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U.S. Department of Health and Human Services

Animal & Veterinary

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CVM GFI #42 Animal Drug Manufacturing Guidelines- Series of Four Guidelines

Revised 1994

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR VETERINARY MEDICINE

Table of Contents

PILOT BATCH MANUFACTURE

  1. INTRODUCTION
  2. RECOMMENDATIONS FOR NADA's AND ANADA's
  3. RECOMMENDATIONS FOR SUPPLEMENTAL NADA's AND ANADA's

TENTATIVE EXPIRATION DATES

  1. INTRODUCTION
  2. DEFINITIONS
  3. RECOMMENDATIONS FOR ESTABLISHING A TENTATIVE EXPIRATION DATE FOR ANADA's

MANUFACTURING SITES

  1. INTRODUCTION
  2. DEFINITIONS
  3. RECOMMENDATIONS FOR THE SUBMISSION OF APPROPRIATE DATA AND INFORMATION

NEW ANIMAL DRUG SUBSTANCE SOURCES

  1. INTRODUCTION
  2. DEFINITIONS
  3. RECOMMENDATIONS FOR THE SUBMISSION OF APPROPRIATE DATA AND INFORMATION

Animal Drug Manufacturing Guidelines

New Animal Drug Applications
Abbreviated New Animal Drug Applications
Supplemental Applications

I. Pilot Batch Manufacture

II. Tentative Expiration Dates

III. Manufacturing Sites

IV. New Animal Drug Substance Sources

1994
(Revised)

Department Of Health And Human Services
Public Health Service
Food And Drug Administration
Center For Veterinary Medicine

Docket No. #92D-0039

OBJECTIVE:

CVM believes that data and information contained in chemistry/manufacturing submissions in ANADA's for evaluation of generic pharmaceutical dosage forms should be consistent as appropriate with the information being used by the Center for Drug Evaluation and Research (CDER) for the evaluation of abbreviated new drug applications (ANDA's). This consistency will help ensure that marketed generic veterinary pharmaceutical dosage forms meet the same criteria of quality, strength and purity as similar human dosage forms; that FDA can harmonize the review process for veterinary and human pharmaceutical dosage forms; and that FDA district offices can apply the same interpretation of CGMP's to both veterinary and human pharmaceutical dosage form drug products.

There are a number of differences in the type and extent of data necessary for ANADA's and NADA's. For this reason, and to provide consistent recommendations for the different types of submissions, the guidelines describe not only the manufacturing data and information necessary for ANADA's and supplemental ANADA's, but also data and information to support the manufacturing and chemistry sections of NADA's and supplemental NADA's.

These guidelines apply only to pharmaceutical dosage forms (tablets, capsules, ointments, creams, implants, parenterals, etc.). Medicated Articles will be addressed in separate guidelines.

Guidelines are presented to cover the following areas:

I. Pilot Batch Manufacture

II. Tentative Expiration Dates

III. Manufacturing Sites

IV. New Animal Drug Substance Sources

These guidelines are not intended to be individual stand-alone documents. Much of the information presented in one guideline may be equally important to the correct interpretation of the other guidelines. Therefore, all four guidelines are being issued concurrently.

Guidelines state procedures or practices that may be useful to the persons to whom they are directed, but are not legal requirements. Guidelines represent the agency's position on a procedure or a practice at the time of their issuance. A person may follow the guidelines or may choose to follow alternate procedures. If a person chooses to use alternate procedures, that person may wish to discuss the matter further with the agency to prevent an expenditure of money and effort on activities that may later be determined to be unacceptable to FDA. A guideline does not bind the agency, and it does not create or confer any rights, privileges, or benefits for or on any person. Where a guideline states a requirement imposed by statute or regulation, the requirement is law and its force and effect are not changed in any way by virtue of its inclusion in the guideline.

Interested persons may submit written comments on these guidelines to the Dockets Management Branch (address below). Comments will be considered in evaluating the need to amend the guidelines. Comments are available for public examination between 9 a.m. and 4 p.m., Monday through Friday, at the Dockets Management Branch.

Dockets Management Branch (HFA-305)
Room 1-23
Food and Drug Administration
12420 Parklawn Drive
Rockville, MD 20857

GUIDELINE I

Pilot Batch Manufacture

1994
(Revised)
Department Of Health And Human Services
Public Health Service
Food And Drug Administration
Center For Veterinary Medicine

A.Introduction:

The information included in this document is intended to provide guidance for the submission of appropriate manufacturing data and information to support the approval of NADA's, ANADA's, and their supplements. This guideline deals with the minimal acceptable batch size, the number of batches, and the batch manufacturing process.

