Guidance for Industry
On the Content and Format of Chemistry, Manufacturing and Controls Information
and Establishment Description Information for an
Allergenic Extract or Allergen Patch Test
[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) 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)
April 1999
TABLE OF CONTENTS
GENERAL INFORMATION
- BACKGROUND
- DEFINITIONS
PART 1 CHEMISTRY, MANUFACTURING AND CONTROLS SECTION
- DRUG SUBSTANCE
- Description and Characterization
- Manufacturer
- Identification
- Floor Diagram(s)
- Manufacture of Other Products
- Contamination Precautions
- Method(s) of Manufacture
- Source Material, Raw Materials, and Other Reagents
- Flow Charts
- Drug Substance Processing
- Batch Production Record
- Process Controls
- In-process Controls
- Process Validation
- Microbiology
- Drug Substance Integrity
- Reference Standard (if applicable)
- Primary Reference Standard
- Working Reference Standard
- Specifications and Analytical Methods
- Specifications and Tests
- Impurities Profile
- Reprocessing
- Container/Closure System
- Drug Substance Stability (Allergen Patch Tests)
- DRUG PRODUCT
- Composition and Characterization
- Drug Substance
- Excipient
- Desiccants
- Adjuvant
- Preservative
- Ancillary Components
- Manufacturer
- Manufacturing Methods
- Batch Production Records
- Process Controls
- Process Validation
- Microbiology
- Reference Standard (if applicable)
- Specifications and Tests
- Reprocessing
- Container/Closure System
- Drug Product Stability
- Stability Protocol
- Stability Data
- INVESTIGATIONAL FORMULATION
- ENVIRONMENTAL ASSESSMENT
- METHODS VALIDATION
PART 2 ESTABLISHMENT DESCRIPTION SECTION
- INTRODUCTION
- GENERAL INFORMATION
- SPECIFIC SYSTEMS
- Water Systems
- General Description
- Validation Summary
- Routine Monitoring Program
- Heating, Ventilation, and Air Conditioning Systems (HVAC)19
- General Description
- Validation Summary
- Routine Monitoring Program
- Contamination/Cross Contamination Issues
- Cleaning Procedures and Validation
- Containment Features
- Lyophilization
- Computer Systems
APPENDIX A
Guidance for Industry
On the Content and Format of Chemistry, Manufacturing and Controls Information
and Establishment Description Information for an
Allergenic Extract or Allergen Patch Test
Draft - Not for Implementation
This guidance document represents the Agency's current thinking on
the content and format of the Chemistry, Manufacturing and
Controls and Establishment Description sections of a license
application for an allergenic extract or allergen patch test. 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, 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 the Chemistry, Manufacturing, and Controls (CMC) section
of a Biologics License Application for an Allergenic Extract or
Allergen Patch Test.
Table of Contents
- DEFINITIONS
Allergenic products
Allergenic products are biological products which are administered
to man for the diagnosis, prevention, or treatment of allergies
[21 CFR 680.1(a)] and include Allergenic Extracts and Allergen
Patch Tests.
Source material
Allergenic products are usually obtained by the extraction or
formulation of active constituents from source material. Source
material includes pollen, insects (including venoms), mold, food,
chemicals, and animals. It may contain either a single allergen
or mixture of allergens.
Biological drug substance
For Allergenic Extracts, the biological drug substance is the
sterile intermediate solution produced from the extraction and
sterile filtration of source material and contains the
biologically active ingredient(s). This intermediate solution is
defined as the bulk or stock concentrate. A bulk product is an
intermediate solution derived from a single allergenic source
and may be filled directly into final containers or used as stock
concentrate. A stock concentrate is used in the manufacture of more than one
lot of product and is an intermediate solution from which
dilutions or mixtures are made [21 CFR 680.3(b)(1)]. For the
Allergen Patch Test , the biological drug substance is defined as
the allergen (or allergen mix) formulated with the vehicle prior
to filling or assembling into the final dosage form.
