Guidance for Industry
For the Submission of Chemistry,
Manufacturing and Controls and
Establishment Description
Information for Human Plasma-
Derived Biological Products, Animal
Plasma or Serum-Derived Products
Additional copies are available from:
Office of Communication, Training and
Manufacturers Assistance (HFM-40)
1401 Rockville Pike
Rockville, MD 20852-1448
(Tel) 301-827-1800
or 1-800-835-4709
(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)
February 1999 TABLE OF CONTENTS
[Note: Page numbering may vary for documents distributed electronically.]
GENERAL INFORMATION...................................................................................................1
I. BACKGROUND...................................................................................................................1
II.  DEFINITIONS....................................................................................................................1
PART 1  CHEMISTRY, MANUFACTURING AND CONTROLS SECTION...................3
I. INTRODUCTION.................................................................................................................3
II. BIOLOGICAL SUBSTANCE/PRODUCT.........................................................................3
A. Description and Characterization....................................................................................3
B. Manufacturer(s)................................................................................................................4
C. Methods of Manufacturing and Packaging.....................................................................6
D. Process Controls................................................................................................................8
E. Reference Standards.........................................................................................................9
F. Specifications/Analytical Methods....................................................................................9
G. Container Closure System/Shipping Containers...........................................................10
H. Stability...........................................................................................................................10
III. INVESTIGATIONAL PRODUCT/FORMULATION....................................................11
IV. ENVIRONMENTAL ASSESSMENT..............................................................................11
V.  METHOD VALIDATION................................................................................................11
PART 2  ESTABLISHMENT DESCRIPTION SECTION.................................................12
I. INTRODUCTION...............................................................................................................12
II. GENERAL INFORMATION............................................................................................12
III. SPECIFIC SYSTEMS......................................................................................................12
A. Water Systems.................................................................................................................12
B. Heating, Ventilation, and Air Conditioning Systems (HVAC).....................................13
C. Contamination/Cross-Contamination Issues.................................................................14
D. Lyophilization.................................................................................................................14
E. Computer Systems...........................................................................................................15
APPENDIX A..........................................................................................................................16
i Guidance for Industry:1
For the Submission of Chemistry, Manufacturing and
Controls and Establishment Description Information for
Human Plasma-Derived Biological Products, Animal Plasma
or Serum-Derived Products
GENERAL INFORMATION
I. BACKGROUND
In the Federal Register of July 8, 1997 (62 FR 36558), the Food and Drug Administration
(FDA) announced the availability of the revised Form FDA 356h, Biologics License
Application (BLA) entitled Application to Market a New Drug, Biologic, or an
Antibiotic for Human Use.  This document provides guidance on the content and format
of the Chemistry, Manufacturing and Controls (CMC) section and the Establishment
Description section of a Biologics License Application for a Human Plasma-Derived
Biological Product, Animal Plasma or Serum-Derived Product.  For these products, FDA
is now implementing the BLA (revised Form FDA 356h) and will accept that application,
instead of two separate license application submissions, the product license application
(PLA) and the establishment license application (ELA).
This document supersedes the draft guidance entitled Guidance for Industry: For the
Submission of Chemistry, Manufacturing and Controls and Establishment Description
Information for Human Plasma-Derived Biological Products or Animal Plasma or Serum-
Derived Products that was announced in the Federal Register of January 21, 1998 (63
FR 3145).
II. DEFINITIONS
Plasma Proteins
The liquid portion of blood contains many dissolved components, primarily proteins
which are important in the humoral immune systems and the coagulation system.
Immune proteins are predominantly immunoglobulins, antibodies, which react
specifically with antigens.  Coagulation proteins contribute to the series of enzyme-
substrate reactions and platelet function which are responsible for maintaining
hemostasis.
                                                       
1 This document represents FDAs current thinking on the content and format of the Chemistry,
Manufacturing and Controls and Establishment Description information for human plasma-derived,
biological products, animal plasma or serum-derived products.  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 Human Plasma-Derived Biological Product
Many important therapeutic products are purified from human plasma.  Plasma is the
liquid portion of blood and is usually separated from the formed components in single
units at collection.  Plasma contains anticoagulants so that the coagulation proteins are
not activated and the collected blood does not clot.  Collection is performed by
apheresis or by centrifugation of whole blood.  The units of plasma are usually pooled
into large batches for separation into the various therapeutic components.  Some of
these components are proteins circulating in normal blood.  In other cases, the plasma
is screened to identify units which may have high amounts (titer) of a specific
component, e.g., immunoglobulins to rabies virus.  These high titered units are then
pooled for fractionation.