Since changes in production methods and batch size are known to have the potential to affect a product's bioavailability and stability, the Center has concluded that there needs to be a guideline on batch size and production conditions of test batches. Previously, sponsors have sometimes developed data to support applications using pilot batches that are significantly smaller than the proposed production batch size. Subsequently, these initial pilot batch sizes are scaled-up. As part of this scale-up, both quantitative and qualitative changes in the excipients included in the formulation are sometimes necessary along with changes in the equipment to manufacture the commercial-size batches. These manufacturing changes may raise questions regarding the bioavailability and stability profile of the drug products made in the production batches when compared with the pilot batch of drug product used for the pivotal target animal studies.

This document addresses the relationship between the size of pre-approval test batches and production batches. Also included in this document are recommendations for post-approval demonstration batch size to support requests for the approval of alternate manufacturing sites and alternate sources of new animal drug substance. The batch sizes recommended in this document may be used to support an NADA, ANADA, or their supplements and not cause significant concern regarding differences in bioavailability or stability between the test batch and production batch.

It is necessary for applicants to understand what is meant by a "batch". According to 21 CFR 210.3(b)(2):

"Batch" means a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture.

In this document, the terms pilot batch, test batch and demonstration batch are interchangeable.

Validated, full production batches are the standard for fulfilling current good manufacturing practice (CGMP) requirements. However, the Center recognizes that this is not a practicable situation to use full production batches to support pending applications.

For sterile and nonsterile drug products, validation and documentation of the manufacture of complete production batches of actual product generally takes place after approval of an NADA or ANADA, but must be completed prior to marketing the drug product. Validation of the efficacy of a sterilization process, however, is necessary prior to approval of NADA's and ANADA's. Validation of a sterilization process, in most cases, is not dependent on the manufacture of production batches of actual product. Whether drug products are sterilized by terminal sterilization, or whether parts of the drug product are independently sterilized and aseptically assembled (e.g. aseptic fill), manufacture of actual production batches of product is not usually necessary to scientifically validate the efficacy of the sterilization process(es). Validation of a sterilization process, as distinguished from total manufacturing process validation, may therefore be carried out independently of the manufacture of production batches of actual drug product.

B.RECOMMENDATIONS FOR NADA's AND ANADA's:
  1. GENERAL:

    The following batch recommendations apply to the manufacture of new animal drug and abbreviated new animal drug pharmaceutical dosage form products:

    NADA's - A total of three test batches of drug product should be manufactured.

    ANADA's - One test batch of drug product should be manufactured.

    The test batch is the source from which finished dosage materials should be taken for use in the following:

    1. Pivotal Target Animal Studies
      1. Clinical/bioequivalence studies.
      2. Residue depletion (withdrawal time) studies.
      3. Target animal safety studies.
    2. Stability studies to support the proposed expiration dating period.
    3. Samples submitted to FDA laboratories for methods validation.
    4. Sample retention.
  2. BATCH SIZE:

    Test batches should ordinarily be a minimum of 10 percent of the largest proposed production batch size. This applies to antibiotic and non-antibiotic dosage forms and includes tablets, capsules, ointments, creams, implants, etc.. True solutions may ordinarily be manufactured in pilot batch sizes smaller than 10 percent of the largest proposed production batch size. In these instances, we recommend a protocol be submitted.

  3. EQUIPMENT AND STANDARD OPERATING PROCEDURES:

    The test batch should be produced using comparable equipment (similar operating principles) to the production equipment proposed in the application. The equipment used to manufacture the test batch may have a different (smaller) capacity than the equipment used for the manufacture of a production lot. The production equipment proposed to be used to produce larger scale production batches must be identified and described in the application. If different pieces of equipment were used to produce the test lot than are to be used to produce the full production lot, then a rationale of how the pieces of equipment are believed to be comparable should be developed. This information will normally be assessed by the FDA field investigational staff. In instances where changes in equipment are determined to significantly impact on the process used for the manufacture of the pilot lots, additional bridging data may be requested by the Center.

    The equipment should be operated by individuals qualified by training and experience who otherwise meet the firms standards for personnel qualified to produce marketed pharmaceutical products in full compliance with CGMP's. The standard operating procedures (SOP's) and controls, formulation and manufacturing procedures used on the test batch should be comparable to those used for the full-scale production batches.

  4. PRODUCTION FACILITY:

    The test batch should be manufactured at the proposed production facility when possible. The facility must be in compliance with CGMP's. When there is a change in facilities between that used for the test batch and that proposed for the manufacture of production lots an assessment will be made to determine if the processes differ significantly. This assessment will normally be performed by the FDA field investigational staff. In instances where the processes are determined to differ significantly additional bridging data may be requested by the Center.

