Wednesday, April 11, 2012
Monday, April 9, 2012
Saturday, March 31, 2012
Q8 Pharmaceutical Development
1. Introduction
1.1 Objective of the Guideline
This guideline describes the suggested
contents for the 3.2.P.2 Pharmaceutical Development section of a regulatory
submission in the ICH M4 Common Technical Document (CTD) format.
The
Pharmaceutical Development section provides an opportunity to present the
knowledge gained through the application of scientific approaches, and risk
management*, to the development of a product and its manufacturing process. It
is first produced for the original marketing application and can be updated to
support new knowledge gained over the lifecycle* of a product. The guideline also indicates areas where the
provision of greater understanding of pharmaceutical and manufacturing sciences
can create a basis for flexible regulatory approaches. The Pharmaceutical
Development section is intended to provide a more comprehensive understanding
of the product and manufacturing process for reviewers and inspectors.
1.2 Background
During the
July 2003 ICH meeting in Brussels, agreement was reached on a common vision and
approach for developing an international plan for a harmonized pharmaceutical
quality system that would be applicable across the life cycle of a product.
This plan emphasizes an integrated approach to review (assessment) and
inspection based on scientific risk management. Several actions were outlined
to implement this vision. An expert-working group (EWG) was established to
develop guidance for pharmaceutical development, which will cover the lifecycle
of a product.
1.3 Scope
This
guideline is intended to provide guidance on the contents of Section 3.2.P.2
(Pharmaceutical Development) for drug products as defined in the scope of
Module 3 of the Common Technical Document (ICH topic M4). The guideline does
not apply to contents of submissions for drug products during the clinical
research stages of drug development. However the principles in this guideline
are important to consider during these stages.
This guideline might also be appropriate for other types of
products. To determine the applicability
of this guideline for a particular type of product, applicants should consult
with the appropriate regulatory authorities.
2. Pharmaceutical
Development
The aim of
pharmaceutical development is to design a quality*
product and the manufacturing process to deliver the product in a reproducible
manner. The information and knowledge gained from pharmaceutical development
studies provide scientific understanding to support the establishing of
specifications and manufacturing controls.
Information
from pharmaceutical development studies is a basis for risk management. It is
important to recognize that quality cannot be tested into products; i.e.,
quality should be built in by design. Changes in formulation and manufacturing
processes during development should be looked upon as opportunities to gain
additional knowledge and further support establishment of the design space. Inclusion of knowledge gained from
experiments giving negative results also can be useful in supporting the
selected product and its manufacturing process.
The
Pharmaceutical Development section should describe the knowledge that
establishes that the type of dosage form selected and the formulation proposed
are satisfactory for the purpose specified in the application. This section should include sufficient
information in each part to provide an understanding of the development of the
drug product and its manufacturing process. Summary tables and graphs are
encouraged.
At a
minimum, those aspects of drug substances, excipients, and manufacturing
processes that are critical and that present a significant risk* to product
quality, and therefore should be monitored or otherwise controlled, should be
identified and discussed. These critical
formulation attributes and process parameters are generally identified through
an assessment of the extent to which their variation can have impact on the
quality of the drug product.
In
addition, the applicant can choose to conduct other pharmaceutical development
studies that can lead to an enhanced knowledge of product performance over a
wider range of material attributes, processing options and process parameters.
Inclusion of this additional information in this section provides an
opportunity to demonstrate a higher degree of understanding of manufacturing
processes and process controls. This
scientific understanding establishes the design space. In these situations,
opportunities exist to develop more flexible regulatory approaches, for
example, to facilitate:
·
risk
based regulatory decisions (reviews and inspections);
·
manufacturing
process improvements, within the approved design space described in the dossier, without further regulatory review;
·
“real time” quality control, leading to a reduction of end-product release
testing.
To realise
this flexibility, the applicant should demonstrate an enhanced knowledge of
product performance over a range of material attributes (e.g. particle size
distribution, moisture content, flow properties), processing options and
process parameters. This knowledge can be gained by, for example, application
of formal experimental designs* or PAT*. Appropriate use of risk management
principles can be helpful in prioritising the additional pharmaceutical
development studies to collect such knowledge.
The design
and conduct of the pharmaceutical development studies should be consistent with
their intended scientific purpose and the stage of the development of the
product. It should be recognized that
the level of knowledge gained, and not the volume of data, provides the basis
for science-based submissions and their regulatory evaluation.
2.1 Components of the Drug Product
2.1.1 Drug Substance
The physicochemical and biological properties of the drug substance that can influence the performance of the drug product and its manufacturability, or were specifically designed into the drug substance (e.g., crystal engineering), should be identified and discussed. Examples of physicochemical and biological properties that might need to be examined include solubility, water content, particle size, crystal properties, biological activity, and permeability. These properties could be inter-related and might need to be considered in combination. Some of these properties can change with time and might be supplier dependent.