Animal Plasma, Serum-Derived Product
Historically, the immunization of animals for the collection of specific immune plasma
or serum is a method that has been very effective and safe.  The serum as a source for
the biological product is different than plasma in that the blood is allowed to clot and
most of the coagulation proteins are removed.
Fractionation
The process of separating specific biological function from the mixture of plasma or
serum proteins is referred to as fractionation.  Plasma is separated into different
fractions using various chemical and physical methods to allow the concentration of
the desired activity and removal of unwanted activity and contaminants.
Virus Clearance
Many manufacturing steps have been demonstrated to remove or inactivate particular
viruses.  This demonstration is performed in the laboratory to avoid contamination of
manufacturing facilities and to properly contain the agents that are used in the
validation studies.  A number of principles may be used to demonstrate expected
removal or inactivation of infectious virus.  One of these is the use of actual
manufacturing materials in an appropriate reproduction of a particular manufacturing
step on a smaller scale.  Where particular agents of interest or testing methods are
unavailable, model viruses which are similar in specific characteristics may be used.
Because of limitations in the attainable titer of particular viruses, individual
manufacturing steps, rather than the entire manufacturing process are usually
evaluated; however, more than one step might be evaluated in a single experiment.  A
manufacturing scheme may include steps which are intended to specifically address
removal and steps which specifically address inactivation.
2 PART 1  CHEMISTRY, MANUFACTURING AND CONTROLS SECTION
I. INTRODUCTION
The starting materials for human plasma-derived products are known to be capable of
transmitting infectious disease and many of the infectious agents of primary concern have
been identified.  The approach to viral safety of plasma-derived materials incorporates
donor screening, testing for agent markers in source material, validation of removal or
inactivation of known and model viruses, lot release testing where appropriate, and
effective surveillance following marketing.  All of these areas should be addressed in
designing and validating the manufacturing process.  All manufacturing methods and
validations of the process should be described in the CMC section of the Biologics License
Application.
II. BIOLOGICAL SUBSTANCE/PRODUCT
Production of a human plasma-derived, animal plasma or serum-derived biological
component requires a complex series of manufacturing steps.  The consistent production
of these materials relies on validation of the processes involved and on the control of the
validated processes.  Each manufacturing step begins with the product from the preceding
step.  The routine control of manufacturing relies on correct raw materials, in-process
testing, and exact adherence to manufacturing procedures as specified and validated.
Thus, the evaluation of a manufacturing process involves all of these factors.  In order for
this evaluation to be complete, all components of the process should be completely
validated and described.
A. Description and Characterization
1.  Description
a.   Names:  This section should contain a list of the names of the product.
This may include, but is not limited to, any of the following:  name(s)
and, as appropriate and available, the established (proper or generic)
and proprietary (brand) names or synonyms.
b. Active Biological Component:  A clear description of the biological
substance should be provided.  This description may include applicable
information that briefly and succinctly characterizes the biological
substance.
2. Characterization
This section should contain specific tests that will provide information
regarding identity, stability and consistency of manufacture for the
biological drug substance.  All test methods should be fully described and
data provided.
a. Physicochemical Characterization (Biological Specifications)
3 In general, characterization may include, but need not be limited to the
following:
  Potency Assays,
  Chromatographic Assays,
  Electrophoresis, e.g., Sodium Dodecyl Sulfate-Polyacrylamide
Gel Electrophoresis (SDS-PAGE),
  Immunoblot Analysis,
  Fluorescence Activated Cell Sorter (FACS) Analysis,
  Enzyme-Linked Immunosorbent Assay (ELISA).
b. Biological Activity Potency
Biological testing performed on the manufacturers reference (standard
lot or test lot) to determine potency/biological activity of the product
should be described.  This description of the potency assay should
include the methods and standards used and the variability and
acceptable limits of the assay.
c. Statistical Analysis/Data Validating Methods
Results of statistical analysis/data validating assay methods and
procedures ensuring accurate results and/or potency levels should be
provided.
B. Manufacturer(s)
1. Identification
This section should include the name(s), address(es), zip code(s),
telephone number(s), FDA registration number, and other pertinent
organizational information for each manufacturer, storage, testing, and
labeling facility responsible for any portion of the manufacture or
testing operations for the biological product.  This may include
independent contractors, animal care facilities or other company
subsidiaries serving as contractors, or other locations/sites owned,
operated and contracted 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.  The steps taken
by the applicant to ensure that each party fulfills its responsibilities
should also be described.