    A non-GMP pilot plant or development laboratory facility should not be used for production of the test batch. These facilities may be used in formulation development work or other developmental activities leading up to production of the test batch.

  5. SCALE-UP:

    There should not be any significant changes in the SOP's, controls, and formulation between the test batch and the maximum production batch except: 1) to use larger amounts of each ingredient which are proportional to the test batch, 2) to add the ingredients by automated or mechanical equipment, 3) to adjust mixing and operating speed and times based upon operating recommendations for the size of equipment and appropriate quality controls, or 4) to use alternative equipment of comparable operating principles but of different capacity. Any significant changes should be explained and justified.

    It remains the responsibility of the sponsor to ensure that any scale up does not result in a material change in the method of manufacture. One or more increases in batch size that do not cumulatively result in a proposed production batch size exceeding ten-times the size of the test batch will ordinarily be acceptable to the Center. It is the responsibility of the sponsor to validate the change in batch size. The sponsor must also report the batch size change in the next DER.

    Following approval, a sponsor wishing to increase a batch size beyond the maximum allowable batch size covered in the application (ie., ten-times the size of the test batch) must submit a supplement.

  6. BRIDGING DATA:

    The Center recognizes that the manufacture of full scale production batches to meet filing requirements may be impractical. Therefore, the Center has generally taken the approach that pilot batch sizes meeting the recommendations specified above are generally satisfactory. There are, however, some instances where the recommendations for batch size, production facility, equipment and standard operating procedures described above may not be practicable. In these cases, sponsors may create an alternative plan to demonstrate that the test batches possess bioavailability and stability characteristics comparable to production batches. This plan should be discussed with the Center prior to implementation. For example, if a sponsor does not meet the batch size recommendation, or if the sponsor makes a significant change in SOP's, controls, or formulation between the test batch and production batch; then, the sponsor may provide information (bridging data) to support that the scale up process or the significant change did not impact the products bioavailability or stability. In some cases this may require a bioequivalence bridging study. However, in many cases other data (i.e., dissolution studies, accelerated stability data, etc.) may be deemed adequate to support the change.

C.RECOMMENDATIONS FOR SUPPLEMENTAL NADA's AND ANADA's:
  1. GENERAL:

    The batch size recommendations in this section apply to the approval of an alternate manufacturing site and alternate source of the new animal drug substance. These changes must be submitted in a supplement to an approved application.

    One test batch of drug product should be manufactured to support alternate manufacturing sites and alternate sources of new animal drug substance.

  2. BATCH SIZE:

    Test batches should ordinarily be a minimum of 10 percent of the largest proposed production batch size. This applies to antibiotic and non-antibiotic dosage forms and includes tablets, capsules, ointments, creams, parenterals, implants, etc..

  3. EQUIPMENT AND STANDARD OPERATING PROCEDURES:

    The test batch should be produced using production equipment specified in the application for the production of the marketed lot at the proposed production facility.

    The equipment should be operated by individuals qualified by training and experience who otherwise meet the firm's standards for personnel qualified to produce marketed pharmaceutical products in full compliance with CGMP's. Comparable standard operating procedures and controls as well as comparable formulation and manufacturing procedures should be used on the test batch and on the full-scale production batches.

  4. SCALE-UP:

    There should not be any significant changes in the SOP's, controls, and formulation between the test batch and the maximum production batch except: 1) to use larger amounts of each ingredient which are proportional to the test batch, 2) to add the ingredients by automated or mechanical equipment, or 3) to adjust mixing and operating speed and times based upon operating recommendations for the size of equipment and appropriate quality controls. Any significant change should be explained and justified.

    It remains the responsibility of the sponsor to ensure that any scale up does not result in a material change in the method of manufacture.

GUIDELINE II

TENTATIVE EXPIRATION DATES

1994
(Revised)
DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR VETERINARY MEDICINE

A.INTRODUCTION:

Guidance for establishing a suitable tentative expiration date for NADA's is contained in the current issue of the Center for Veterinary Medicine's Drug Stability Guidelines. This document supplements the guidelines. It is intended to provide guidance for the submission to abbreviated new animal drug applications of appropriate data and information to support the assignment of tentative expiration dating periods. In addition, this guideline contains recommendations for extending tentative expiration dating periods.

The information in this document is applicable to the request for a tentative expiration date for a drug product manufactured at an alternate site (NADA's and ANADA's) when supported by three month accelerated stability data. Ordinarily, the expiration dating established in the application will apply to all manufacturing sites for that drug product.

The design of the stability study is intended to establish, based on testing a batch of drug product, a tentative expiration dating period applicable to future batches of the drug product manufactured under similar circumstances. The test batch should, therefore, be representative in all respects (e.g., formulation, container-closure system, manufacturing process, source and quality of bulk material) to the production batches (refer to I.B. and I.C.) of that drug product and should conform to all product specifications.

