Guidance for Industry
Content and Format of Chemistry,
Manufacturing and Controls Information
and Establishment Description
Information for a Biological In Vitro
Diagnostic Product
Additional copies are available from:
Office of Communication, Training and
Manufacturers Assistance (HFM-40)
1401 Rockville Pike, Rockville, MD 20852-1448
(Tel) 1-800-835-4709 or 301-827-1800
(Internet)  http://www.fda.gov/cber/guidelines.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
March 1999 TABLE OF CONTENTS
[NOTE: Page numbers may vary for documents distributed electronically.]
GENERAL INFORMATION...................................................................................................1
I. INTRODUCTION.................................................................................................................1
II.  DEFINITIONS....................................................................................................................2
PART 1  CHEMISTRY, MANUFACTURING AND CONTROLS SECTION...................2
I. IN VITRO SUBSTANCE.......................................................................................................2
A. DESCRIPTION AND CHARACTERIZATION.................................................................2
1. Description.......................................................................................................................2
2. Characterization................................................................................................................2
a. Physicochemical Characterization...................................................................................2
b. Activity of the in vitro Substances..................................................................................3
B. MANUFACTURERS..........................................................................................................4
1. Identification.....................................................................................................................4
2. Floor Diagram(s)..............................................................................................................4
3. Manufacture of Other Products.........................................................................................4
4. Contamination Precautions................................................................................................4
C. METHOD OF MANUFACTURE.......................................................................................5
1. Raw Materials and Substances..........................................................................................5
2. Flow Charts......................................................................................................................6
3. Detailed Description.........................................................................................................6
a. Animal Sources..............................................................................................................6
b. Human Sources.............................................................................................................7
c. Cellular Sources.............................................................................................................7
d. Synthetic Sources..........................................................................................................8
D. PROCESS CONTROLS.....................................................................................................8
1. In-process Controls...........................................................................................................8
2. Process Validation............................................................................................................8
E. REFERENCE STANDARDS/PANELS..............................................................................9
1. Reference Standard...........................................................................................................9
2. In-house Reference Standard...........................................................................................10
F. SPECIFICATIONS/ANALYTICAL METHODS..............................................................10
1. In vitro Substance Specifications and Tests.....................................................................10
2. Impurities Profile............................................................................................................10
G. CONTAINER/CLOSURE SYSTEM................................................................................10
H. STABILITY.....................................................................................................................10
i II. IN VITRO PRODUCT.......................................................................................................11
A. MANUFACTURER..........................................................................................................11
B. COMPOSITION...............................................................................................................11
C. METHODS OF MANUFACTURING AND PACKAGING..............................................11
D. SPECIFICATIONS AND TEST METHODS....................................................................12
E. CONTAINER/CLOSURE SYSTEM.................................................................................12
F. MICROBIOLOGY............................................................................................................12
G. STABILITY.....................................................................................................................12
H. BATCH PRODUCTION RECORDS................................................................................13
III.  ENVIRONMENTAL ASSESSMENT............................................................................13
IV.  METHOD VALIDATION...............................................................................................13
PART 2  ESTABLISHMENT DESCRIPTION SECTION.................................................13
I. INTRODUCTION...............................................................................................................13
II. GENERAL INFORMATION............................................................................................14
III.  SPECIFIC SYSTEMS.....................................................................................................14
A. WATER SYSTEMS.........................................................................................................14
1. General Description........................................................................................................14
2. Validation Summary........................................................................................................14
3. Routine Monitoring Program..........................................................................................15
B. HEATING, VENTILATING AND AIR CONDITIONING SYSTEMS (HVAC)..............15
1. General Description........................................................................................................15
2. Validation Summary........................................................................................................15
3. Routine Monitoring Program..........................................................................................16
C. CONTAMINATION/CROSS CONTAMINATION ISSUES............................................16
1. Cleaning Procedures and Validation................................................................................16
a. Dedicated Equipment...................................................................................................16
b. Shared Equipment........................................................................................................16
2. Containment Features.....................................................................................................16
D. COMPUTER SYSTEMS..................................................................................................17
APPENDIX A..........................................................................................................................18
ii Guidance for Industry: 1
Content and Format of Chemistry, Manufacturing and Controls
Information and Establishment Description Information for a
Biological In Vitro Diagnostic Product
GENERAL INFORMATION
I. INTRODUCTION
In the Federal Register of July 8, 1997 (62 FR 36558), the Food and Drug Administration
announced the availability of Revised Form FDA 356h Application to Market a New Drug,
Biologic, or an Antibiotic for Human Use.  This document provides guidance on the content and
format of information to be submitted to the Chemistry, Manufacturing, and Controls (CMC)
section and Establishment Description section of a License Application for a biological in vitro
diagnostic (IVD) product.
This document is intended for use by those firms which manufacture any licensed in vitro
diagnostics used to screen donor blood, determine donor suitability, test for retroviral infection,
or determine transfusion compatibility. This document is not intended to cover those in vitro
diagnostics for which a Pre-Market Application (PMA) or a 510K must be submitted.  The
Guideline for the Manufacture of In Vitro Diagnostic Product while designed to address
products regulated by the Center for Devices and Radiological Health may provide information
useful in preparing an application for licensure.  It should be noted that some of the guidance
documents included as references are directed primarily at injectable products and consequently
certain of their recommendations, e.g., those concerning endotoxin testing, are not appropriate for
IVD products.  This document, the associated references, and Office of Blood Research and
Review (OBRR) staff should be consulted  when preparing the Chemistry, Manufacturing and
Controls (CMC) section of the Biologic License Application (BLA).  For questions concerning
information to be submitted in the Establishment Description section, the staff of the Division of
Manufacturing and Product Quality should be consulted.
                                                       