2. Floor Diagram(s)
For each manufacturing/testing/storage location, a floor diagram should
be included that indicates the general facility(ies) layout.  The 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 the adjacent areas that are not the subject
of the application.  This diagram should be sufficiently clear so that the
reviewer may visualize the flow of production of the biological
4 substance and would be able to identify areas or room proximities
that may be of concern for particular operations (e.g., segregation of
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 charts described in Part 1, Section II.C.2. of this document.
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. A
brief description should be provided as to the type and developmental
status (including pre-clinical and investigational) of the additional
products.  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).
4. Contamination
For all manufacturing areas, 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 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., 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 product in a single area, or the use of any
piece of equipment for more than one product, should be indicated and
measures to ensure prevention of cross-contamination should be discussed.
5 C. Methods of Manufacturing and Packaging
This section should be completed for each biological substance described in
Part 1 Section II.  A detailed description of the manufacturing and controls
should be provided to demonstrate proper quality control or prevention of
possible contamination with adventitious agents.  The inclusion of a list of all
relevant Standard Operating Procedures (SOPs) is recommended.
1. Starting Materials
Materials used in the collection and processing of the biological substance
should be fully described.  This description should include a list of starting
materials, reagents, and auxiliary materials with specifications or statements
of the quality of each.  Any alternative methods or variations in the
manufacturing process should be included with an explanation of the
circumstances under which they would be used.
a.   For purchased raw materials, representative certificates of analysis from
the suppliers or the manufacturers own acceptance testing results
should be submitted.  This should include information on expiration
dating, and frequency limits of re-testing if raw material is not used
within a specified time.
b.  The tests and specifications for materials of animal source that may
potentially be contaminated with adventitious agents, e.g., Bovine
Spongiform Encephalopathy (BSE) for fetal bovine serum, and viruses
in products of human and animal origin should be fully described.
Information or certification supporting the freedom of reagents from
adventitious agents should be included in the submission.
c.   The plasma source should be described and whether it was obtained as
recovered, source or under short supply agreements.  A description of
the type of shipping and the storage temperature, and the disposal of
rejected plasma should be included.
d. A list of tests and specifications for all special reagents and materials
used in the manufacture of the drug substance, e.g., buffers, sera,
antibiotics, monoclonal antibodies, and preservatives should be
included.  In some cases (e.g., a monoclonal antibody used in
manufacture of the biologic) a detailed description of their preparation
and characterization should be provided.  If human tissues are used for
absorption or adsorption, testing for donor suitability should be
described.
e. Many plasma fractionation facilities receive intermediate products from
other manufacturers.  A description of the specifications for the
intermediate product should be provided along with data supporting its
stability during storage and shipping.
f. The receipt or manipulation of materials to be used for different
products in a single area or piece of equipment should be indicated and
6 measures to ensure prevention of cross-contamination should be
discussed (e.g., some fractionation facilities may process plasma
collected outside the United States for use outside the U.S.)
2. Flow Charts
In this section, a complete visual representation of the manufacturing
process flow should be provided.  This flow chart should show the steps in
production, equipment, and materials used, room or area where the
operation is performed (may reference diagrams in other sections 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, (e.g., open transfers under
laminar flow units).  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.
Reference may be made to other sections of the application for more
detailed process information.  If equipment is dedicated to specific areas or
products, it should be identified.
 
3.  Detailed Description
a. Animal sources and procedures should be fully described.  The
following should be addressed in detail.
  How animals are entered into production;
  Source of animals;
  Immunization methods;
  Animal husbandry procedures including;
-   Adventitious agent screening and quarantine procedures;
-   Veterinary oversight;
-   Bleeding protocols;
-   A description of the areas and environmental conditions for
manipulating production animals;
-   A description of any special equipment and cleaning methods;
and
-   A description and illustration of the physical separation between
animal facilities and other manufacturing areas and personnel
flow between these areas.  Segregation procedures for multi-
product areas should be described.  Reference may be made to
other sections of the submission as applicable.
b.  A detailed description of the fractionation, formulation, and purification
should be provided.  This should include a rationale for the chosen
methods, and the precautions taken to assure containment and
prevention of contamination or cross-contamination.  In-process
bioburden and endotoxin limits should be specified where appropriate.
Any reprocessing or related method should be fully validated and
7 described.  The allowable conditions for reprocessing of all or part of
any batch should be described. Critical operations during which product
or product contact surfaces are exposed to the environment should be
described.  If barrier isolator systems are used, a description of the
system and the conditions of its use should be provided.  Information
and data on drug product filtration should be provided.
4. Batch Records:  A completed batch record of the process of production
of the biologic product should be included.