To evaluate
the potential effect of drug substance physicochemical properties on the
performance of the drug product, studies on drug product might be
warranted. For example, the ICH Q6A
Specifications: Test Procedures and Acceptance Criteria for New Drug Substances
and New Drug Products: Chemical Substances describes some of the
circumstances in which drug product studies are recommended (e.g., Decision
Tree #3 and #4 (Part 2)). The knowledge gained from the studies investigating
the potential effect of drug substance properties on drug product performance
can be used, as appropriate, to justify elements of the drug substance
specification (3.2.S.4.5).
The
compatibility of the drug substance with excipients listed in 3.2.P.1 should be
discussed. For products that contain
more than one drug substance, the compatibility of the drug substances with
each other should also be discussed.
2.1.2 Excipients
The excipients chosen, their
concentration, and the characteristics that can influence the drug product
performance (e.g., stability, bioavailability) or manufacturability should be
discussed relative to the respective function of each excipient. Compatibility
of excipients with other excipients, where relevant (for example combination of
preservatives in a dual preservative system), should be established. The
ability of excipients (e.g., antioxidants, penetration enhancers,
disintegrants, release controlling agents) to provide their intended
functionality, and to perform throughout the intended drug product shelf life,
should also be demonstrated. The information on excipient performance can be
used, as appropriate, to justify the choice and quality attributes of the
excipient, and to support the justification of the drug product specification
(3.2.P.5.6).
Information to support the safety of
excipients, when appropriate, should be cross-referenced (3.2.P.4.6).
2.2 Drug
Product
2.2.1 Formulation
Development
The summary should highlight the
evolution of the formulation design from initial concept up to the final
design. This summary should also take into consideration the choice of drug
product components, (e.g. the properties of the drug substance, excipients,
container closure system, any relevant dosing device) the manufacturing
process, and, if appropriate, experiences gained from the development of
similar drug product(s).
Information from formal experimental
designs can be useful in identifying critical or interacting variables that
might be important to ensure the quality of the drug product. Any excipient ranges included in the batch
formula (3.2.P.3.2) should be justified in this section of the application:
this justification can often be based on the experience gained during the
development of the formulation and manufacturing process.
A summary of all formulations used
in clinical safety and efficacy, bioavailability, or bioequivalence studies
should be provided. Any changes between the proposed commercial formulation and
those formulations used in pivotal clinical batches and primary stability
batches should be clearly described and the rationale for the changes provided.
Information from comparative in
vitro studies (e.g., dissolution), or comparative in vivo studies (e.g.,
bioequivalence), that links clinical formulations to the proposed commercial
formulation described in 3.2.P.1 should be summarized and a cross-reference to the studies
(with study numbers) should be provided. Where attempts have been made to
establish an in vitro/in vivo correlation the results of those studies, and a
cross-reference to the studies (with study numbers), should be provided in this
section. A successful correlation can assist in the selection of appropriate
dissolution acceptance criteria, and can potentially reduce the need for
further bioequivalence studies following changes to the product or its
manufacturing process.
Any special design features of the
drug product (e.g., tablet score line, overfill, anti-counterfeiting measure)
should be identified and a rationale provided for their use. Information to
support the appropriateness of such features should be provided.
2.2.2 Overages
The use of overages
of drug substance(s) in drug products is discouraged.
An overage is a fixed amount of the drug substance added to the
formulation in excess of the label claim. Any overages in the manufacture of
the drug product, whether they appear in the final formulated product or not,
should be justified
considering the safety and efficacy of the product. Information should be provided on the 1) amount of overage, 2) reason
for the overage, (e.g., to compensate for expected and documented manufacturing
losses), and 3) justification for the amount of overage. The overage should be included in the
amount of drug substance listed in the representative batch formula
(3.2.P.3.2).
2.2.3 Physicochemical and Biological Properties
A summary of the development studies
that were carried out to investigate the potential impacts of the
physicochemical and biological properties of the drug product and the
appropriateness of the drug product acceptance criteria should be reported in
this section of the application (3.2.P.2.2.3). These studies could include, for
example, the development of a dissolution or drug release test, or the
development of a test for respirable fraction of an inhaled product, where
appropriate. Physiological implications of drug substance and formulation
attributes should be addressed. For
example, information could be provided from studies to investigate whether
acceptance criteria for polymorphism should be included in the drug product
specification. Similarly, information to support the robustness of the
formulation and manufacturing process with respect to the selection of
dissolution versus disintegration testing, or other means to assure drug
release, could be provided in this section. See also ICH Q6A Specifications:
Test Procedures And Acceptance Criteria For New Drug Substances And New Drug
Products: Chemical Substances; Decision Tree #4 (Part 3) and Decision Tree
#7 (Part 1).