1 This guidance has been prepared by the Center for Biologics Evaluation and Research (CBER) at the Food and
Drug Administration. This guidance document represents FDAs current thinking on the content and format of the
Chemistry, Manufacturing and Controls information and Establishment Description information for a biological
in vitro diagnostic product.  It does not create or confer any rights for or on any person and does not operate to bind
FDA or the public.  An alternative approach may be used if such approach satisfies the requirements of the
applicable statute, regulations, or both.
1 II. DEFINITIONS
In Vitro SUBSTANCES
In vitro substances are defined as any and all raw materials and intermediates used in the
manufacture of the final in vitro product as defined in 21 CFR 820.3(c).
In Vitro PRODUCT
The In Vitro product is defined as the licensed product in its final form and all assembled
supporting components.
PART 1  CHEMISTRY, MANUFACTURING AND CONTROLS SECTION
I. IN VITRO SUBSTANCE
A. DESCRIPTION AND CHARACTERIZATION
1. Description
A clear description of each in vitro substance should be provided.  These
descriptions may include, but are not limited to, any of the following: chemical
structure, primary and subunit structure, molecular weight, molecular formula,
established USAN name, antibody class/subclass, etc., as appropriate.
2. Characterization
A description and the results of all the analytical testing performed to characterize
the in vitro substances should be submitted (17, 19, 20, 22).  Information from
specific tests regarding identity, potency, specificity, purity, stability, consistency,
etc. of the in vitro substances should be submitted.
a. Physicochemical Characterization
Examples of analyses for which information may be submitted include, but
are not necessarily limited to the following.
  amino acid analysis
  amino- and carboxyl-terminal sequencing
  full amino acid sequencing
  peptide mapping/enzymatic mapping
  determination of disulfide linkage
2   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 substance-related proteins including deaminated,
oxidized, clipped, and aggregated forms and other variants, e.g.,
amino acid substitutions, adducts/derivatives
  assays to detect residual non-specific host proteins, DNA, reagents
  immunochemical analyses
  assays to quantitate bioburden, endotoxin
  antibody neutralization
  hemagglutination
  hemagglutination inhibition
  antibody nitrogen level
Additional physicochemical characterization may be necessary for
substances undergoing post-translational modifications, e.g., glycosylation,
and for substances derivatized with other agents, including other proteins,
enzymes, radionuclides, or chemicals.  The information submitted should
include the degree of derivatization or conjugation, the amount of
unmodified substance, removal of free materials (e.g., enzymes, proteins
radionuclides, etc.), and the stability of the modified substance as a result
of the manufacturing process.
All test methods should be fully described, validated, and the results
provided.  The application should also include the actual data such as
chromatograms, photographs of SDS-PAGE or agarose gel, spectra, etc.
b. Activity of the in vitro Substances
A description and results of all relevant in vitro (and where applicable in
vivo) testing which is performed to show the potency, specificity,
activity(ies) and acceptance criteria for each in vitro substance should be
provided.  (14 - 17, 21).  The description and validation of each assay
employed should include the methods and standards used, procedural steps,
the inter- and intra-assay variability, linearity, and the acceptable limits of
the assay.
3 B. MANUFACTURERS
 