D. Process Controls
1.  A description of the control checks performed at various stages of the
manufacture, processing, and packaging of the biological substance
should be submitted.  The description should include the specifications
and tests for any intermediate steps with justification, as needed, for
their use.  Yield calculations at each major step in manufacturing
should be performed.
 
2.  A description of in-process and final controls, including analytical tests
and appropriate data to support the specifications should be submitted.
3. Any additional information regarding the processing or possible
reprocessing of the final product should be submitted.  This should
include the rationale for the reprocessing, and a description of the
circumstances under which reprocessing would be allowed as well as
any validation data to indicate how reprocessing would affect the
product.
4.  Validation data should be provided for a number of processes.
a.   A description of the validation studies which identify, and establish
acceptable limits for critical parameters to be used as in-process
controls, to assure the success of routine production.  Reference
may be made to flow charts or diagrams as appropriate.
b.  Validation studies for the purification process; a description of the
validation of the purification process to demonstrate adequate
removal of extraneous substances such as chemicals used in the
purification, column contaminants, endotoxin, antibiotics, residual
plasma proteins, non-viable particulates, and viruses should be
provided.
 
5.  Microbiology
a. If the product is intended to be sterile, information on all
sterilization and aseptic processes (e.g., formulation through filling
8 and sealing) 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 and Guideline on Sterile Drug Products Produced by
Aseptic Processing.
b. A description of the validation studies for any processes used for
inactivation of waste for release into the environment should be
provided.
E. Reference Standards
1. Primary reference standard
a. If an international standard (World Health Organization, National
Institute of Biological Standards and Control) or compendial
reference standard (United States Pharmacopoeia) is to be used, the
citation for the standard and a certificate of analysis should be
submitted.
b. If there is no reference standard and the applicant establishes its
own, a description of the preparation, characterization, and
specifications of the standard should be provided.  The results of
standard testing, such as biologic activity determination, should be
submitted, and a certificate of analysis should be provided.  The
SOPs to be used for qualifying a new reference standard should be
included.  Stability data on the standard should also be provided.
c.   A description of the storage conditions and control procedures
should be provided.
2. Working reference standard
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. Biological drug product specifications and tests
a. Specifications and analytical methods used for release testing,
expiration dating, acceptable regulatory specifications and tests for
the product, sufficient to assure its identity, purity, strength, or
potency and lot-to-lot consistency should be submitted.  Validation
of the analytical systems and the data should be provided for non-
compendial methods to demonstrate the system suitability.
b. Lot release protocols, including specification ranges of
representative lots of the product should be provided.
9 Specifications may include, but not be limited to, biochemical
purity, safety, appearance, pH, residual moisture, excipients,
endotoxins, and sterility.
c. A description of all materials packaged with the biological products
such as diluent or syringe, should be described and their appropriate
FDA designation if approved separately.
d.  Methods and standards of acceptance, including the sampling plan
and the accuracy and precision of the analytical methods should be
sufficiently detailed to permit duplication and verification.
2. Excipients
a. A list of compendial excipients and citations for each should be
submitted.
b.  For non-compendial excipients, tests and specifications should be
described. For novel excipients, the preparation, characterization,
and controls should be described.  For inactive ingredients of
human or animal origin, provide certification or results of testing or
other procedures demonstrating their freedom from adventitious
agents.
 
3. Impurities Profile
A discussion of the impurity profiles, with supporting analytical data,
should be provided.  Profiles of variants of the protein including
proteolytic break down products, aggregated forms, chemically
modified forms which are all product related substances should be
determined.  Non-product related impurities, e.g., process reagents,
should be identified where possible.  In addition, other active plasma
components that may be present should be identified.  Specifications
should be set for each of these categories of impurity.
G. Container Closure System/Shipping Containers
A description of the container and closure system, and its compatibility with
the biological substance should be submitted.  This should include detailed
information concerning the supplier, address, and the results of compatibility,
toxicity and biological tests.  Evidence of container and closure integrity
should be provided.  If the container or closure manufacturer has a Master File
with the FDA, a letter authorizing the applicant to cross-reference that file
should be submitted.
H. Stability
1. A description of the storage conditions, study protocols and results
supporting the stability of the biological product and any intermediates that
are stored should be submitted.
10 2. Data from tests to monitor the biological activity or degradation products,
if any, should be included as appropriate.
3.  Measures taken to assure that acceptable conditions are maintained during
transport should be described, and the validation that the product is stable
under those conditions should be submitted.