Biological drug product
The biological drug product is the finished dosage form in its
final container. For Allergenic Extracts , it may be the single or
mixed allergen extract individually filled, mixed with other
allergens, diluted, adsorbed to alum, or lyophilized in the final
container. For lyophilized Allergenic Extracts , the diluent used
for reconstitution is considered to be a component of the
biological drug product. For Allergen Patch Tests , the biological
drug product can be an allergen or allergen mix dissolved or
suspended in a vehicle, packaged in a final container to be
applied to the skin through the use of a suitable holding device
(e.g., Finn chamber along with surgical tape), or the biological
drug product can be an allergen or allergen mix uniformly
dispersed in a gel and coated onto a support (e.g., a plastic
sheet cut into patches which are assembled onto surgical tape and
directly applied to the skin).
Table of Contents
PART 1 CHEMISTRY, MANUFACTURING AND CONTROLS SECTION
- DRUG SUBSTANCE
Please refer to the "Guideline for Submitting Supporting
Documentation in Drug Applications for the Manufacture of Drug
Substances" for further guidance (reference 1 in Appendix A). For
regulatory guidance on source materials, please refer to reference
11 in Appendix A.
The information that follows may be referenced to a Drug Master
File.
- Description and Characterization
This section should be completed for each biological drug
substance identified as being present in the final drug
product. This section should contain a description of the
active biological substance; this may, if applicable,
include the allergen and gel matrix for the Allergen Patch
Test. For chemical substances, the description should also
include chemical structure; molecular weight; molecular
formula; established USP or USAN name; commonly accepted
chemical name; physical characteristics, including particle
size; and active allergenic component (if known).
- Manufacturer
- Identification
The application should include the name(s), address(es), FDA
registration number and other pertinent organizational
information for each manufacturer responsible for any
portion of the manufacture or testing operations for the
drug substance. This may include independent contractors
or other company subsidiaries serving as contractors, or
other locations/sites owned and operated by the applicant.
Also included in this section should be a discussion of
the operations performed by each party and the
responsibilities delegated to each party by the applicant.
- Floor Diagram(s)
For each manufacturing location, a simple floor diagram of
the general layout of the facilities, which traces the drug
substance through the manufacturing process, should be
included. This diagram need not be a detailed engineering
schematic or blueprint, but rather a simple drawing that
clearly depicts the relationship of each manufacturing area,
suite, or room to the others. The uses made of adjacent
areas that are not the subject of the application should
also be included. The diagram should be sufficiently clear
to enable visualization of the production flow and to
identify adjacent operations that may create particular
concerns, e.g., the proximity of live viral cultures to
inactivated intermediates, segregation of animal
facilities, etc. Room numbers or other unique identifiers
should be clearly indicated. Reference can be made to the
manufacturing flow chart in section I.C.2.
- Manufacture of Other Products
A comprehensive list of all additional products that are
manufactured or manipulated in the areas used to produce the
drug substance that is the subject of the application should
be provided. This section should include a description of
the type and developmental status of the additional drug
substances/products and indicate the areas into which these
other products will be introduced, whether on an ongoing
or a campaign basis, and what manufacturing steps will be
performed in the multiple-use area(s). Also, the applicant
should indicate whether the production of other products
will utilize the same product contact equipment and, if so,
how that equipment will be cleaned and validated between
operations for the manufacturing of different products.
Data should be provided for the validation and cleaning in
the appropriate section.
- Contamination Precautions
For all areas in which manufacturing or processing is being
performed, the following information concerning precautions
taken to prevent contamination or cross-contamination should
be provided:
- Air quality classification of the room(s) or area(s) in
which the 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, cleaning of
containers used for storage, 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 identify contamination or cross-contamination.
The manipulation of more than one organism in a single area,
or the use of any piece of equipment for more than one
organism, should be indicated and measures taken to ensure
prevention of cross-contamination should be discussed.
For further guidance in this section, see references 2, 3,
4, and 5 in Appendix A.
- Method(s) of Manufacture
This section should be completed for each drug substance
described in I.A. A detailed description of the manufacturing
and controls should be provided which demonstrate proper
quality control and prevention of contamination. The
inclusion of a list of relevant standard operating procedures
(SOP) is recommended.
