GUIDANCE FOR INDUSTRY

FOR THE SUBMISSION OF CHEMISTRY, MANUFACTURING, AND CONTROLS INFORMATION FOR A
THERAPEUTIC RECOMBINANT DNA-DERIVED PRODUCT OR A MONOCLONAL ANTIBODY PRODUCT
FOR IN VIVO USE






















Center for Biologics Evaluation and Research (CBER)
Center for Drug Evaluation and Research (CDER)
August 1996
TABLE OF CONTENTS
                                                       

I.  INTRODUCTION  . . . . . . . . . . . . . . . . . . . . . .  1

II. DRUG SUBSTANCE  . . . . . . . . . . . . . . . . . . . . .  1

  A. Description And Characterization . . . . . . . . . . . .  2

    1. Description . . . . . . . . . . . . . . . . . . . . . . 2

    2. Characterization / Proof Of Structure . . . . . . . . . 2

      a. Physicochemical Characterization of Reference  . . .  2
         Standard and Qualifying Lots

      b. Biological Activity  . . . . . . . . . . . . . . . .  3 
 
  B. Manufacturer(s) . . . . . . . . . . . . . . . . . . . . . 4

    1. Identification . . . . . . . . . . . . . . . . . . . .  4

    2. Floor Diagram . . . . . . . . . . . . . . . . . . . . . 4

    3. Other Products . . . . . . . . . . . . . . . . . . . .  5

    4. Contamination Precautions . . . . . . . . . . . . . . . 5
 
  C. Method(s) Of Manufacture . . . . . . . . . . . . . . . .  6

    1. Raw Materials And Reagents . . . . . . . . . . . . . .  6

    2. Flow Charts . . . . . . . . . . . . . . . . . . . . . . 7
   
    3. Detailed Description . . . . . . . . . . . . . . . . .  7

      a. Animal Sources . . . . . . . . . . . . . . . . . . .  7

      b. Cellular Sources . . . . . . . . . . . . . . . . . .  8

        i. Cell Substrate / Host Cell / Expression . . . . . . 8
           Vector System

          a. Recombinant DNA Products Including . . . . . . .  8
             RDNA-Derived Monoclonal Antibodies

            i. Host Cells . . . . . . . . . . . . . . . . . .  8

            ii. Gene Construct . . . . . . . . . . . . . . . . 8
 
            iii. Vector . . . . . . . . . . . . . . . . . . .  9

            iv. Final Gene Construct . . . . . . . . . . . . . 9

            v. Cloning And Establishment Of The . . . . . . .  9
               Recombinant Cell Lines

          b. Monoclonal Antibodies . . . . . . . . . . . . .  10

        ii. Cell Seed Lot System . . . . . . . . . . . . . .  10

          a. Master Cell Bank (MCB)   . . . . . . . . . . . . 10

          b. Working Cell Bank . . . . . . . . . . . . . . .  11

          c. End Of Production Cells (EPC) . . . . . . . . .  11

        iii. Cell Growth And Harvesting . . . . . . . . . . . 12

      c. Purification And Downstream Processing . . . . . . . 13

    4. Batch Records . . . . . . . . . . . . . . . . . . . .  13

  D.  Process Controls . . . . . . . . . . . . . . . . . . .  14

    1. In-Process Controls . . . . . . . . . . . . . . . . .  14

    2. Process Validation . . . . . . . . . . . . . . . . . . 14

      a. Validation Studies For The Cell Growth And . . . . . 14
         Harvesting Process 