4. A complete description of, and data derived from, studies of the suitability
of the biological product, including information showing the stability of the
analytical method(s) used, should be submitted.  This should include
descriptions of any additional stability studies underway or contemplated.
Stability data should be submitted for the biological product as packaged in
the container in which it is to be marketed.  The expiration dating period
proposed to be shown on the label should be stated and the date of
manufacture should be described, as well as how it is assigned.  The
validation demonstrating that the product is stable under the conditions in
which it is used should be submitted.
III.INVESTIGATIONAL PRODUCT/FORMULATION
A discussion of any differences in formulation, manufacturing process, or site between
the clinical trials materials and commercial production batches of biological drug
substance/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, as 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.
IV.ENVIRONMENTAL ASSESSMENT
An environmental assessment (EA), as outlined in 21 CFR Part 25, or a request for a
categorical exclusion with the basis for the exclusion, should be submitted.  If an EA is
appropriate, it 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.  Refer to Guidance for Industry: Environmental Assessment of Human Drug
and Biologics Applications.
V. METHOD VALIDATION
Information as described in the Guideline for Submitting Samples and Analytical Data
for Methods Validation should be provided.
11 PART 2  ESTABLISHMENT DESCRIPTION SECTION
I. INTRODUCTION
In the Federal Register of July 8, 1997, 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 section provides guidance on the
content and format of information submitted in the establishment description section of
a Biologics License Application for products derived from human plasma, animal
serum or animal plasma.
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
The following 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.  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.  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;
12   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.
3. A narrative description of the routine monitoring program should be
submitted, to include:
  The tests performed;
  The frequency of testing;
  The alert and action limits used; and
  A summary of actions to be taken when limits are exceeded.
B. Heating, Ventilation, and Air Conditioning Systems (HVAC)
1. 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. 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.
3. A narrative description of the routine monitoring program should be
provided including:
  The tests performed and frequencies of testing for viable and
nonviable particulate monitoring parameters;
  Viable and nonviable particulate action and alert limits for
production operations for each manufacturing area; and
13   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:
  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. Lyophilization
A validation summary for lyophilization of the drug substance/product should be
given, which includes:
  A narrative description of the validation (or protocol);
  Certification that IQ and OQ have been completed;
14   A validation data summary;
  Explanation of all excursions or failures; and
  Deviation reports and results of investigations of all excursions or failures.
 
E. 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.
15 APPENDIX A
Guidelines
1.  Interpretive Guidelines for the Additional Standards for Source Plasma (Human)
Standards (10/73)
2.  Guideline for Submitting Documentation for Packaging for Human Drugs and
Biologics (2/87)
3.  Guideline for Submitting Documentation for the Stability of Human Drugs and
Biologics (2/87)
4.  Guideline on Sterile Drug Products Produced by Aseptic Processing (6/87)
5.  Guideline on General Principles of Process Validation (5/87)
6.  Guideline on Validation of the Limulus Amebocyte Lysate Test as an End-product
Endotoxin Test for Human and Animal Parenteral Drugs, Biological Products and
Medical Devices (12/87)
7.  Guidelines for Reviewing Amendments to Include Plasmapheresis of Hemophiliacs
(7/76)
8.  Guideline for the Determination of Residual Moisture in Dried Biological Products
(1/90)
9.  Guidance for Industry for the Submission of Documentation for Sterilization Process
Validation in Applications for Human and Veterinary Drug Products (11/94)
10.  Guideline for Submitting Samples and Analytical Data for Methods Validation (2/87)
11.  Guidance for Industry: Environmental Assessment of Human Drug and Biologics
Applications (7/98)
12.  FDA Guidance Concerning Demonstration of Comparability of Human Biological
Products, Including Therapeutic Biotechnology Derived Products (4/96)
Points to Consider
1.  Points to Consider in the Production and Testing of New Drugs and Biologicals
Produced by Recombinant DNA Technology (4/85)
2.  Points to Consider in the Manufacture and Testing of Therapeutic Products for Human
Use Derived from Transgenic Animals (1995)
International Conference on Harmonization (ICH) Guidelines
1. Stability Testing of New Drug Substances and Products (9/94)
2. Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological
Products (7/96)
3. Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human
or Animal Origin (5/96)
16 Other Publications
1.  Revised Recommended Methods for Evaluating Potency, Specificity, and Reactivity
for Anti-Human Globulin (5/92)
2.  FDAs Policy Statement Concerning Cooperative Manufacturing Arrangements for
Licensed Biologics (11/92)
3.  Office of Establishment Licensing and Product Surveillance Advertising and
Promotional Labeling Staff Revised Procedural Guide (8/94)
17