2.3 Manufacturing Process Development
The
selection, the control, and any optimisation of the manufacturing process
described in 3.2.P.3.3 (i.e., intended for commercial production batches)
should be explained. It is important to consider the critical formulation
attributes, together with the available manufacturing process options (e.g.,
dry granulation vs. wet granulation, terminal sterilisation vs. aseptic
processing), in order to address the selection of the manufacturing process and
confirm the appropriateness of the components (i.e., excipients).
Appropriateness of the equipment used for the intended products should be
discussed. Process development studies should provide the basis for process
optimisation, process validation and process control requirements. Where
appropriate, such studies should address microbiological as well as physical
and chemical attributes. The knowledge gained from process development studies
can be used, as appropriate, to justify the drug product specification
(3.2.P.5.6). An assessment of the
ability of the process to reliably produce a product of the intended quality
(e.g., the performance of the manufacturing process under different operating
conditions, at different scales, or with different equipment) should be
provided.
The manufacturing process development programme
should identify the critical process parameters that should be monitored or
controlled (e.g., granulation end point) to ensure that the product is of the
desired quality.
For those products intended to be sterile an
appropriate method of sterilization for the drug product and primary packaging
material should be chosen and the choice justified.
Significant differences between the
manufacturing processes used to produce the clinical safety and efficacy,
bioavailability, bioequivalence, or primary stability batches and the process
described in 3.2.P.3.3 should be discussed. The discussion should summarise the
influence of the differences on the performance and manufacturability of the
product. The information should be
presented in a way that facilitates comparison of the processes and the
corresponding batch analyses information (3.2.P.5.4). The information should
include, for example, (1) the identity
(e.g., batch number) and use of the batches produced using the specified
equipment (e.g., bioequivalence study batch number), (2) the manufacturing
site, (3) the batch size, and (4) any significant equipment differences (e.g.,
different design, operating principle, size).
In order to
provide flexibility for future process optimisation, when describing the
development of the manufacturing process, it is useful to describe any
measurement systems that allow monitoring of critical attributes or process
end-points. Collection of process monitoring data during the development of the
manufacturing process can provide useful information to enhance process
understanding. The process controls that provide process adjustment
capabilities to ensure control of all critical attributes should be
described. These provide a means for a
risk control strategy.
An assessment of process robustness can be useful in risk assessment and risk
reduction*, to support future manufacturing and
process optimisation, especially in conjunction with the use of structured risk
management tools.
2.4 Container Closure System
The choice and rationale for selection of the container closure system(s)
for the commercial product(s) (described in 3.2.P.7) should be discussed.
Consideration should be given to the intended use of the drug product and the
suitability of the container closure system for storage and transportation
(shipping), including the storage and shipping container for bulk drug product,
where appropriate.
The choice of materials for primary packaging should be justified. The
discussion should describe studies performed to demonstrate the integrity of
the container and closure. A possible interaction between product and
container(s) or label should be considered. This applies also to
admixture or dilution of products prior to administration e.g. product added to
large volume infusion containers.
The choice of primary packaging materials should consider, e.g., choice
of materials, protection from moisture and light, compatibility of the
materials of construction with the dosage form (including sorption to container
and leaching), and safety of materials of construction.
If a dosing
device is used (e.g., dropper pipette, pen injection device), it is important
to demonstrate that a reproducible and accurate dose of the product is
delivered under testing conditions which, as far as possible, simulate the use
of the product.
2.5 Microbiological Attributes
Where
appropriate, the microbiological attributes of the drug product should be
discussed in this section (3.2.P.2.5). The discussion should include, for
example:
·
The
rationale for performing or not performing microbial limits testing for
nonsterile drug products, (e.g., Decision Tree #8 in ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical Substances)
·
The
selection and effectiveness of preservative systems in products containing
antimicrobial preservative or the antimicrobial effectiveness of products that
are inherently antimicrobial
·
For
sterile products, the integrity of the container closure system as it relates
to preventing microbial contamination.
Although chemical testing for preservative
content is the attribute normally included in the drug product specification,
antimicrobial preservative effectiveness should be demonstrated during
development. The lowest specified concentration of antimicrobial preservative
should be demonstrated to be effective in controlling microorganisms by using
an antimicrobial preservative effectiveness test.
2.6 Compatibility
The compatibility of
the drug product with reconstitution diluent(s) or dosage devices (e.g.,
precipitation of drug substance in solution, sorption on injection vessels,
stability) should be addressed to provide appropriate and supportive
information for the labelling. This information should cover the recommended
in-use shelf life, at the recommended storage temperature and at the likely
extremes of concentration. Where the label recommends dilution or mixing of
solid dose forms (for example with drinks) prior to administration, appropriate
compatibility studies should be described.