A description of the tests and specifications for materials of
human or animal source that may potentially be contaminated
with adventitious agents, e.g., mycoplasma, Bovine Spongiform
Encephalopathy (BSE) agent for bovine derived products, and
other adventitious agents of human and animal origin should be
submitted. Validation data or certification supporting the
freedom of reagents from adventitious agents should be
included in the submission.
- Source Material, Raw Materials, and Other Reagents
Source Material, Raw Materials, and Other Reagents
(including components and reagents used in the propagation
or processing of raw material)
The source material contains the active substance (allergen
or allergen mix). The active substance(s) is(are)
responsible for the biologic allergenic response, either
directly or indirectly.
A summary of the history of the processing of the source
material should be submitted. This summary should outline
each step involved in processing (including the method of
propagation, collection, harvesting, and processing) the
source material.
A list of all components used in the propagation and
processing of the source material and drug substance and
their tests and specifications or reference to official
compendia should be provided. This includes the components
used in the formulation of growth media for mites and
insects, the Allergen Patch Test vehicle, and preservatives
and stabilizers. Each lot of raw or processed source
material should be accompanied by a certificate of
conformance to compendial specifications, where applicable,
and/or a certificate of analysis, where provided. For
purchased materials, representative certificates of analysis
from the component supplier(s) and manufacturer's own
acceptance testing results should be provided. Process gases
(e.g., air, carbon dioxide) and water are considered raw
materials. Validation methods and data documenting the
removal of growing media and residues of harmful chemicals
from the source material should also be included or in lieu
of validation, a description of the tests performed on each
lot of source material.
Each lot of source material should be assayed for identity,
purity, and potency using validated in-house analytical
procedures, if applicable. Analytical procedures may
include, but not be limited to, RAST, ELISA, IEF, RID,
SDS-PAGE, immunoblotting, microscopy, spectroscopy,
chromatography, titrimetry, reagent colorimetry. This
information should be provided along with specifications and
acceptable limits. All test methods should be fully
described. The application should include representative
data along with chromatograms, spectra, etc. Validation
data should include results of studies establishing
parameters for linearity, intra-assay precision
(repeatability), inter-assay precision (intermediate
precision), and recovery. For further guidance in this
section, see references 14, 15, 16 and 17 in Appendix A.
In addition to this information:
- Source Materials Derived from Biological Materials:
- Identification (General)
The genus and species, common name, and microscopic and macroscopic characteristics should be included.
- Epidermal Source Material
Documentation that the material is obtained from animals
in good health prior to the collection of the source
material should be included. For animals of the equine
genus intended for use as a source material, 21 CFR
680.1(b)(3)(ii) and (iii) requires that documentation be
submitted which demonstrates the animal's immunity to
tetanus.
- Mold Source Materials
A description of the propagation, harvest, and
downstream processing should be provided. This
description should be sufficient to insure the purity,
identity through microscopic examination of mold source
material. Under 21 CFR 680.1(b)(2), Standard Operating
Procedures which describe the performance of these
activities and which specify the acceptable limits and
kinds of contamination are required to be submitted for
review. The Standard Operating Procedures should
address, but not be limited to, the following:
- inoculation and propagation
- each step in propagation, from the source, identity
(i.e., ATCC catalog number, if applicable) and
inoculation of the seed culture to harvest; media
used at each step (including water quality), with
details of the media preparation and sterilization;
- inoculation and growth of initial and subcultures,
including volumes, time, and temperature of
incubation; method of transfer of the subculture;
- precautions taken to control contamination;
- in-process testing to insure purity, identity;
- detailed description of the maintenance of the stock
culture system, including storage temperatures,
frequency and limits of stock culture transfers
and/or subcultures, and identification and purity
determination procedures; and
- any antibiotics in the medium.
- harvest
- each step in the harvesting procedure, including
separation of the source material from the
propagation system (precipitation, centrifugation,
filtration, etc.), chemicals, and equipment;
- process parameters monitored;
- precautions taken to prevent cross-contamination and
introduction of any contaminants;
- criteria for harvest; determination of yields;
criteria for pooling more than 1 harvest, if
applicable; and
- bioburden monitoring prior and subsequent to harvest.
If the harvested source material is held prior to
further processing, a description of the storage
conditions and time limits should be provided.