1. Identification
The name(s), address(es), FDA registration number(s) and other pertinent
organizational information for each manufacturer responsible for any portion of the
manufacture or testing operations for the in vitro substance should be submitted.
This may include contractors or other company subsidiaries serving as contractors,
or other locations/sites owned and operated by the applicant.  A brief description
of the operations performed by each party and the responsibilities conferred upon
each party by the applicant should be submitted.
2. Floor Diagram(s)
For each manufacturing location, a floor diagram that indicates the facility(ies)
layout should be submitted.  This diagram need not be a detailed engineering
schematic or blueprint, but rather a simple drawing that depicts the relationship of
the 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 in vitro 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.  Room
numbers or other unique identifiers should be provided, however the location of
processing equipment within rooms and areas is not necessary.  Reference can be
made to manufacturing flow information presented in other areas of the submission
and the General Information portion of the Establishment Description section.
3. Manufacture of Other Products
A comprehensive list of all additional substances to be manufactured or
manipulated in the areas used for the product which is the subject of the
application should be submitted.  The applicant should indicate in which rooms the
additional substances will be introduced and the manufacturing steps that will be
performed.  An explanation should be given as to whether additional substances
will be introduced on a campaign basis or concurrently during production of the
substance which is the subject of the application.  Indication should also be given
to additional substances that may share contact with equipment (dedicated vs.
multi-use equipment should be delineated for each process step in this section or
other appropriate sections of the application) used in the production.  A brief
description should be provided as to the type and developmental status of the
additional substances.
4. Contamination Precautions
4 For all areas in which operations for the preparation of cell banks and product
manufacturing are performed, the following information concerning precautions
taken to prevent contamination or cross-contamination should be submitted:
  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, e.g., provide if design represents an
open or closed system or provides for a sterile or non-sterile operation;
 
  a description of the in-process controls performed to prevent or to identify
contamination or cross contamination.  The manipulation of more than one
substance (e.g., cell lines, sera, antigens) in a single area or processed by
non-dedicated equipment should be described and the measures used to
ensure prevention of cross contamination should be discussed.
C. METHOD OF MANUFACTURE
1. Raw Materials and Substances
A list of all components used in the manufacture of the in vitro substance, and their
qualifying tests and specifications, or reference to official compendia, should be
submitted.  For purchased raw materials, representative certificates of analysis
from the supplier(s) and in-house acceptance testing results should be submitted.
Note that process gases (e.g., air, carbon dioxide, etc.) and water are considered
raw materials.
A list of qualifying tests, test results and acceptance criteria for all special reagents
and materials used in the manufacture of the in vitro substance, e.g., culture media,
diluents, dyes, reagents, buffers, sera, antibiotics, monoclonal antibodies,
preservatives should be submitted.  In some cases (e.g., a peptide or monoclonal
antibody used in manufacture of the in vitro substance), a detailed description of
preparation and characterization may be required (14 - 17).
A description of the tests and specifications for materials from an animal source
that may potentially be contaminated with adventitious agents, e.g., mycoplasma,
Bovine Spongiform Encephalophathy agent (BSE) for bovine derived products,
and other adventitious agents of human and animal origin should be submitted.
5 Information (validation data) or certification supporting the freedom of substances
from adventitious agents should be included in the submission.
In some cases an applicant may wish to purchase, rather than manufacture a
licensed component of the final product.  There are several possible regulatory
approaches that might be used.  Discussion of these approaches with CBER at the
planning stage is recommended.
2. Flow Charts
A complete visual representation of the manufacturing process flow should be
submitted.  This flow chart should indicate for each step in production the
equipment and materials used, the room or area where the operation is performed
(may reference other parts of the application) 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, building sites, etc.  References can be made to other sections of the
application for more detailed process information.
3. Detailed Description
a. Animal Sources
Detailed guidance in this area may be obtained from the Draft 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.
Information submitted concerning animals used in manufacturing, such as
mice used for ascites production, rabbits used for serum-antibody
production, or transgenic animals, should include detailed information on
the following:
  source and type of animals used (if transgenic, include the method
of creation and the genetic stability)
  adventitious agent screening and the quarantine procedures used
  animal husbandry procedures
  veterinary oversight
  for bovine products specify geographic source and location of
herd(s)
  immunogens used
6 -   immunogenicity
-   specificity
-   purity
-   sterility
-   stability
-   immunization type, dose and schedule
-   adjuvant if any
  Substance harvested
-   description of substance of interest
-   collection method, volume, receptacle, and schedule
-   description of processing steps and component(s) used
-   testing performed (titer/potency, affinity, specificity, sensitivity,
bioburden, stability)
-   storage conditions
-   other characteristics unique to the substance, process or
intended use.
 
