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
[PDF version of this document]
Additional copies of this guidance document are available from:
Office of Communication, Training and Manufacturers Assistance, (HFM-40)
Center for Biologics Evaluation and Research (CBER)
Food and Drug Administration
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
GENERAL INFORMATION
- BACKGROUND
- DEFINITIONS
PART I - CHEMISTRY, MANUFACTURING AND CONTROLS SECTION
- INTRODUCTION
- BIOLOGICAL SUBSTANCE/PRODUCT
- Description and Characterization
- Manufacturer(s)
- Methods of Manufacturing and Packaging
- Process Controls
- Reference Standards
- Specifications/Analytical Methods
- Container Closure System/Shipping Containers
- Stability
- INVESTIGATIONAL PRODUCT/FORMULATION
- ENVIRONMENTAL ASSESSMENT
- METHOD VALIDATION
PART II - ESTABLISHMENT DESCRIPTION SECTION
- INTRODUCTION
- GENERAL INFORMATION
- SPECIFIC SYSTEMS
- Water Systems
- Heating, Ventilation, and Air Conditioning Systems (HVAC)
- Contamination/Cross-Contamination Issues
- Lyophilization
- Computer Systems
APPENDIX A
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
This document represents FDA's 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. |
GENERAL INFORMATION
- 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 Control
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).
Table of Contents
- 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.
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.
Table of Contents
PART 1 - CHEMISTRY, MANUFACTURING AND CONTROLS SECTION
- 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.
- 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.
- Description and Characterization
- Description
- 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.
- 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.
- 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.
- Physicochemical Characterization (Biological Specifications)
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).
- Biological Activity Potency
Biological testing performed on the manufacturer's
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.
- 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.
- Manufacturer(s)
- 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.
- 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
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.
- 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).
- 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.
- 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.
- 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.
- For purchased raw materials, representative certificates
of analysis from the suppliers or the manufacturer's 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.
- 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.
- 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.
- 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.
- 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.
- The receipt or manipulation of materials to be used for
different products in a single area or piece of equipment
should be indicated and 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.)
- 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.
- Detailed Description
- 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.
- 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 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.
- Batch Records: A completed batch record of the process
of production of the biologic product should be included.
- Process Controls
- 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.
- A description of in-process and final controls, including
analytical tests and appropriate data to support the
specifications should be submitted.
- 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.
- Validation data should be provided for a number of
processes.
- 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.
- 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.
- Microbiology
- If the product is intended to be sterile, information
on all sterilization and aseptic processes (e.g.,
formulation through filling 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."
- A description of the validation studies for any
processes used for inactivation of waste for release
into the environment should be provided.
- Reference Standards
- Primary reference standard
- 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.
- 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.
- A description of the storage conditions and control
procedures should be provided.
- 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.
- Specifications/Analytical Methods
- Biological drug product specifications and tests
- 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.
- Lot release protocols, including specification ranges
of representative lots of the product should be
provided. Specifications may include, but not be
limited to, biochemical purity, safety, appearance,
pH, residual moisture, excipients, endotoxins, and
sterility.
- 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.
- 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.
- Excipients
- A list of compendial excipients and citations for each
should be submitted.
- 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.
- 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.
- 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.
- Stability
- 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.
- Data from tests to monitor the biological activity or
degradation products, if any, should be included as
appropriate.
- 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.
- 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.
Table of Contents
- 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.
Table of Contents
- 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."
Table of Contents
- METHOD VALIDATION
Information as described in the "Guideline for Submitting Samples and
Analytical Data for Methods Validation" should be provided.
Table of Contents
PART 2 - ESTABLISHMENT DESCRIPTION SECTION
- 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.
- 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.
Table of Contents
- SPECIFIC SYSTEMS
- 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.
- 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.
- 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.
- 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.
- Heating, Ventilation, and Air Conditioning Systems (HVAC)
- 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.
- 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.
- 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
- A summary of actions to be taken when limits are exceeded.
- 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.
- Cleaning procedures and validation
- 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.
- 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.
- 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.
- 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;
- A validation data summary;
- Explanation of all excursions or failures; and
- Deviation reports and results of investigations of all
excursions or failures.
- 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.
Table of Contents
APPENDIX A
Guidelines
- Interpretive Guidelines for the Additional Standards for Source
Plasma (Human) Standards (10/73)
- Guideline for Submitting Documentation for Packaging for Human Drugs
and Biologics (2/87)
- Guideline for Submitting Documentation for the Stability of Human
Drugs and Biologics (2/87)
- Guideline on Sterile Drug Products Produced by Aseptic Processing
(6/87)
- Guideline on General Principles of Process Validation (5/87)
- 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)
- Guidelines for Reviewing Amendments to Include Plasmapheresis of
Hemophiliacs (7/76)
- Guideline for the Determination of Residual Moisture in Dried
Biological Products (1/90)
- Guidance for Industry for the Submission of Documentation for
Sterilization Process Validation in Applications for Human and
Veterinary Drug Products (11/94)
- Guideline for Submitting Samples and Analytical Data for Methods
Validation (2/87)
- Guidance for Industry: Environmental Assessment of Human Drug and
Biologics Applications (7/98)
- FDA Guidance Concerning Demonstration of Comparability of Human
Biological Products, Including Therapeutic Biotechnology Derived
Products (4/96)
Points to Consider
- Points to Consider in the Production and Testing of New Drugs and
Biologicals Produced by Recombinant DNA Technology (4/85)
- 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
- Stability Testing of New Drug Substances and Products (9/94)
- Quality of Biotechnological Products: Stability Testing of
Biotechnological/Biological Products (7/96)
- Viral Safety Evaluation of Biotechnology Products Derived from Cell
Lines of Human or Animal Origin (5/96)
Other Publications
- Revised Recommended Methods for Evaluating Potency, Specificity, and
Reactivity for Anti-Human Globulin (5/92)
- FDA's Policy Statement Concerning Cooperative "Manufacturing
Arrangements for Licensed Biologics" (11/92)
- Office of Establishment Licensing and Product Surveillance
Advertising and Promotional Labeling Staff Revised Procedural Guide (8/94)
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