      b. Validation Studies For The Purification Process . .  14

      c. Microbiology . . . . . . . . . . . . . . . . . . . . 15

  E. Reference Standard(s) . . . . . . . . . . . . . . . . .  15

    1. Primary Reference Standard . . . . . . . . . . . . . . 15

    2. Working Reference Standard (If Used) . . . . . . . . . 15

  F. Specifications / Analytical Methods . . . . . . . . . .  16

    1. Drug Substance Specifications And Tests . . . . . . .  16

      a. Specifications And Analytical Methods . . . . . . .  16

      b. Certificates Of Analysis And Analytical Results . .  16

    2. Impurities Profile . . . . . . . . . . . . . . . . . . 16

  G. Container/Closure System . . . . . . . . . . . . . . . . 16
  
  H. Drug Substance Stability . . . . . . . . . . . . . . . . 17

III. DRUG PRODUCT . . . . . . . . . . . . . . . . . . . . . . 17

  A. Composition . . . . . . . . . . . . . . . . . . . . . .  17

  B. Specifications & Methods For Drug Product Ingredients. . 17

    1. Drug Substances Including All Active Ingredients. . .  17

    2. Excipients . . . . . . . . . . . . . . . . . . . . . . 18

      a. Compendial Excipient(s) . . . . . . . . . . . . . .  18 

      b. Non-Compendial Excipient(s) . . . . . . . . . . . .  18

  C. Manufacturer(s). . . . . . . . . . . . . . . . . . . . . 18

  D. Methods Of Manufacture And Packaging . . . . . . . . . . 18
   
  E. Specifications & Test Methods For Drug Product . . . . . 19

      1. Sampling Procedures . . . . . . . . . . . . . . . .  19

      2. Specifications & Methods . . . . . . . . . . . . . . 19

  F. Container/Closure System . . . . . . . . . . . . . . . . 19

  G. Microbiology . . . . . . . . . . . . . . . . . . . . . . 20

  H. Drug Product Stability . . . . . . . . . . . . . . . . . 20

IV. INVESTIGATIONAL PRODUCT/FORMULATION  . . . . . . . . . .  20

V.  ENVIRONMENTAL ASSESSMENT . . . . . . . . . . . . . . . .  21

VI. METHOD VALIDATION . . . . . . . . . . . . . . . . . . . . 21

VII. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . 21
GUIDANCE FOR INDUSTRY

 FOR THE SUBMISSION OF
CHEMISTRY, MANUFACTURING, AND CONTROLS INFORMATION
FOR A THERAPEUTIC RECOMBINANT DNA-DERIVED PRODUCT OR 
A MONOCLONAL ANTIBODY PRODUCT FOR IN VIVO USE


I.   INTRODUCTION

In the Federal Register of May 14, 1996, the Food and Drug Administration
published the final rule Elimination of the Establishment License Application
for Specified Biotechnology and Specified Synthetic Biological Products.
Under this rule manufacturers of therapeutic recombinant DNA-derived products
and/or monoclonal antibody products for in vivo use are no longer required to
submit an Establishment License Application and may use the interim FDA Form
3439.  This document provides guidance on the content and format of the
Chemistry, Manufacturing, and Controls (CMC) section of a Biologics License
Application for therapeutic recombinant DNA-derived products and monoclonal
antibody products for in vivo use.

II. DRUG SUBSTANCE  

The drug substance is defined as the unformulated active substance which may be
subsequently formulated with excipients to produce the drug product.

A. Description and Characterization

1. Description

A clear description of the drug substance should be provided.  This description
may include, but not be limited to, any of the following: chemical structure,
primary and subunit structure, molecular weight, molecular formula, established
USAN name, antibody class/subclass (if appropriate), etc.

2. Characterization / Proof of Structure

a.  Physicochemical Characterization of Reference Standard and Qualifying Lots:

A description and the results of all the analytical testing performed on
the manufacturers reference standard lot and qualifying lots to
characterize the drug substance should be included (See references 7, 8,
10).  Information from specific tests regarding identity, purity, stability
and  consistency of manufacture of the drug substance should be provided. 
Examples of analyses for which information may be submitted include, but
are not necessarily limited to the following:
                    
    amino acid analysis
    amino acid sequencing, entire sequence or amino- and carboxy-terminal
     sequences
    peptide mapping
    determination of disulfide linkage
    Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis (SDS-PAGE)
     (reduced and non-reduced)
    isoelectric focusing
    Conventional and High Pressure Liquid Chromatography (HPLC) e.g.,
     reverse-phase, size exclusion, ion-exchange, etc.
    mass spectroscopy
    assays to detect product-related proteins including deamidated,
     oxidized, cleaved, and aggregated forms and other variants e.g., amino
     acid substitutions, adducts/derivatives.
    assays to detect residual host proteins, DNA, reagents
    immunochemical analyses
    assays to quantitate bioburden, endotoxin