b. Human Sources
The information submitted concerning the use of source material of human
origin should include, but is not limited to, the following:
  donor suitability/acceptance criteria
  collection method, volume, and receptacle
  anticoagulants used
  description of component of interest
  component processing
  testing performed
-   infectious disease marker tests
-   titer (potency)
-   affinity
-   specificity
-   sensitivity
-   bioburden
-   stability
  purification and inactivation procedures
  storage conditions
  viral inactivation procedures
  immunization dose and schedule
  other characteristics unique to the substance, process or intended
use.
c. Cellular Sources
7 The information submitted concerning the use of source material of cellular
origin, e.g., in monoclonal antibody or recombinant DNA technology,
should include, but is not limited to, the following:
  source and type of cells
  phenotype and genotype of cells
  characterization of the parent cell line
  cloning procedures
  immortilization procedures
  testing and monitoring procedures
  characterization of gene construct
  characterization of vector
  establishment, characterization, maintenance, and stability of cell
banks
  cell culture procedures
  harvesting procedures
  purification and inactivation procedures
  downstream processing procedures
  other characteristics unique to the substance process or intended
use.
Further information can also be found in the 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 dated August 1996.
d. Synthetic Sources
Information should be submitted concerning the use of materials from
synthetic sources, e.g., synthetic peptides.  The detail of the peptide
synthesis including purification procedures should be provided as outlined
in the Guidance for Industry for the Submission of Chemistry,
Manufacturing, and  Controls Information for Synthetic Peptide
Substances.
D. PROCESS CONTROLS
1. In-process Controls
A description of the methods used for in-process controls, i.e., monitoring, testing,
etc., used to assure that the functional requirement of the final product is met, e.g.,
integrity of solid-phase coatings, purity of enzyme labeled antibody/antigen
conjugates, and potency, should be submitted.
2. Process Validation
8 A description and the results of the process validation studies should be submitted.
If the manufacturing process was changed or scaled-up for commercial production
and involved changes in the manufacturing steps, the re-evaluation of the process
should be described, and the data and results provided.  The description should
include studies for the following processes which identify critical parameters to be
used as in-process controls to ensure the success of routine production.  Refer to
the manufacturing flow diagram(s) as appropriate.
Validation studies should be submitted for the following:
  cell growth and harvesting processes
  purification processes
  inactivating or removing any infectious pathogens from substances used in
the manufacturing process
  to demonstrate microbiologic control over those processes susceptible to
microbiological contamination for substances labeled as sterile or where
preservatives are used.
  solid-phase coating processes
  conjugation processes
  potency adjustments
  others as appropriate
E. REFERENCE STANDARDS/PANELS
1. Reference Standard
If an International Reference Standard (World Health Organization), CBER
Reference Standard or compendial reference standard (U. S.
Pharmacopoeia/National Formulary) is used, the citation for the standard and a
certificate of analysis should be submitted.  If no reference standard exists and the
applicant establishes in-house, primary reference standards, a description of the
characterization and specifications of the standards should be provided.  The
results of testing, such as amino acid analysis and biologic activity determination of
the standard should be submitted.  The Standard Operating Procedures (SOPs) to
be used for qualifying a new reference standard should be included.  Information
should be provided on the stability of any reference standard.
9 2. In-house Reference Standard
In-house working reference standards should be used and the descriptions of the
preparation, characterization, specifications, testing, substitutions, and results
should be provided.  The SOPs to be used for manufacture and qualification of a
new in-house standard should be included.  The data from the calibration of the in-
house working reference standards should be compared against a primary
reference standard and those results submitted.
F. SPECIFICATIONS/ANALYTICAL METHODS
1. In vitro Substance Specifications and Tests
Specifications and analytical methods used for release testing, shelf life
determination and distribution conditions should be described in detail.
Specifications and tests for the in vitro substance which are used to assure its
identity purity, strength and/or potency, specificity, and batch to batch consistency
should be described in detail.  (See applicable guidance documents in Appendix A).
The analytical systems should be validated and the data should be provided for
non-compendial methods to demonstrate the system suitability.
2. Impurities Profile
A discussion of the impurity profiles with supporting analytical data, should be
provided.  Profiles of variants of the protein in vitro substance (e.g., clipped,
aggregated, deaminated, and oxidized forms), as well as non-product related
impurities (e.g., process reagents and cell culture components), should be included.
G. CONTAINER/CLOSURE SYSTEM
A description of the in-process container and closure systems and their compatibility with
the in vitro substance should be included (5).  Detailed information concerning the
supplier, address, and the results of compatibility, e.g., adsorption, leachables, biological
tests, etc., should be included. Evidence of container and closure integrity for the duration
of the proposed storage period should be provided.
H. STABILITY
A description of the storage conditions, SOPs, study protocols and results supporting the
stability of the in vitro substance should be provided (3, 22, 24).  This should include
information on the stability of intermediate fluids or formulated bulk under specified
holding or shipping conditions, as appropriate.  Data from tests to monitor the biological
activity and degradation products such as aggregated, deaminated, oxidized, and clipped
forms should be included, as appropriate.
10 II. IN VITRO PRODUCT
A. MANUFACTURER
Include the name(s), and address(es) of all manufacturers involved in the manufacture and
testing of the in vitro product, including contractors, and a description of the
responsibility(ies) of each.  A list of all other products (R&D, clinical or approved) made
in the same rooms should be provided.  If an investigational product formulation was
different from that of the to-be-marketed finished product, clinical data to support
equivalence of the two formulations should be provided, as appropriate.
B. COMPOSITION
A description of all components, including quantities, ratios or formulas used in the
manufacture of the in vitro product in accordance with the Guideline for Submitting
Documentation for the Manufacture of and Controls for Drug Products should be
included.  If an investigational product formulation was different from that of the to-be-
marketed finished product, clinical data to support equivalence of the two formulations
should be provided, as appropriate.
C. METHODS OF MANUFACTURING AND PACKAGING
A complete description of the manufacturing process flow for each formulated bulk should
be provided.  This discussion should include a description of non-sterile operations, as
well as sterilization operations, aseptic processing procedures, vialing/filling,
lyophilization, labeling, 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 other portions of
the application) 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
connections, sanitary connection, open transfers under laminar flow units, etc.  Such
transfers should be described for the movement of product between equipment,
areas/rooms, building and sites.  References can be made to other sections of the
application for more detailed process information.  Provide an assessment of baseline
environmental conditions, a description of monitoring methods, specifications, and results
obtained, and a description of methods of environmental control throughout all
manufacturing areas used in production of the product.
11 D. SPECIFICATIONS AND TEST METHODS
This section should contain a description of all test methods and specifications used to
assure the identity, purity, strength, and/or potency, specificity, and lot to lot consistency
of the final finished product.  The information submitted should include, but not be limited
to:
  The sampling procedures for monitoring a lot of finished in vitro product.
  The validation data for system suitability for all non-compendial tests.
  The results of validation studies to ensure non-interference of special inactive
ingredients, in USP compendial methods.
  Certificates of analysis and analytical results from in-house testing for at least three
consecutive qualification lots of the in vitro substance should be provided.
  A description and results of all relevant in vitro (and where applicable in vivo)
testing which is performed to show the potency, specificity, activity(ies) and
acceptance criteria for each in vitro product, including
-   the methods and standards used,
-   procedural steps,
-   the inter- and intra-assay variability,
-   linearity,
-   the acceptable limits of the assay, and
-   bioburden testing.
 