B.DEFINITIONS:

Accelerated Testing: Testing designed to increase the rate of chemical or physical degradation of a drug product by using exaggerated storage conditions.

Exaggerated Storage Conditions: These conditions include 37 - 40o C and 75% relative humidity for dosage forms proposed for controlled room temperature storage, and 25o C and ambient humidity for the dosage forms proposed for refrigerated storage. Non-isothermal and higher temperature studies may also be utilized where advisable.

Expiration Dating Period: The interval that a drug product is expected to remain within the approved registration specifications, in the proposed market container, following the date of manufacture. The expiration dating period is used to establish the expiration date of individual batches.

Tentative Expiration Dating Period: A provisional expiration dating period determined by projecting results from less than full-term data (such as, accelerated studies) using the drug product stored in the proposed container/closure system.

Primary Stability Data: Data on the product stored in the proposed container-closure for marketing under storage conditions that support the proposed tentative expiration date, as well as data produced post-approval during on-going stability studies.

Supportive Stability Data: Data other than primary stability data, e.g., data on investigational formulations not proposed for marketing, references to other submissions on file with the agency with appropriate letters of authorization. Supportive stability data may include data for an identical product approved and manufactured in a foreign country.

C.RECOMMENDATIONS FOR ESTABLISHING A TENTATIVE EXPIRATION DATE FOR ANADA's:
  1. GENERAL:

    Primary stability data for ANADA products should be generated on a drug product batch which meets batch size requirements (refer to I. B.).

    Tentative expiration dates based on three month accelerated (exaggerated) stability data will normally be assigned to generic animal drug pharmaceutical dosage forms. This reduced requirement for obtaining tentative expiration dating periods for generic animal drugs is possible since the stability profile of the new animal drug substance and pioneer drug product are known to CVM.

    The proposed generic product will not be assigned the same expiration dating period as the pioneer product on the basis of three month accelerated stability data.

    Accelerated stability testing and long-term room temperature stability testing should be initiated at the time of manufacture of the pilot lot. This lot should be the same batch of drug product on which bioequivalence studies are conducted. Long-term room temperature stability testing should be conducted as recommended in the CVM Drug Stability Guidelines. In the absence of full-term stability data for the drug product, adequate accelerated stability data will be acceptable to establish a tentative expiration dating period.

    Accelerated stability data should be generated at initial, 1, 2, and 3 month test stations. Under certain circumstances, accelerated stability data may be inadequate to support an expiration date. An example of this might be for dosage forms not previously marketed (e.g., those for which FDA approved a suitability petition). Under these circumstances, full term stability data may be required to support the labeled storage conditions. Likewise, generic copies of pioneer products that have a demonstrated history of stability-related problems may be required to place additional pilot lots into the stability program and/or provide extended stability data to support a tentative expiration date.

    A maximum twenty-four month tentative expiration dating period will be considered for generic animal drug pharmaceutical dosage forms submitted with satisfactory 3 month accelerated stability data. These tentative expiration dating periods should also be supported by the results of the long-term room temperature stability testing. The results of long-term stability testing should continue to be submitted throughout the review of the ANADA.

    An expiration date longer than twenty-four months may be proposed. However, requests for expiration dates which are longer than twenty-four months should be supported by additional primary stability data similar to that necessary to support proposed expiration dates for NADA submissions. These data are described in the CVM Drug Stability Guidelines and may include one-year accelerated stability data and shelf-life data approximating the proposed expiration date for three batches of drug product.

    A written stability program, stability commitments, and specific stability testing should be provided. These recommendations are the same for new animal drug applications and abbreviated new animal drug applications. The current issue of the Center for Veterinary Medicine's Drug Stability Guidelines should be referred to for further guidance.

  2. EXPIRATION DATE EXTENSION:

    All requests for the extension of a tentative expiration date for an NADA and ANADA should be supported by a minimum of three production size batches manufactured post-approval and meet the data recommendations described in the CVM Drug Stability Guidelines.

    Statistical evaluation of these data should be performed as recommended below.

  3. STATISTICAL EVALUATION:

    Statistical evaluation data should be provided for both the accelerated and long-term room temperature stability studies on the demonstration batches of drug product (NADA and ANADA).

    When establishing the tentative expiration dating period for a drug product (NADA or ANADA), supporting data are obtained from the observed pattern of degradation for the quantitative drug product characteristic under study (e.g., strength, percent of label claim).