- downstream processing
- cleaning, drying, milling, and grinding of the mold
mat;
- inactivation of mold and viability testing;
- method(s) and agent(s) used to make the mold
nonviable;
- stage of production where killing is performed;
- parameters which are monitored;
- limits and acceptance criteria; and
- effectiveness.
- purification
- methods used;
- process parameters monitored;
- determination of yields;
- criteria for pooling more than 1 batch (if
applicable); and
- precautions taken to prevent contamination and to
monitor bioburden introduced during purification,
including the bioburden testing procedure which
describes the type and level of contamination,
acceptance criteria and limits;
- analytical tests (if applicable);
- methods used to demonstrate identity, purity, if
available, of the source material; and
- methods used to measure levels of residual solvents,
chemicals, or reagents that may persist from prior
processing or purification steps.
The final acceptance criteria for the mold source
material should be provided. If the source material is
held prior to further manufacture, a description of the
storage conditions, including temperature and time
limits, should be included.
A typical growth description should be included for a
representative species subject to these Standard
Operating Procedures.
A list of in-process controls and testing for purity,
identity, and viability, as well as time points at which
testing is performed, should be included in the flow
chart (section I.C.2.) and the Batch Production Record
(section I.C.4.). The flow chart should also include a
description of the major equipment utilized in the
production of mold cultures (i.e., growth flasks,
blenders, mills, screens). A brief description and
floor diagram of the facility areas, including air
quality classification, where inoculation, propagation,
and harvesting occur should be submitted in section
I.B.2. Precautions taken to control contamination,
e.g., during sample removal and transfers, should be
provided in section I.B.4.
- Food Source Material
Canned and processed foods should not be used as source
materials for food extracts. The commercial
container/package label from the store where the food is
purchased should be part of the batch production record.
If the produce is not labeled, the location and identity
of the store where purchased should be included in the
batch record.
- Synthetic Chemical Substances that may Represent
Complex Mixtures (e.g., synthetic polymers)
Detailed information regarding the source, processing and
specifications of these substances should be provided.
Identity testing should demonstrate acceptable consistency
between batches of source materials.
If any of the above information is included in a Master
File, the Master File number and permission to
cross-reference the Master File should be provided.
- Flow Charts
In this section, a complete visual representation of the
manufacturing process flow should be provided for each drug
substance. 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. In-process holding steps should be included,
with time and temperature limits indicated. For chemical
synthesis, a flow chart should include all of the steps
in the general synthesis cycle with other specific steps,
such as fragment condensation or peptide cleavage,
indicated. 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.
- Drug Substance Processing
- Allergenic Extracts
The following information should be included:
- Extraction
Each step of the extraction process should be described
including, but not limited to, starting materials, ratio
of source material to buffer, temperature and time
limits, storage conditions (if stored prior to
clarification).
- Clarification
Each step of the clarification procedure should be
described including, but not limited to, temperature and
time limits, filter apparatus and pore size, storage
conditions (if stored).
- Sterile Filtration
A detailed description of the sterile filtration
process, to include the temperature and time limits,
filter apparatus and pore size, should be included in
this section.
- Source Material
Each lot of source material should be assayed for
identity, purity, and potency using validated in-house
analytical procedures, if applicable. Analytical
procedures may include, but not be limited to, RAST,
ELISA, IEF, RID, SDS-PAGE, immunoblotting, microscopy,
spectroscopy, chromatography, titrimetry, reagent
colorimetry. This information should be provided along
with specifications and acceptable limits. All test
methods should be fully described. The application
should include representative data along with
chromatograms, spectra, etc. Validation data should
include results of studies establishing parameters for
linearity, intra-assay precision (repeatability),
inter-assay precision (intermediate precision), and
recovery. For further guidance in this section, see
references 14, 15, 16 and 17 in Appendix A.
- Filling and Labeling
A detailed description of the filling of the sterile
drug substance into storage containers, to include
temperature, time limits, equipment used, and storage
conditions, and the labeling of these storage
containers, both procedure and content, should be
included in this section.
- Allergen Patch Tests
A detailed description should be provided which describes
the processing used to produce the drug substance,
including micronization and pulverization processes,
blending, temperature controls, and aging.
