify that the specified, acceptable limits of identity, strength, quality and purity are retained throughout the assigned expiry period.) (Note: There is no need to submit the actual stability study protocol.) Summarize, in tabular or graphical format, the data supporting the expiry period assigned currently to the investigational  drug product.
 (Note: There is no need to submit detailed stability data.) 4.  Investigational drug product labels and labeling For an investigational drug product manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Submit a mock-up or printed representation of the label that will be attached to the container of the investigational drug product. (Note: the product container label should contain, at a minimum, the name and address of the manufacturer; the identify of the investigational drug substance; the quantity of the investigational drug substance per unit (e.g.,capsule or tablet) or volume; the assigned batch or lot number; the specifications of “sterile” and “pyrogen-free” (if applicable); the conditions for appropriate storage of the product; the expiration date; and the statement, “Caution: New Drug – Limited by Federal (or United States) law to investigational use.”) Submit, if applicable, any additional labeling materials that will be provided to the investigators involved in clinical studies of the investigational drug product. (Note: The labeling of the investigational drug product shall not bear any statement that is false or misleading and shall not represent that the product is safe or effective for the purposes for which it is being investigated.) Alternately, if the cGMP manufacturer of the investigational drug product has submitted, or will submit, a respective Drug Master File to the FDA (or if the manufacturer has in place a FDA-accepted IND for the investigational drug product), the product container label information may be addressed by incorporating (i.e., into a referenced appendix of the IND application) a letter or written notification from the manufacturer authorizing the FDA to access its Drug Master File (or IND or NDA) in support of chemistry, manufacturing and control information required to be submitted under this IND application.) Alternately, if the investigational drug product is approved by the FDA for commercial marketing, specify such and incorporate (i.e., into a referenced appendix of the IND application) the corresponding FDA-approved product labeling (i.e., product insert). For an investigational drug product not manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Submit a mock-up or printed representation of the label that will be attached to the container of the investigational drug product. (Note: the product container label should contain, at a minimum, the name and address of the manufacturer; the identity of the investigational drug substance; the quantity of the investigational drug substance per unit (e.g.,capsule or tablet) or volume; the assigned batch or lot number; the specifications of “sterile” and “pyrogen-free” (if applicable); the conditions for appropriate storage of the product; the expiration date; and the statement, “Caution: New Drug – Limited by Federal (or United States) law to investigational use.”) Submit, if applicable, any additional labeling materials that will be provided to the investigators involved in clinical studies of the investigational drug product. (Note: The labeling of the investigational drug product shall not bear any statement that is false or misleading and shall not represent that the product is safe or effective for the purposes for which it is being investigated.) 5.  Placebo: composition, manufacture, and control information (Incorporate only if applicable)
 Provide a description of the placebo that will be used in the clinical research study (studies) including its physical, chemical (e.g., chemical identity and/or structure), or biological characteristics. Identify the manufacturer of the placebo product; to include the manufacturer’s full address.   Specify if the manufacture of the placebo product was or was not (will or will not be) performed in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards.  If so, include with the manufacturer’s address, its FDA Drug Establishment Registration Number. For a placebo product manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Provide a flow diagram of the process for manufacture and packaging of the placebo product; and incorporate a list of all of the components used in the manufacturing process.  (Note: For a sterile placebo product, the flow diagram should address the sterilization process.) Summarize the quantitative composition of the placebo product.  I.e., address the quantity of the placebo substance and the quantities of any components that are intended to appear in the placebo product.  For any components used in the manufacture of the placebo product, but which are not intended to appear in the final product, describe the manufacturing processes or procedures that result in the elimination of these components. Specify the acceptable limits of quality and purity of that will form the basis for the release of the placebo product for human use; and provide a description of the various test (i.e., analytical) methods that will be used to establish that the placebo product meets these defined limits. (Note: The test (i.e., analytical) methods that should be submitted will vary according the dosage form of the placebo product.  