    An acceptable approach for drug characteristics that are expected to decrease with time is to determine the time at which the 95% one-sided lower confidence limit for the mean degradation curve intersects the acceptable lower specification (e.g., strength) limit. If this approach is used, there is a 95% confidence that the average drug product characteristic (e.g., strength) will remain within specifications up to the end of the tentative expiration period. It is not acceptable to determine the allowable expiration dating period by determining where the fitted least-square line intersects the appropriate specification limit. This approach is as likely to overestimate the expiration dating period as to underestimate it, and only provides a 50% confidence that the product characteristic will remain within specification at the tentative expiration date.

    The accelerated data from a generic product will be compared with the degradation profile of the pioneer (on file with the Center). Alternatively, the applicant may wish to provide accelerated stability data for both the pioneer and proposed generic product. The accelerated stability data for the generic product should have a profile similar to that observed for the pioneer product. Furthermore, the long-term stability data, when appropriately analysed, should also support the tentative expiration date.

    There may be cases where the data show so little degradation and variability that it is readily apparent that the tentative expiration dating period can be confirmed. Under these circumstances, it would not be necessary to go through formal calculations. However, this case is the exception rather than the rule, and the final judgment on whether the calculations are necessary lies with the Center. Therefore, it is recommended that the analysis be carried out routinely and that the newest long-term stability data for the pilot batch be submitted throughout the review process.

GUIDELINE III

MANUFACTURING SITES

1994
(Revised)
DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR VETERINARY MEDICINE

A.INTRODUCTION:

The information included in this document is intended to provide guidance for the submission of appropriate data and information to support the approval of primary and alternate manufacturing sites in NADA's, ANADA's, and their supplements.

Sponsors may propose alternate manufacturing sites in their NADA or ANADA submissions. However, it is suggested that a single (primary) manufacturing site be proposed in the original application and that additional alternate manufacturing sites be provided for through the supplemental approval process.

The data and information needed for primary and alternate manufacturing facilities that meet the criteria of a new manufacturing site, as defined below, will be more than for a facility where the same dosage forms as the proposed drug are already being manufactured. For example, it may be necessary to place additional pilot lots into the stability program and/or provide extended stability data to support the proposed expiration date.

All proposed manufacturing facilities in an application should be identified as primary (NADA's and ANADA's) or alternate (NADA's, ANADA's, supplemental NADA's and ANADA's) manufacturing sites. Additionally, a proposed primary or alternate facility should be identified as a new manufacturing site, as defined below; or as a facility where the manufacture of the same dosage form as the proposed drug is already being performed.

B.DEFINITIONS:

Primary Manufacturing Site: The primary manufacturing site is the facility designated for the manufacture of the product in the original application.

Alternate Manufacturing Site: The alternate manufacturing site is an additional facility designated for the manufacture of the drug product. An alternate manufacturing site may be designated in an original submission or may be proposed as an additional facility/facilities after approval of the original application.

New Manufacturing Site: A new manufacturing site is a facility where the manufacturer has no experience with the same dosage form or process for the manufacture of the product

C. RECOMMENDATIONS FOR THE SUBMISSION OF APPROPRIATE DATA AND INFORMATION:
  1. TEST BATCH:

    1. NADA's:
      A total of three batches of drug product (refer to I.B.) should be manufactured for NADA's. The test batches should be manufactured at the proposed production facility when possible. Alternatively, the pilot batches may be manufactured at either the sponsors clinical supplies facility or at a facility under contract to the sponsor. The facility must be in compliance with CGMP's. When there is a change in facility between that used for the test batch and that proposed for the manufacture of production lots an assessment will be made to determine if the processes differ significantly. This assessment will normally be performed by the FDA field investigational staff. In instances where the processes are determined to differ significantly additional bridging studies may be requested by the Center.

      If the sponsor manufactures the pilot lots at the proposed production facilities, then, at least two of the batches should be manufactured at the primary facility. The third batch may be manufactured at a proposed alternate site. With the exception of true solutions, each additional alternate facility should manufacture a batch of drug product.

      A completed batch record should be provided. Additional batch records may be requested.

    2. ANADA's, Supplemental NADA's and ANADA's Footnote/1
      A completed batch record for one batch of drug product meeting minimum batch size requirements, manufactured under production conditions, in the primary facility (ANADA's) and each alternate facility (ANADA's, supplemental NADA's and ANADA's) should be provided. Ordinarily, for true solutions it will not be necessary to manufacture batches at each alternate facility.

      In the case where approval is sought for multiple strengths of a product to be manufactured at an alternate site, and where at least one batch of product has previously been prepared in support of each strength at the primary site, then only one batch of one strength needs to be made at the alternate manufacturing site. This batch should be prepared for the same strength product as would be used in the bioequivalence study.