- Batch Production Record
A completed (executed) Batch Production Record should be
submitted which includes the processing of the source
material and further manufacture into the drug substance.
- Process Controls
- In-process Controls
For all in-process testing indicated in the flow chart, a
brief description of sampling procedures and test methods
designed to insure the identity, purity and potency of the
source material and drug substance should be provided.
For testing performed at significant phases of production,
the criteria for accepting or rejecting an in-process batch
should be specified. For further guidance in this section,
see references 3, 15, 16, and 17 in Appendix A.
- Process Validation
A summary including protocol and results should be provided
for the validation studies of each critical process or
factor that affects source material or drug substance
specifications, i.e., removal of processing chemicals,
filter integrity testing, aseptic assembly operations. The
validation study reports should document the variability in
each process as it relates to final specifications and
quality with statistical rigor. For further guidance in
this section, see references 2, 3, and 4 in Appendix A.
- Microbiology
A description and documentation of the validation studies
for any processes used for media sterilization, etc., should
be provided. If the drug substance is intended to be
sterile, information should be submitted as described in the
"Guidance for Industry for the Submission of Documentation
for Sterilization Process Validation in Applications for
Human and Veterinary Drug Products" (see reference 2 in
Appendix A).
- Drug Substance Integrity
Validation testing results which demonstrate that the drug
substance remains free of extraneous contaminants during its
storage period prior to final filling should be submitted.
Acceptable limits for bioburden, storage time and
temperature should be provided.
- Reference Standard (if applicable)
- Primary Reference Standard
If a CBER Reference Standard is used, the name and the lot
number of the reference standard should be provided.
- Working Reference Standard
If an in-house working reference standard is used, a
description of the preparation, specifications, testing, and
results should be provided. The data from the calibration
of the in-house working reference standard against a
primary reference standard should also be provided. For
further guidance in this section, see references 15, 16, and
17 in Appendix A.
- Specifications and Analytical Methods
- Specifications and Tests
Specifications, acceptable limits, and analytical methods
used to insure the safety, identity, purity, potency, as
well as lot-to-lot consistency should be provided.
Validation of the analytical systems, including validation
data, should be provided if this application is a request
for the use of a new testing method or equivalent methods
and processes. Materials to be submitted include (but are
not limited to) chromatograms, instrumental recordings,
calibration curves, linear regressions, etc. For testing
that does not entail a specific analytical method, such as
microscopic determination of purity and identity,
specifications and acceptable limits should be provided.
Certificates of analysis and analytical results for
representative lots should also be included. For further
guidance in this section, see references 14, 15, 16, and 17
in Appendix A.
- Impurities Profile
A discussion of impurity profiles, with supporting
analytical data, should be provided in this section for a
drug substance derived from chemicals. Profiles of variants
of the drug substance or products produced by interaction of
mixed components, as well as non-product related impurities
should be included.
- Reprocessing
A description should be provided of the conditions and
criteria which indicate the need for reprocessing the drug
substance. Evidence derived from validation studies which
demonstrates that the product's identity, purity and potency
has not changed during reprocessing should be submitted. For
further guidance in this section, see references 4, 15, 16,
and 17 in Appendix A.
- Container/Closure System
A description of the container and closure system and its
compatibility with the drug substance should be included.
Detailed information concerning the supplier and the results
of compatibility, toxicity, and integrity testing should be
provided for the container/closure system.
- Drug Substance Stability (Allergen Patch Tests)
A description of the storage conditions, study protocols
and results supporting the stability of the drug substance
should be submitted. Data from tests to monitor the
biological activity and degradation products, such as oxidized
forms, should be included, as appropriate. Data supporting
any proposed storage of intermediate(s) should also be
provided. For further guidance in this section, see
references 7, 12, 13, 16, and 17 in Appendix A.
Table of Contents
- DRUG PRODUCT
This section should contain information on the final biological
drug product including all active ingredients and excipients in
the final product. If any proprietary preparations or mixtures
are used as components, the information should include a complete
statement of composition and other information that will properly
describe and identify these materials. For all ingredients of
human or animal origin, testing results or certificates of
analysis demonstrating their freedom from adventitious agents
should be provided. Appropriate information may be cross
referenced to those under the section on the drug substance. For
further guidance in this section, see reference 8 in Appendix A.