Additional physicochemical characterization may be required for products
undergoing post-translational modifications, for example, glycosylation,
sulfation, phosphorylation, or formylation.   Additional physicochemical
characterization may also be required for products derivatized with other
agents, including other proteins, toxins, drugs, radionuclides, or
chemicals.  The information submitted should include the degree of
derivatization or conjugation, the amount of unmodified product, removal of
free materials (e.g., toxins, radionuclides, linkers, etc.), and the
stability of the modified product.

All test methods should be fully described and the results provided. The
application should also include the actual data such as legible copies of
chromatograms, photographs of SDS-PAGE or agarose gel, spectra, etc.

b.  Biological Activity

A description and results of all relevant in vivo and in vitro biological
testing performed on the manufacturers reference standard lot to show the
potency and activity(ies) of the drug substance should be provided. 
Results of relevant testing performed on lots other than the reference
standard lot, that might have been used in establishing the biological
activity of the product, should also be included.  (See references 7 - 10,
12)  The description and validation of the bioassays should include the
methods and standards used, the inter- and intra-assay variability, and the
acceptable limits of the assay.   

B. Manufacturer(S)

1. Identification

The application should include the name(s), address(es), FDA registration
number, and other pertinent organizational information for each
manufacturer performing any portion of the manufacture or testing
operations for the drug substance.  This may include contractors or company
subsidiaries serving as contractors, or other locations/sites owned and
operated by the applicant.  A brief description of the operations performed
at each location, the responsibilities conferred upon each party by the
applicant and a description of how the applicant will ensure that each
party fulfills their responsibilities should be submitted. 

2. Floor Diagram(s)

For each manufacturing location, a floor diagram should be included that
indicates the general facility(ies) layout.  This diagram need not be a
detailed engineering schematic or blueprint, but rather a simple drawing
that depicts the relationship of the subject manufacturing areas, suites,
or rooms to one another, and should indicate other uses made of adjacent
areas that are not the subject of the application.   This diagram should be
sufficiently clear such that the reviewer may visualize the flow of the
production of the drug substance and would be able to identify areas or room
"proximities" that may be of concern for particular operations, e.g.
segregation of pre and post viral inactivation material and operations,
segregation of animal facilities, etc.  Room numbers or other unique
identifiers should be provided, however it is not necessary to include the
location of processing equipment within rooms and areas.  Reference
can be made to manufacturing flow information presented in response to section
II. C. 2. of this guidance.

3. Other Products

A comprehensive list of all additional products to be manufactured or
manipulated in the areas used for the product should be provided.  The
applicant should indicate in which rooms the additional products will be
introduced and the manufacturing steps that will take place in the room.
An explanation should be given as to whether these additional products will be
introduced on a campaign basis or concurrently during production of the
product which is the subject of the application.  Any additional products that
may share product contact equipment with the product in question should be
indicated (dedicated vs. multi-use equipment should be delineated for each
process step, in this section or other appropriate sections of the application).
A brief description should be provided as to the type and developmental
status of the additional products. 

4. Contamination Precautions

For all areas in which operations for the preparation of cell banks and product
manufacturing are performed, including areas for the handling of animals used in
production, the following information concerning precautions taken to prevent
contamination or cross-contamination should be provided:
    air quality classification of room or area in which operation is performed,
     as validated and measured during operations;
    a brief, narrative description of the procedures and/or facility design
     features for the control of contamination, cross contamination and
     containment (air pressure cascades, segregation of operations and product,
     etc.) - this is of particular importance for multi-use areas or for work
     with live organisms;
    general equipment design description, eg. does design represent an open or
     closed system or provide for a sterile or non-sterile operation, and; 
    a description of the in-process controls performed to prevent or to
     identify contamination or cross contamination.

The manipulation of more than one cell line in a single area, or the use of any
piece of equipment for more than one cell line, should be indicated and measures
to ensure prevention of cross contamination should be discussed.
 