E. CONTAINER/CLOSURE SYSTEM
A description of the container and closure systems, and their compatibility with the in
vitro product should be provided.  Detailed information concerning the supplier, address,
and the results of compatibility and biological tests should be included.  A device or drug
master file (DMF) may be referenced for this information. Evidence of container and
closure integrity should be provided for the duration of the proposed expiry period.
F. MICROBIOLOGY
If the product is 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.  For additional guidance on other
aspects of microbiologically controlled products, please refer to Guideline for the
Manufacture of In Vitro Diagnostic Products.
G. STABILITY
A description of the storage conditions, study protocols and results supporting the stability
of the in vitro 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.  Stability data supporting the proposed shelf-life of the
12 reconstituted in vitro product and for all labeled dilutions should be provided.  The
validated results of all tests used to monitor performance characteristics, preservative
effectiveness and the presence of degradation products such as aggregated, deaminated,
oxidized, and clipped forms of the in vitro product should be provided (3, 11, 22, 24).
H. BATCH PRODUCTION RECORDS
A completed (executed) batch production record/device history record representative of
the entire process of manufacturing and testing for the in vitro product should be
submitted.
III. ENVIRONMENTAL ASSESSMENT
An environmental assessment should be prepared as outlined in 21 CFR Part 25.  Provide a
description of the action that is being considered and 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.
IV. METHOD VALIDATION
Information as described in the Guideline for Submitting Samples and Analytical Data for
Methods Validation should be provided.
PART 2  ESTABLISHMENT DESCRIPTION SECTION
I. INTRODUCTION
This section provides guidance on the content and format of information submitted in the
Establishment Description section of a License Application for biological in vitro diagnostic
products.  The establishment description information submitted should be appropriate for the in
vitro devices being manufactured and in accordance with 21 CFR Part 820 and other in vitro
standards as appropriate.  The information contained in this section need not be submitted for
recombinant DNA derived In Vitro substances, synthetic peptide In Vitro substances, or
monoclonal antibody In Vitro substances.  For final In Vitro products that contain In Vitro
substances in one or more of these three categories and other In Vitro substances, the information
in this section should be submitted for the other In Vitro substances and all processes downstream
of their incorporation into the final product.
13 II. GENERAL INFORMATION
For each manufacturing location, a floor diagram should be included that indicates the general
facility layout.  The following information should be provided on each floor diagram and/or in an
accompanying narrative:
 