- Composition and Characterization
A list of all components found in the drug product,
including the active and other ingredients, with their
strengths and batch quantities should be specified (the
resultant strengths of the drug product should also be
included). For some inactive ingredients, the quantity may
be expressed as a percentage or concentration.
- Drug Substance
A list of each drug substance should be provided.
- Excipient
This section should contain a list of all inactive
components with the rationale for inclusion of each in the
final product. The information should include certificates
of analysis, a list and description of tests performed,
results of analytical testing or other information that will
describe or identify each excipient. If compendial
excipients are used, citations may be included in lieu of
analytical testing. Excipients may include, but not be
limited to, the following:
- diluents;
- bulking agents;
- adsorbents (other than adjuvants); and
- stabilizers
- Desiccants
Any agent used to promote dryness should be included in this
section.
- Adjuvant
This section should contain a list of the chemical formula
and precise quantity of each adjuvant. The method for
quantity determination should also be specified.
- Preservative
Each preservative should be identified by chemical as well
as any trade name. The results of the preservative
effectiveness validation should be included in the
Microbiology section of this document. Reference may be
made to other files or compendial sources.
- Ancillary Components
For the Allergen Patch Test, a description of the ancillary
components used to apply the drug product, such as syringes,
or to hold the product in place, such as the support and
surgical tape, should be provided.
- Manufacturer
The application should include the name(s), address(es), FDA
registration number and other pertinent organizational
information for each manufacturer responsible for any portion
of the manufacture or testing operations for the drug product.
This may include independent contractors or other company
subsidiaries serving as contractors, or other locations/sites
owned and operated by the applicant. Also included in this
section should be a discussion of the operations performed by
each party and the responsibilities delegated to each party
by the applicant.
- Manufacturing Methods
This section should contain a detailed description of the
manufacturing process flow of the finished drug product
including the sterilization operations, aseptic procedures,
lyophilization, and packaging. A flow chart of the process
should accompany the description and a listing of all
in-process controls and tests performed on the product at
each step. A Batch Production Record should be provided which
includes complete manufacturing instructions for formulation,
including adsorption to an adjuvant and dilution; filling;
labeling, including labeling used in-house; and packaging,
including cutting of the individual allergen/gel/support
patches and their incorporation onto suitable adhesive backing
for the patch test panel (see Item D. of this section).
References may be made to other sections of this application
for more detailed information. For further guidance in this
section, see references 3, 5, 15, 16, and 17 in Appendix A.
- Batch Production Records
One completed (executed) Batch Production Record should be
submitted which includes the manufacture, filling, packaging,
and labeling of the drug product (see Item C. of this
section).
- Process Controls
- Process Validation
A summary including protocol and test results should be
provided for the validation studies of each critical process
or factor that affects the drug product. For further
guidance in this section, see references 2, 3, and 4 in
Appendix A.
- Microbiology
- Allergenic Extracts
A description of the validation studies for any aseptic or
microbiologically controlled processes used, such as
aseptic filling, sterilization of growth media, etc.,
should be submitted in this section. 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" (see reference 2 in Appendix
A).
- Allergen Patch Tests
Allergen Patch Tests are not certified as sterile and are
for topical use only. Limits for the number of organisms
per dose or volume should be established and the absence
of specific pathogenic organisms should be specified. The
United States Pharmacopoeia, General Chapter 61, Microbial
Limits Tests, should be consulted for guidance.
- Reference Standard (if applicable)
Please refer to section I.E. for guidance in this section.
- Specifications and Tests
Specifications, acceptable limits, and analytical methods used
for release testing of the drug product, including diluent (if
applicable), should be provided. Please refer to section I.F.
for detailed guidance. In addition, a description of the
selection and storage of retention samples should be provided
including the conditions and length of storage. For further
guidance, see references 15, 16, and 17 in Appendix A.
- Reprocessing
Please refer to section I.G. for detailed guidance on this
section for the reprocessing of the drug product.
- Container/Closure System
A description of the container/closure system, including
vial sizes, and its compatibility with the drug product to
include the supplier(s) and the results of compatibility,
toxicity and integrity testing should be submitted.