C. Method(S) of Manufacture

1. Raw Materials and Reagents

A list of all components used in the manufacture of the drug substance, and
their tests and specifications or reference to official compendia should be
provided.  For purchased raw materials representative certificates of analysis
from the supplier(s) and/or manufacturer's acceptance criteria should be
included in the submission.   Process gases (e.g., air, carbon dioxide) and
water are considered raw materials.  

A list with tests and specifications of all special reagents and materials used
in the manufacture of the drug substance, e.g., culture media, buffers, sera,
antibiotics, monoclonal antibodies, preservatives, should be submitted.  In
cases where an ancillary biological product is used in the manufacture of the
drug substance (e.g., a monoclonal antibody used in affinity chromotagraphy), a
detailed description of the preparation and characterization of the reagent
should be submitted (Reference 7, 10).  

A description of the tests and specifications for materials of human or animal
source that may potentially be contaminated with adventitious agents, e.g.,
mycoplasma, Bovine Spongioform Encephalopathy (BSE) agent for bovine derived
products, and other adventitious agents of human and animal origin should be
submitted.  Validation data or certification supporting the freedom of reagents
from adventitious agents should be included in the submission.

2. Flow Charts

A complete visual representation of the manufacturing process flow should be
provided.  This flow chart should indicate the step in production, the equipment
and materials used, the room or area where the operation is performed (may
reference the simple diagram in II. B. 2.) and a complete list of the in-process
controls and tests performed on the product at each step.  This diagram should
also include information (or be accompanied by a descriptive narrative) on the
methods used to transfer the product between steps, i.e. Sterile, steam-in-place
(SIP) connection, sanitary connection, open transfers under laminar flow units
etc.  Such transfers should be described for movement of product between
equipment, areas/rooms, buildings and sites.  Manufacturing steps which are
computer controlled should be identified.  References can be made to other
sections of the application for more detailed process information.     

3. Detailed Description

a.  Animal Sources 

The information submitted concerning animals used in production, such as
mice used for ascites or transgenic animals, should include detailed
descriptions of the following:
    source of animals;
    method of creating and the genetic stability of transgenic animals;
    adventitious agent screening and quarantine procedures used to assure
     animals are appropriate for use in manufacturing;
    animal husbandry procedures, and;
    veterinary oversight.  

More detailed guidance in these areas may be obtained from the Points to
Consider in the Manufacture and Testing of Monoclonal Antibody Products for
Human Use and the Points to Consider in the Manufacture and Testing of
Therapeutic Products for Human Use Derived from Transgenic Animals.

b. Cellular Sources

i. Cell Substrate / Host Cell / Expression Vector System

a. Recombinant DNA Products including rDNA-Derived Monoclonal Antibodies. 
             
The submission should include a detailed description of the host cell
and expression vector system and their preparation as delineated
below: (See References 9, 10, 12)

i. Host Cells

A description of the source, relevant phenotype, and genotype should
be provided for the host cell used to construct the biological
production system. The results of the characterization of the host
cell for phenotypic and genotypic markers, including those that will
be monitored for cell stability, purity, and selection should be
included.

ii. Gene Construct

A detailed description of the gene which was introduced into the host cells
cells, including both the cell type and origin of the source material,
should be provided.  A description of the method(s) used to prepare
the gene construct and a restriction enzyme digestion map of the
construct should be included.  The complete nucleotide sequence of the
coding region and regulatory elements of the expression construct,
with translated amino acid sequence, should be provided, including
annotation designating all important sequence features.  
 
iii. Vector

Detailed information regarding the vector and genetic elements should
be provided, including a description of the source and function of the
component parts of the vector, e.g. origins of replication, antibiotic
resistance genes, promoters, enhancers.  A restriction enzyme
digestion map indicating at least those sites used in construction of
the vector should be provided. The genetic markers critical for the
characterization of the production cells should be indicated.

iv. Final Gene Construct

A detailed description should be provided of the cloning process which
resulted in the final recombinant gene construct.  The information
should include a step-by-step description of the assembly of the gene
fragments and vector or other genetic elements to form the final gene
construct.  A restriction enzyme digestion map indicating at least
those sites used in construction of the final product construct should
be provided.

v. Cloning and Establishment of the Recombinant Cell Lines.