  2. STABILITY DATA:

    1. NADA's:
      Stability data obtained in accordance with the current issue of the Center for Veterinary Medicine's Drug Stability Guidelines should be included in the new animal drug application.
    2. ANADA's, Supplemental NADA's and ANADA's:
      Three month accelerated (37 - 40deg.C, 75% RH) stability data is recommended for the batch manufactured at the primary (ANADA's) and alternate facility (ANADA's, supplemental NADA's and ANADA's).

      The stability data should be generated on product stored in the market container and should include all appropriate testing as specified in the NADA or ANADA. Accelerated stability data will ordinarily not be requested for the manufacture of true solutions at alternate facilities. Rather, a commitment to place the first three production batches at the alternate facility into the approved stability program will generally be acceptable.

  3. VALIDATION OF STERILIZATION PROCESSES:

    Information and data in support of the efficacy of sterilization processes will be necessary for the primary manufacturing facility (NADA's and ANADA's) and alternate manufacturing facility (NADA's, ANADA's, supplemental NADA's and ANADA's). Validation of sterilization processes should be completed at each manufacturing site prior to the approval of the application.

  4. DISSOLUTION DATA:

    Comparative dissolution data should be submitted where appropriate

  5. BIOEQUIVALENCE DATA:

    Bioequivalence data may be requested where applicable. The Center does not anticipate that bioequivalence studies will be requested unless there are specific concerns regarding the effects that a change to an alternate manufacturing site will have on the bioavailability of the drug product. This assessment will be made on the basis of whether the manufacture of the product at the proposed alternate manufacturing site also involves a change in production equipment, production procedure, and the extent of the total change.

    Milk-out studies (for mastitis products manufactured at the alternate sites) will generally not be necessary. Ordinarily, bridging data may be provided by a comparison of physiochemical data (particle size, viscosity, crystalline structure, etc.). However, when milk out studies are necessary, the submission of protocols prior to the initiation of the studies is strongly recommended.

  6. ENVIRONMENTAL INFORMATION:

    This information should include:

    An environmental assessment (EA) according to 21 CFR 25.31a which addresses the manufacturing at each site should be submitted. The type of information necessary for each manufacturing site is specified in the draft guidance document entitled Environmental Review of Generic Animal Drugs. This guidance document was provided as an attachment to the Center's generic policy letter, dated June 7, 1989. A complete copy of the policy letter and guidance document is available upon written request from the Industry Information Staff (HFV-12), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville MD 20855.

  7. GENERAL INFORMATION:

    1. Stability Program/Commitment:
      A stability commitment consistent with the current issue of the Center for Veterinary Medicine's Drug Stability Guidelines, should be submitted for each facility. The generation of stability data should be as specified in the NADA or ANADA. A commitment to place the first three production lots manufactured at each facility into the approved stability program and to generate stability data at the intervals specified in the approved Stability Protocol in the application, should be provided. The stability commitment should also provide for 3-10% (minimum of one per annum) of the lots manufactured at each facility to be placed into the stability testing program.
    2. Expiration Date:
      An expiration date for product manufactured at the primary and alternate facilities should be proposed. Presumably, for NADA's and ANADA's the initial expiration date will be the same for both primary and alternate facilities since both should be based on equivalent stability data.

      A request for an expiration date for product manufactured at the alternate facility that is based solely on three-month accelerated data should take into consideration that the accelerated stability data required for one batch of drug product manufactured at the alternate facility is the most relevant information supporting the proposed expiration date. Therefore, a request for a tentative 24 month expiration date based on the accelerated stability data for product manufactured at the alternate facility may be appropriate (refer to II. C.).

      These expiration periods may be extended to the previously approved expiration date for product manufactured at the primary facility on the basis of additional stability data generated on product manufactured at the alternate facility. Whether an already approved expiration date can be granted for an alternate site depends on whether there is a change in production equipment, production procedure, and the extent of the total change. Extensions in expiration dating may be considered separately for each site based on stability data generated on product manufactured at the primary and alternate facilities.

    3. Manufacturing Information:
      Information should be submitted for the manufacture of the product at each facility, such as: 1) complete name/address of the actual site of manufacture (the address of the administrative headquarters of the firm may not be substituted), 2) authorization to reference Master Files, 3) name/address of the U.S. agent if a foreign manufacturer is proposed, and a letter of appointment from the manufacturer, 4) facilities, 5) equipment (laboratory and manufacturing), 6) general/specific operations, 7) manufacturing process instructions, 8) sterilization process(es) validation, 9) labels (product and shipping), and 10) certification of compliance with CGMPs.

      This information may be submitted in the application or by reference to a master file provided to the Agency.