Even though Allergen Patch Tests are not required to be
sterile, evidence of container/closure integrity should be
provided.
- Drug Product Stability
This section should state the proposed expiration dating
period for the drug product and the recommended storage
conditions. The criteria for determining the date of
manufacture, from which the expiration dating period begins,
should be defined. For lyophilized products, a proposed
expiration dating period prior and subsequent to
reconstitution should be provided.
- Stability Protocol
A stability protocol should be provided which includes, but
is not limited to:
- Storage conditions
- temperature;
- vial sizes; and
- vial positions.
- Assays
- potency;
- sterility (or microbial limits) or appropriate
- integrity test;
- residual moisture (if lyophilized);
- total protein;
- preservatives and stabilizers; and
- identity.
- Frequency of testing
- Detailed statistical plan for interpretation of testing
results.
- Stability Data
The summary results which support the proposed expiration
dating period, under the recommended conditions, in the
final container and closure system, should be provided.
For further guidance in this section, see references 7, 9,
12, 13, 15, 16, and 17 in Appendix A.
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- INVESTIGATIONAL FORMULATION
This section should contain a summary of all differences in
formulation, manufacturing processes, or sites between the
clinical trials materials and commercial production batches of the
drug substance and the drug product. If an investigational
biological formulation is different from that of the
to-be-marketed finished product, data to support comparability of
the two formulations should be provided. For further guidance in
this section, see reference 6 in Appendix A.
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- ENVIRONMENTAL ASSESSMENT
An environmental assessment report should be prepared as outlined
in 21 CFR Part 25 with a description of the action that is being
considered and should address all the components involved in the
manufacture and disposal of the product, including the ultimate
use of the product. A statement of categorical exclusion may be
provided, if applicable.
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- METHODS VALIDATION
This section should contain information as described in the
"Guideline for Submitting Samples and Analytical Data for Methods
Validation" (reference 10 in Appendix A).
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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 Section 15, the Establishment
Description section, of a License Application for an allergenic
extract or allergen patch test.
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- 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.
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- 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;
- 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 process
(or protocol);
- certification that IQ and OQ have been completed;
- a validation data summary;
- an explanation of all excursions or failures; and
- deviation reports and results of investigations for
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 narrative description of the
validation process (or protocol) for each of these systems,
which includes:
- 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.
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APPENDIX A
Guidance Documents
- Guideline for Submitting Supporting Documentation in
Drug Applications for the Manufacture of Drug Substances
(1987).
- Guidance for Industry for the Submission of
Documentation for Sterilization Process Validation in
Applications for Human and Veterinary Drug Products
(1994).
- Guideline on Sterile Drugs Produced by Aseptic
Processing (1987).
- Guideline on General Principles of Process Validation
(1987).
- Guideline for Submitting Documentation for the
Manufacture and Controls for Drug Products (1987).
- FDA Guidance Concerning Demonstration of Comparability
of Human Biological Products, Including Therapeutic
Biotechnology-derived Products (1996).
- Guideline for Submitting Documentation for the Stability
of Human Drugs and Biologics (1987).
- Guideline for Submitting Supporting Documentation in
Drug Applications for the Manufacture of Drug Products
(1987).
- Draft Guidance for Industry on Testing Limits in
Stability Protocols for Standardized Grass Pollen
Extracts (1997).
- Guideline for Submitting Samples and Analytical Data for
Methods Validation (1987).
- Letter to Source Material Suppliers and Manufacturers of
Allergenic Extracts (May 16, 1995).
International Conference on Harmonization (ICH) Guidelines
- Stability Testing of New Drug Substances and Products
(9/22/94).
- Quality of Biotechnological Products: Stability Testing
of Biotechnological/Biological Products (7/10/96).
- Validation of Analytical Procedures: Methodology
(5/19/97); and Text on Validation of Analytical
Procedures (3/1/95).
Laboratory Manuals
- Methods of the Allergenic Products Testing Lab (1993).
- Methods of Analysis, Laboratory of Analytical Chemistry,
Division of Product Quality Control/CBER (1993).
- Laboratory of Analytical Chemistry Standard Operating
Procedures (1996).
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