  Product, personnel, equipment, waste and air flow;
  An illustration or indication of which areas are served by each air handling unit; and
  Air pressure differentials between adjacent areas.
Alternatively, this information may be illustrated on the floor diagram requested in the CMC
section.  The manufacturing flow chart requested in the CMC section may also be referenced as
applicable.
III. SPECIFIC SYSTEMS
A. WATER SYSTEMS
Information on water purification systems for the production of water for use in
manufacturing and rinsing of product contact equipment, and containers and closures
should be provided.
1. General Description
A general description of the water system(s) should be submitted, including water
source, major components, and a general discussion of the type of water used for
each stage of processing.
2. Validation Summary
 
  A validation summary should be provided containing:
 
  a narrative description of the validation process (or protocol) including
acceptance criteria
  certification that installation qualification (IQ) and operational qualification
(OQ) have been completed;
  the length of the validation period;
  the parameters monitored and tests performed;
  the frequency of monitoring each point of use during the validation period;
  a validation data summary; and
  an explanation of all excursions or failures, including deviation reports and
results of investigations.
14 3. Routine Monitoring Program
A narrative description of the routine monitoring program should be submitted, to
include:
  the tests performed and their specifications;
  the frequency of testing;
  the alert and action limits used; and
  a summary of actions to be taken when limits are exceeded.
B. HEATING, VENTILATING AND AIR CONDITIONING SYSTEMS (HVAC)
1. General Description
 