    4. CGMP Compliance:
      Satisfactory compliance with CGMP requirements for the primary and alternate sites will be determined by making a CGMP inspection request to the appropriate FDA District Offices. CGMP inspections may include verification of the information provided in the EA.
  8. NEW MANUFACTURING SITE:

    In addition to the recommendations noted above, the sponsor of an application proposing a primary manufacturing facility (NADA's and ANADA's) or alternate manufacturing facility (NADA's, ANADA's, supplemental NADA's and ANADA's) that meets the criteria of a new manufacturing site, as defined above, may be requested to submit additional data (e.g., 2-3 batches meeting minimum batch size requirements, extended accelerated and RT stability data). The submission of protocols for new manufacturing sites is recommended prior to the submission of the application.

GUIDELINE IV

NEW ANIMAL DRUG SUBSTANCE SOURCES

1994
(Revised)
DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR VETERINARY MEDICINE

A.INTRODUCTION:

The information included in this document is intended to provide guidance for the submission of appropriate data and information to support the approval of alternate sources of a new animal drug substance (NADS) in NADA's, ANADA's and their supplements.

Sponsors may propose multiple sources of new animal drug substance in their NADA or ANADA submissions. However, it is suggested that NADA's and ANADA's propose a single (primary) source of the NADS and that additional sources of NADS be provided for through the supplemental approval process.

The terms new animal drug substance supplier and new animal drug substance source are interchangeable in this document. The terms refer to the actual source/supplier and not the vendor.

The approval of an NADA or ANADA is usually based on clinical/bioequivalence data from drug product manufactured with a single source of the new animal drug substance. There is no assurance that other sources of the NADS will produce a product with the same stability characteristics and bioavailability profile. In order to establish confidence that use of alternate sources of the NADS will not result in a difference in product shelf-life or bioavailability, the following recommendations for supporting data and information are being made.

B.DEFINITIONS:

New Animal Drug Substance: Any substance that when used in the manufacture, processing, or packing of a drug causes that drug to be a new animal drug, but does not include intermediates used in the synthesis of such substances.

Primary Source of New Animal Drug Substance: The primary source of the new animal drug substance is the source designated for the manufacture of the product in the application.

Alternate Source of New Animal Drug Substance: The alternate source of the new animal drug substance is an additional source of the NADS designated for the manufacture of the drug product in a submission or after approval of the application.

C.RECOMMENDATIONS FOR THE SUBMISSION OF APPROPRIATE DATA AND INFORMATION:
  1. TEST BATCH:

    1. NADA's:

      A total of three batches of drug product (refer to I. B.) should be manufactured for NADA's. The test batches should be manufactured with the proposed source of NADS when possible. However, the Center recognizes that innovator companies frequently manufacture new chemical entities in small quantities and at facilities other than those that will be used for the supply of NADS for the approved drug product; and that this is the material used for the formulation of drug product for pivotal target animal and stability studies in the application. This practice is acceptable. The facility used for the manufacture of NADS should be in compliance with CGMP's. When there is a change in the source of NADS between that used for the test batch and that proposed as a source for the approved drug product an assessment will be made to determine if the processes differ significantly. This assessment will normally be performed by both Center review staff and FDA field investigational staff. In instances where the processes are determined to differ significantly additional bridging studies may be requested by the Center.

      If the NADS is available from the proposed source(s), then, at least two of the batches should be manufactured with the primary source of the NADS. The third batch may be manufactured with an alternate source of the NADS. With the exception of true solutions, each alternate source of the NADS should be used in the manufacture of a batch of drug product.

    2. ANADA's, Supplemental NADA's and ANADA's: Footnote/2

      A completed batch record for one batch of drug product meeting minimum batch size requirements, manufactured under production conditions, with the primary source of the NADS (ANADA's) and each alternate source of the NADS (ANADA's, supplemental NADA's and ANADA's) should be provided. Ordinarily, for true solutions it will not be necessary to manufacture additional batches with each alternate source of NADS.

      Where in an ANADA or supplement approval is sought for multiple strengths of a product to be manufactured with a subsequent source of the NADS and, using the first source of the NADS, at least one batch of product has previously been prepared in support of each strength, then only one batch of one strength needs to be made for the subsequent source of the NADS. The batch should be prepared for the same strength product as the batch that would be used in the bioequivalence study.

  2. STABILITY DATA:

    1. NADA's:

      Stability data obtained in accordance with the current issue of the Center for Veterinary Medicine's Drug Stability Guidelines, should be submitted for each NADS source.