Depending on the methods to be utilized to transfer a final gene
construct or isolated gene fragments into its host, the mechanism of
transfer, copy number, and the physical state of the final construct
inside the host cell (i.e. integrated or extrachromosomal), should be
provided.  In addition, the amplification of the gene construct, if
applicable, selection of the recombinant cell clone, and establishment
of the seed should be completely described. 

b. Monoclonal Antibodies.  

A detailed description of the development of the monoclonal antibody
should be provided including characterization of the parent cells,
donor history for human cells, immunogen, immortalization procedures,
screening, and cell cloning procedures.  (See Reference 7, 9)

ii. Cell Seed Lot System

a. Master Cell Bank (MCB)
  
A detailed description of the preparation and testing of the MCB, as
outlined below and in the ICH guideline Analysis of the Expression
Construct in Cells used for Production of R-DNA Derived Protein
Products, should be submitted.

The MCB should be described in detail, including methods, reagents and
media used, date of creation, quantity of the cell bank, in-process
controls, and storage conditions.  The results of the characterization
of the MCB for identity and purity using appropriate phenotypic 
markers such as morphology, auxotrophy, isoenzyme, etc. should be
included.  Restriction enzyme analysis and DNA sequencing data
supporting the integrity of the introduced genetic sequence and data
supporting the stability of both the host cell and final gene
construct during storage should also be submitted.  For bacterial
cells, the results of tests for contamination with both lytic and
lysogenic bacteriophages and non-host microorganism(s) should be
included.

The testing of the MCB for endogenous and adventitious agents (e.g.
Murine retroviruses, Epstein-Barr virus, mycoplasma, bacteria, fungi,
other viruses and/or virus-like particle), as appropriate, as outlined
in "Points to Consider in Characterization of Cell Lines used to
Produce Biological Products", 1993, and Points to Consider in the
Manufacture and Testing of Monoclonal Antibody Products for Human Use
should be described.  If new Master Cell Banks are to be generated by
transfer of final DNA construct to host cells or by expansion of an
existing MCB or Working Cell Bank (WCB), then acceptance criteria for
both the new cell bank and the drug substance(s) produced by the new
bank should be described.  In particular, documentation of the
fidelity of the introduced nucleotide sequence in the new MCB and
restriction mapping analysis should be submitted.

b. Working Cell Bank
 
A  detailed description of the preparation and testing of the WCB such
as those outlined in the applicable guidance documents (References 7,
9, 10, 12) should be submitted. 

The production of the Working Cell Bank should be described in detail,
including methods, reagents and media  used, date of creation,
quantity of the cell bank, number of cell doublings from the MCB and
storage conditions.  If there is no MCB, the results of the
characterization of the WCB should be provided in the format detailed
for the MCB (Section II. C. 3. b. ii.).

c. End of Production Cells (EPC)
 
A detailed description of the characterization of the EPC that
demonstrates that the biological production system is consistent
during growth should be provided.  The results of the analysis of the
EPC for phenotypic or genotypic markers to confirm identity and purity
should be included.  This section should also contain the results of
testing supporting the freedom of the EPC from contamination by
adventitious agents.  The results of restriction enzyme analysis of
the gene constructs in the EPC should be submitted.  Further guidance
can be obtained from the ICH document on Analysis of the Expression
Construct in Cells Used for Production of R-DNA Derived Protein
Products and Points to Consider in the Manufacture and Testing of
Monoclonal Antibody Products for Human Use.

iii. Cell Growth and Harvesting

A detailed description of the process of inoculation, cell growth and
harvesting should be submitted.  The composition of the medium, equipment
preparation and sterilization, as well as fermentation medium
sterilization, should be described.  For all stages of any fermentation
process the procedures which prevent contamination with adventitious agents
should be described.  