For example, for sterile placebo products, the sterility and bacterial endotoxin (i.e., pyrogen) test methods should be submitted.) Provide copies of analytical data verifying that the manufacturing process results in a placebo product that meets or exceeds the specified, acceptable limits of identity, strength, quality and purity. Submit a copy of the “certificate of analysis” that will form the basis for release of the placebo product human use. Provide a copy of the labeling that will be assigned to the placebo product. (Note: the placebo product container label should address, at a minimum, the name and address of the manufacturer; the identity of the placebo product; the assigned batch or lot number; the specifications of “sterile” and “pyrogen-free” (if applicable); the conditions for appropriate storage of the product ;and the expiration date.) Alternately, if the cGMP manufacturer of the placebo product has submitted, or will submit, a respective Drug Master File to the FDA (or if the manufacturer already has in place a FDA-accepted IND that addresses the placebo product), incorporate (i.e., within a referenced appendix to the IND application) a letter or written notification from the manufacturer authorizing the FDA to access its Drug Master File (or IND) in support of the chemistry, manufacturing, and control information for the placebo product. Submit a copy of the “certificate of analysis” that will form the basis for release of the placebo product human use. Alternately, if the placebo product is FDA-approved for commercial marketing, specify such.  No additional information is required For a placebo product not manufactured in full compliance with the FDA’s current Good Manufacturing Practice (cGMP) standards:
 Provide a flow diagram of the process for manufacture and packaging of the placebo product; and incorporate a list of the components (including quality specifications and quantities) used in the manufacturing process.  (Note: For a sterile placebo product, the flow diagram should address the sterilization process.) (Note: Alternately, incorporate Drug Master Card(s) that list the components [including quality specifications and quantities] and step-by-step procedures used in the preparation of the placebo product.) Summarize the quantitative composition of the placebo product.  I.e., address the quantity of the placebo substance and the quantities of any components that are intended to appear in the placebo product.  For any components used in the manufacture of the placebo product, but which are not intended to appear in the final product, describe the manufacturing processes or procedures that result in the elimination of these components. Specify the acceptable limits of quality and purity of that will form the basis for the release of the placebo product for human use; and provide a description of the various test (i.e., analytical) methods that will be used to establish that the placebo product meets these defined limits.   (Note: The test (i.e., analytical) methods that should be submitted will vary according the dosage form of the placebo product.  For example, for sterile placebo products, the sterility and bacterial endotoxin (i.e., pyrogen) test methods should be submitted.) Summarize the procedures that will be used to verify the correct operation of the respective analytical equipment.  Provide copies of analytical data verifying that the manufacturing process results in a placebo product that meets or exceeds the specified, acceptable limits of identity, strength, quality and purity.  Submit a copy of the “certificate of analysis” that will form the basis for release of the investigational drug product human use. (Note: Alternately, submit a copy of the Drug Master Card(s) outlining the acceptable limits of identity, strength, quality and purity and corresponding test (i.e., analytical) methods that will form the basis for release of the placebo product for human use.) Provide a copy of the labeling that will be assigned to the placebo product. (Note: the placebo product container label should address, at a minimum, the name and address of the manufacturer; the identity of the placebo product; the assigned batch or lot number; the specifications of “sterile” and “pyrogen-free” (if applicable); the conditions for appropriate storage of the product; and the expiration date.) 6.  Claim for categorical exclusion from or submission of an environmental assessment Incorporate the following statement, as written, unless there is a reason to believe that the distribution and use of the investigational drug product could have an environmental impact The submission of this IND application qualifies for a categorical exclusion from the requirement to submit an environmental assessment or an environmental impact statement in accordance with 21 CFR Sec. 25.31 (e).   To the Sponsor-Investigator’s knowledge, no extraordinary circumstances exist.           

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Adapted from Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic , Biotechnology-Derived Products; Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research, U.S. Food and Drug Administration; November, 1995.