    2. ANADA's, Supplemental NADA's and ANADA's:

      Three month accelerated (37 - 40o C, 75% RH) stability data should be provided for the batch manufactured with the primary source of NADS (ANADA's) and for each alternate source of NADS (ANADA's, supplemental NADA's and ANADA's). The stability data should be generated on product stored in the approved market container and should include all appropriate testing as specified in the NADA or ANADA. For true solutions, accelerated stability data will not ordinarily be requested for alternate sources of NADS. Rather, a stability commitment to place the first three production batches manufactured with the alternate source of NADS into the approved stability program will generally be acceptable.

  3. DISSOLUTION DATA:

    Comparative dissolution data should be submitted where appropriate.

  4. BIOEQUIVALENCE DATA:

    A request for waiver of in vivo bioequivalence requirements for drug product manufactured with the alternate source of the NADS should be made. The Center does not anticipate difficulties concerning the bioavailability for alternate sources of the NADS for products that are eligible for a waiver of in vivo bioequivalence study requirements (i.e., parenterals and oral solutions). However, where there are concerns regarding particle size, isomeric forms, solubility, narrow therapeutic window, etc., a bioequivalence study may be requested.

    Milk-out studies (for mastitis products manufactured with the alternate NADS) will generally not be necessary. Ordinarily, bridging data may be provided by a comparison of physiochemical data (particle size, viscosity, crystalline structure, etc.). However, when milk out studies are necessary, the submission of protocols prior to the initiation of the studies is strongly recommended.

  5. ENVIRONMENTAL INFORMATION:

    This information should include:

    An environmental assessment (EA) according to 21 CFR 25.31a which addresses the manufacturing at each site should be submitted. The type of information necessary for each manufacturing site is specified in the draft guidance document entitled Environmental Review of Generic Animal Drugs. This guidance document was provided as an attachment to the Center's generic policy letter, dated June 7, 1989. A complete copy of the policy letter and guidance document is available upon written request from the Industry Information Staff (HFV-12), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville MD 20855.

  6. GENERAL INFORMATION:

    1. Stability Program/Commitment:
      A commitment to place the first three production lots manufactured with each NADS source into the approved stability program and to generate stability data at the intervals specified in the approved Stability Protocol, should be provided. Additionally, a commitment to place 3 - 10% (minimum of one per annum) of the lots manufactured with each source of the NADS into the approved stability program, should be provided.
    2. Certificate of Analysis:
      A certificate of analysis from the supplier of the NADS showing compliance with all NADA or ANADA requirements, should be provided.
    3. Test Results for the NADS:
      Complete testing of each source of the NADS should be provided by the sponsor. Testing which uses chromatographic methods or other instrumental techniques which produce graphical data should include copies of those charts. HPLC/GC peaks and TLC spots for reference standards and test samples should be identified
    4. Manufacturing Information:
      Information should be submitted for the manufacture of the NADS at each facility. This information includes: 1) complete name/address of the actual site of manufacture (the address of the administrative headquarters of the firm may not be substituted), 2) authorization to reference master files, 3) name/address of the U.S. agent; if a foreign manufacturer is proposed, a letter of appointment from the manufacturer, 4) facilities, 5) equipment (laboratory and manufacturing), 6) raw materials, 7) impurity profile and limits, 8) general/specific operations (ingredients, specifications, tests, methods, synthesis, fermentation process), 9) manufacturing process and batch record, 10) analytical controls, 11) stability data, 12) information for the container/closure, 13) labels (product and shipping), and 14) certificate of compliance with CGMPs.

      This information may be submitted in the application or by reference to a master file provided to the agency.

    5. GMP Compliance:
      Satisfactory compliance with CGMP requirements for the primary and alternate sources of the NADS will be determined by making a CGMP inspection request to the appropriate FDA, District Office (domestic source) or International Programs and Technical Support Branch (foreign source). CGMP inspections may include verification of the information in the EA.

    Footnotes:

    1/Supplemental NADA's and ANADA's - When an alternate site is proposed for the manufacture of multiple drug products within the same dosage form class (e.g., tablets), and the manufacturing processes do not differ significantly from the approved processes, the sponsor may request that pilot batches not be manufactured for all affected drug products (NADA's and ANADA's). Rather, the sponsor may propose a rationale for selecting fewer drug products within the same dosage form class as representative of the manufacturing process, equipment, etc. at the proposed alternate facility. In these instances, we recommend that a protocol be submitted for review and evaluation prior to the submission of supplements for multiple NADA's and ANADA's.

    2/ Supplemental NADA's and ANADA's - When an alternate source of bulk drug substance is proposed for the manufacture of multiple drug products, the sponsor may request that pilot batches of product not be manufactured for all affected drug products (NADA's and ANADA's). Rather, the sponsor may propose a rationale for selecting fewer drug products. In these instances, we recommend that a protocol be submitted for review and evaluation prior to the submission of supplements for multiple NADA's and ANADA's.