The stages of cell growth should be described in detail including the
selection of inoculum, scale-up for propagation, and established and
proposed (if different) production batch size.  All operating conditions
and in-process controls should also be described and appropriate ranges for
operating and control parameters, such as fermentation time, cell doubling
time, cell culture purity, cell viability, pH, CO2, etc.,  established.  If
induction is required for production of protein, detailed  information
including induction conditions and controls employed should also be
described.  

The submission should include the process used to inactivate cells utilized
in the production of a drug substance prior to their release into the
environment.  For cell lines meeting the criteria of Good Large Scale
Practice (GLSP) organisms (July 18, 1991 FR notice, Vol. 56, no 138, p.
33174), which do not require inactivation prior to release into the
environment, the information supporting their qualification as GLSP
organisms should be provided.  A description of the procedures used, in the
event of a contamination, to inactivate a GLSP culture prior to release
should be included.

If the culture supernatant or cell pellet is stored prior to processing,
data supporting its stability during storage should be provided.

The manipulation of more than one cell line in a single area or the use of
any piece of equipment for more than one cell line should be indicated and
measures to ensure prevention of cross contamination should be discussed.

c.  Purification and Downstream Processing

A detailed description of the purification and downstream processing,
including a rationale for the chosen methods, and the precautions taken to
assure containment and prevention of contamination or cross contamination
should be provided.  In-process bioburden and endotoxin limits should be
specified where appropriate. Any reprocessing using a validated
reprocessing method and the conditions for batch eligibility should be
described.  

If applicable, indication (or reference to II. B. 2. ) should be made as to
the multi-use nature of areas and equipment (e.g. campaigning vs.
concurrent manufacture; dedicated vs. shared equipment) used for these
procedures.  A brief description of the controls employed to ensure
segregation and prevent cross contamination, or reference to another
section containing this information, should be provided.

4. Batch Records

A completed (executed) representative batch record of the process of production
of the drug substance should be submitted.


D. Process Controls

1. In-Process Controls

A description of the methods used for in-process controls, e.g., those involved
in fermentation, harvesting and downstream processing, should be provided.

2. Process Validation

A description and documentation of the validation studies should be provided. 
If the process was changed or scaled up for commercial production and involved 
changes in the fermentation steps, the re-validation of cell line stability
during growth should be described, as in the previous section, and the data and
results provided.

a.  Validation Studies for the Cell Growth and Harvesting Process

A description and documentation of the validation studies which identify
critical parameters to be used as in-process controls, to ensure the
success of routine production should be submitted.  Reference may be made
to the flow diagram(s) as appropriate.

b.  Validation Studies for the Purification Process  

A description and documentation of the validation of the purification
process to demonstrate adequate removal of extraneous substances such as
chemicals used for purification, column contaminants, endotoxin,
antibiotics, residual host proteins, DNA, and viruses, where appropriate,
should be provided.  (See references 4, 7 - 10)

c. Microbiology

A description and documentation of the validation studies for any processes
used for media sterilization, inactivating cells prior to their release to
the environment, if such inactivation is required, etc., should be
provided.  If the drug substance is intended to be sterile, information
should be submitted as described in the Guidance for Industry for the
Submission of Documentation for Sterilization Process Validation in
Applications for Human and Veterinary Drug Products.

E. Reference Standard(s)

1. Primary Reference Standard

If an international reference standard (WHO, NIBSC) or compendial reference
standard (USP)is used, submit the citation for the standard and a certificate of
analysis.  If no biological potency or chemical reference standard exists, and
the applicants establish their own primary reference standard, a description of
the characterization, and specifications of the standard should be provided. 
Submit the results of testing, such as physicochemical and biologic activity
determinations, of the standard and provide a certificate of analysis.  The
Standard Operating Procedures (SOPs) to be used for qualifying a new reference
standard should be included.  Information should also be provided on the
stability of any reference standard. 

2. Working Reference Standard (if used)

If an in-house working reference standard is used, a description of the
preparation, characterization, specifications, testing and results should be
provided.  The data from the calibration of the in-house working reference
standards against a primary reference standard should also be submitted.  

F. Specifications/Analytical Methods

1. Drug Substance Specifications and Tests

a.  Specifications and analytical methods used for release testing, shelf life
and distribution should be described. 