A general description of the HVAC system(s) should be provided including:
  the number and segregation of air handling units;
  whether air is once-through or recirculated;
  containment features; and
  air changes/hour.
The information required for some of these features is described below in greater
detail in the contamination/cross contamination section of this document.
Reference may be made to information in the CMC section.
2. Validation Summary
A validation summary with the following information should be provided for the
system, which contains:
  a narrative description of the validation process (or protocol), including the
acceptance criteria;
  certification that IQ, OQ, and certification of filters has been completed;
  length of the validation period;
  a validation data summary (validation data should include Performance
Qualification data accumulated during actual processing); and
  an explanation of all excursions or failures, including deviation reports and
results of investigations.
15 3. Routine Monitoring Program
A narrative description of the routine monitoring program should be provided
including:
  the tests performed and frequencies of testing for viable, nonviable
particulate, and surface monitoring parameters;
  viable and nonviable particulate action and alert limits for production
operations for each manufacturing area; and
  a summary of actions to be taken when limits are exceeded.
C. CONTAMINATION/CROSS CONTAMINATION ISSUES
The following information regarding methods to prevent contamination and cross
contamination should be provided to supplement the information requested in the CMC
section of the application.
1. Cleaning Procedures and Validation
a. Dedicated Equipment
A brief description of the cleaning procedures and cleaning reagents used
should be provided.  This section should also contain a certification that the
cleaning validation for removal of product residuals and cleaning agents has
been successfully completed.
b. Shared Equipment
This section should contain:
  a brief description of the cleaning procedures and cleaning reagents;
  a rationale for the cleaning procedures chosen which addresses their
effectiveness for the residual products to be removed; and
  a validation report describing the cleaning validation procedures for
removal of product residues and cleaning agents.  The report
should identify the sampling and analytical methods used and
address their sensitivities and specificities.
2. Containment Features
This section should contain a description of segregation and containment
procedures for areas, manufacturing operations, personnel, equipment and waste
materials designed to prevent contamination of products.  The features that are
employed to maintain segregation and containment should be discussed.  These
features might include but not be limited to:
16   air pressure differentials between adjacent manufacturing areas;
  segregation of air handling units;
  air supply and return (recirculated, once-through, HEPA filtered out, etc.);
and
  use of airlocks
Reference may be made to information in the CMC section.
D. COMPUTER SYSTEMS
This section should contain information on computer systems which control critical
manufacturing processes.  The developer of the system, i.e., whether in-house or
contractor, should be identified.  The information provided should also include a brief
description of procedures for changes to the computer system.  For each of these systems
a list of the manufacturing steps which are computer-controlled should be provided.  This
section should also contain a validation summary for each of these systems, which
includes:
  a narrative description of the validation process (or protocol), including acceptance
criteria;
  certification that IQ and OQ have been completed;
  an explanation of the parameters monitored and tests performed;
  a validation data summary;
  an explanation of all excursions or failures; and
  deviation reports and results of investigations for all excursions or failures.
17 APPENDIX A
Guidance
1.  Guidance for Industry for the Submission of Documentation for Sterilization Process
Validation in Applications for Human and Veterinary Drug Products (1994)
 
2.  Guideline on Sterile Drug Products Produced by Aseptic Processing (1987)
 
3.  Guideline for Submitting Documentation for the Stability of Human Drugs and Biologics
(1987)
 
4.  Guideline for Submitting Samples and Analytical Data for Methods Validation (1987)
 
5.  Guideline for Submitting Documentation for Packaging for Human Drugs and Biologics
(1987)
 
6.  Guideline on General Principles of Process Validation (1987)
 
7.  Guideline for Collection of Blood and Blood Products from Donors with Positive Tests for
Infectious Disease Markers (High Risk Donors) (1989)
 
8.  Guideline for Determination of Residual Moisture in Dried Biological Products (1990)
 
9.  Draft Guideline for Reporting-ABRs-Adverse Reactions to Licensed Biological Products
(1990)
 
10. Draft Guideline for Quality Assurance in Blood Establishments (1993)
 
11. Draft Recommended Methods for Evaluating Potency, Specificity, and Reactivity of Anti-
Human Globulin (1992)
 
12. Draft Recommended Methods for Blood Grouping Reagents Evaluation (1992)
 
13. FDAs Policy Statement Concerning Cooperative Manufacturing Arrangements for Licensed
Biologicals (1992)
 
14. Guideline for the Manufacture of In Vitro Diagnostic Products (1994)
15.Guidance for Industry for the Submission of  Chemistry, Manufacturing, and Controls
Information for Synthetic Peptide Substances (1994)
18 Points to Consider
 
16.Draft Points to Consider in the Manufacture and Clinical Evaluation of In Vitro Tests to
Detect Antibodies to the Human Immunodeficiency Virus, Type 1 (1989)
 
17.Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for
Human Use (1997)
 
18.Points to Consider in the Manufacture and Testing of Therapeutic Products for Human Use
Derived From Transgenic Animals (1995)
 
19.Points to Consider-Characterization of Cell Line Used to Produce Biological Products (1993)
 
20.Points to Consider in the Design and Implementation of Field Trials for Blood Grouping
Reagents and Anti-Human Globulins (1992)
 
21.Points to Consider in the Manufacture of In Vitro Monoclonal Antibody Products for Further
Manufacture into Blood Grouping Reagents and Anti-Human Globulins (1992)
 
International Conference on Harmonization (ICH) Guidelines
 
22.Stability Testing of New Drug Substances and Products (9/22/94)
 
23.Analysis of the Expression Construct in Cells Used for Production of R-DNA Derived Protein
Products (2/23/96)
 
24. Q  uality of Biotechnological Products:  Stability Testing of Biotechnological/ Biological
Products (7/10/96)
19