Specifications and tests for the drug substance sufficient to assure its
identity, purity, strength and/or potency, as well as lot-to-lot
consistency should be submitted. (See references 3, 4, 7 - 11, 13) 
Validation of the analytical systems and the data should be provided for
non-compendial methods to demonstrate the system suitability.

b.  Certificates of Analysis and Analytical Results

Certificates of analysis and analytical results for at least three
consecutive qualification lots of the drug substance should be submitted.

2. Impurities Profile

A discussion of the impurities profiles, with supporting analytical data, should
be provided.  Profiles of variants of the protein drug substance (e.g., cleaved,
aggregated, deamidated, oxidized forms, etc.), as well as non-product related
impurities (e.g., process reagents and cell culture components), should be
included.

G. Container/Closure System(S)

A description of the container and closure system, and its compatibility with
the drug substance should be submitted.  The submission should include detailed
information concerning the supplier, address, and the results of compatibility,
toxicity and biological tests. Alternatively, a Drug Master File (DMF) may be
referenced for this information.  If the drug substance is intended to be
sterile, evidence of container and closure integrity for the duration of the
proposed expiry period should be provided.    

H. Drug Substance Stability

A description of the storage conditions, study protocols and results supporting
the stability of the drug substance should be submitted in this section.  (Refer
to ICH document Stability Testing of Biotechnological/Biological Products or
other FDA documents such as " Guideline for Submitting Documentation  for the
Stability of Human Drug and Biologics" for specific information.)

Data from tests to monitor the biological activity and degradation products such
as aggregated, deamidated, oxidized, and cleaved forms should be included, as
appropriate.  Data supporting any proposed storage of intermediate(s) should
also be provided.

III. DRUG PRODUCT

A. Composition, including components  

A tabulated list of all components with their unit dose and batch quantities for
the drug product or diluent in accordance with the Guideline for Submitting
Documentation for the Manufacture of and Controls for Drug Products should be
submitted.  The composition of all ancillary products that might be included in
the final product should be included.

B. Specifications & Methods for Drug Product Ingredients

1. Drug Substances Including All Active Ingredients and Ancillary Components  

This section should contain a description of tests and specifications for all
active ingredients, if not specified in the Drug Substance section.  The
specifications for all ancillary products that are included in this product
should be provided.

2. Excipients:

Information on all excipients including process gases and water should be
included.

a. Compendial Excipient(s) 

A list of compendial excipients and the citations for each should be
submitted.

b.  Non-Compendial Excipient(s) 

Tests and specifications should be described.  For a novel excipient, the
description should include its preparation, characterization, and controls. 
For inactive ingredients of human or animal origin, certification, results
of testing or other procedures, or validation data demonstrating their
freedom from adventitious agents should be provided.

C. Manufacturer(s)

The name(s) and address(s) of all manufacturers involved in the manufacture and
testing of the drug product including contractors, and a description of the
responsibility(ies) of each should be submitted.  A list of all other products
(research & development, clinical or approved) made in the same rooms should be
provided.  See II. B. 3. of this document for detailed guidance.

D. Methods of Manufacture and Packaging

A complete description of the manufacturing process flow of the formulated bulk
and finished drug product should be provided.  This discussion should include a
description of sterilization operations, aseptic processing procedures,
lyophilization, and packaging procedures.  Accompanying this narrative, a flow
chart should be provided that indicates the production step, the equipment and
materials used, the room or area where the operation is performed (may reference
the simple diagram in II. B. 2.) and a listing of the in-process controls and
tests performed on the product at each step.  This flow diagram or narrative
should also include information on the methods of transfer of the product
between steps, i.e. Sterile, SIP connection, sanitary connection, open transfers
under laminar flow units, etc.  Such transfers should be described for movement
of product between equipment, areas/rooms, buildings and sites.   References can
be made to other sections of the application for more detailed process
information.    

E. Specifications & Test Methods for Drug Product

1. Sampling Procedures 

The sampling procedures for monitoring a batch of finished drug product should
be included.

2. Specifications & Methods

A description of all test methods selected to assure the identity, purity,
strength and/or potency, as well as the lot-to-lot consistency of the finished
product and the specifications used for the drug product should be submitted. 
Certificates of analysis and analytical results for at least three consecutive
batches should be provided.  
  
The validation data for system stability for all non-compendial tests should be
provided.  If compendial methods have to be validated to ensure non-interference
of special inactive ingredients, the results of those validation studies should
be submitted.

F. Container/Closure System(s)

A description of the container and closure system, and its compatibility with
the drug product should be submitted.  Detailed information concerning the
supplier(s), address(es), and the results of compatibility, toxicity and
biological tests should be included.  Alternatively, a DMF can be referenced for
this information.  For sterile product, evidence of container and closure
integrity should be provided for the duration of the proposed expiry period.

G. Microbiology

Information should be submitted as described in the Guidance for Industry for
the Submission of Documentation for Sterilization Process Validation in
Applications for Human and Veterinary Drug Products.

H. Drug Product Stability

A description of the storage conditions, study protocols and results supporting
the stability of the drug product should be provided.  This should include
information on the stability of intermediate fluids or formulated bulk under
specified holding or shipping conditions, as appropriate.  For products
administered through pumps or other such delivery devices, data on the stability
of the drug product in the delivery system should be provided.  Stability data
supporting the proposed shelf-life of the reconstituted drug product and for all
labeled dilutions should be included.  The results of all tests used to monitor
biological activity and the presence of degradation products such as aggregated,
deamidated, oxidized, cleaved, etc. forms of the drug substance should also be
included.  (See references 3, 7 - 13)

IV. INVESTIGATIONAL PRODUCT/FORMULATION

A discussion of any differences in formulation, manufacturing process, or site
between the clinical trials materials and commercial production batches of drug
substance and drug product should be submitted.  If there are differences, a
complete description of these differences should be included.  If an
investigational drug formulation was different from that of the to-be-marketed
finished product, data to support comparability, bioequivalence and/or
pharmacokinetic equivalence of the two formulations should be provided, if
appropriate.  If the manufacturing process and/or site was different, data from
appropriate testing to assess the comparability of the investigational and
commercial products should be provided (See reference 6).

V. ENVIRONMENTAL ASSESSMENT

An environmental assessment should be prepared as outlined in 21 CFR Part 25.
This submission should include a description of the action that is being
considered and should address all the components involved in the manufacture and
disposal of the product.  A statement of exemption under a Categorical Exclusion
may be provided if applicable.


VI. METHOD VALIDATION

Provide information as described in the Guideline for Submitting Samples and
Analytical Data for Methods Validation.


VII. REFERENCES

Guidelines

1    Guidance for Industry for the Submission of Documentation for Sterilization
     Process Validation in Applications for Human and Veterinary Drug Products 

2    Guideline on Sterile Drug Products Produced By Aseptic Processing.

3    Guideline for Submitting Documentation  for the stability of Human Drugs
     and Biologics

4    Guideline for Submitting Documentation for the Manufacture of and Controls
     for Drug Products

5    Guideline for Submitting Samples and Analytical Data for Methods Validation

6    FDA Guidance Concerning Demonstration of Comparability of Human Biological
     Products, Including Therapeutic Biotechnology-derived Products

Points To Consider

7    Points to Consider in the Manufacture and Testing of Monoclonal Antibody
     Products for Human Use (1994)

8    Points to Consider in the Manufacture and Testing of Therapeutic Products
     for Human Use Derived from Transgenic Animals, 8/22/95

9    Points to Consider - Characterization of Cell Line used to Produce
     Biological Products, 7/12/93

10   Points to Consider in the Production and Testing of New Drugs and
     Biologics Produced by Recombinant DNA Technology, 4/10/85

International Conference on Harmonization (ICH) Guidelines

11   Stability Testing of New Drug Substances and Products, 10/27/93

12   Analysis of the Expression Construct in Cells used for Production of R-DNA
     Derived Protein Products, 11/28/95

13   Quality of Biotechnological Products: Stability Testing of
     Biotechnological/Biological Products, 11/30/95