3. Glossary
Design Space: the design space is the established range of
process parameters that has been demonstrated to provide assurance of quality.
In some cases design space can also be applicable to formulation attributes.
Working within the design space is not generally considered as a change of the
approved ranges for process parameters and formulation attributes. Movement out
of the design space is considered to be a change and would normally initiate a
regulatory post approval change process.
Formal
Experimental Design: a
structured, organized method for determining the relationship between factors
(Xs) affecting a process and the output of that process (Y). Also known as “Design of
Experiments”.
Lifecycle:
all phases in
the life of a product from the initial development through pre- and
post-approval until the product’s discontinuation.
PAT: Process Analytical Technologies - a system for
designing, analyzing, and controlling manufacturing through timely measurements
(i.e., during processing) of critical quality and performance attributes of raw
and in-process materials and processes with the goal of assuring final product
quality.
Quality: degree to which a set of inherent properties
of a product, system or process fulfils requirements
Risk: the combination of the probability of occurrence of harm and the severity of that harm (from ISO/IEC Guide 51)
Risk
Management: systematic application of
quality management policies, procedures, and practices
to the tasks of assessing, controlling and communicating risk.
Risk
Reduction: actions taken to lessen the probability of occurrence of harm and
the severity of that harm
Friday, March 30, 2012
Thursday, March 29, 2012
Tuesday, March 27, 2012
IND APPLICATION TEMPLATE: CMC section
IND
CHEMISTRY, MANUFACTURING AND CONTROL
INFORMATION
D. Chemistry, Manufacturing and Control
Information 1.
Introduction:
1.1 Potential human
risk(s) Indicate if 1) the chemistry of either the investigational drug
substance (i.e., the active ingredient) or the investigational drug product, or
2) the manufacturing process for either the investigational drug substance or investigational
drug product, presents any signals of potential human risk. If so, discuss the signals of potential
risks; to include a description of the steps proposed to monitor for such
risk(s), or the reason(s) why the signals should be dismissed. 1.2 Chemistry and
manufacturing: Pre-clinical versus clinical studies Describe any chemistry or manufacturing
differences between the investigational drug product proposed for clinical research
study use versus the investigational drug product that was used in the
pre-clinical (i.e, animal) toxicology studies that formed the basis that it was
safe to proceed with the clinical research study. If there are no differences in the investigational
drug product, this should be specifically stated. If there are differences in the investigational
drug product, discuss how these differences may affect the safety profile of
the investigational drug product. 2. Investigational Drug
Substance: 2.1 Description of
investigational drug substance
Provide a description of the investigational drug substance
(i.e., the active drug substance); including its physical, chemical (e.g.,
chemical name and/or structure), or biological characteristics. 2.2 Manufacturer of the investigational drug
substance Provide
the name and full address of the manufacturer of the investigational drug substance. Specify if the manufacture of the investigational drug
substance was or was not (will or will not be) performed in full compliance
with the FDA’s current Good Manufacturing Practice (cGMP) standards at 21 CFR
Part 211. If so, include with the
manufacturer’s address, its FDA Drug Establishment Registration Number. 2.3
Method of preparation of the investigational drug substance
For an investigational drug substance
manufactured in full compliance with the FDA’s current Good Manufacturing
Practice (cGMP) standards:
Provide a detailed flow diagram of the process for
manufacture of the investigational drug substance; and incorporate a list of the
components (i.e., reagents, solvents, excipients, catalysts, etc.) used in the
manufacturing process. (Note: Step-by-step procedures for, and a listing of the
specifications and quantities of the components used in, the manufacture of the
investigational drug substance are ordinarily not required to be included in
the IND application for the initial stage of drug development; as it is assumed
that the manufacturer will establish such procedures and specifications consistent
with cGMP compliance.) Alternately, if the cGMP manufacturer of the investigational
drug substance has submitted, or will submit, a respective Drug Master File to
the FDA (or if the manufacturer has in place a FDA-accepted IND for the investigational
drug substance/product), incorporate (i.e., into a referenced appendix of the
IND application) a letter or written notification from the manufacturer
authorizing the FDA to access its Drug Master File (or IND) in support of the chemistry,
manufacturing and control information required to be submitted under this IND
application. If the investigational drug product is approved by the FDA
for commercial marketing, specify such and incorporate (i.e., into a referenced
appendix of the IND For an investigational drug substance not manufactured in full compliance with the FDA’s
current Good Manufacturing Practice (cGMP) standards:
Provide a flow diagram of the process for manufacture of the
investigational drug substance. Incorporate Drug Master Card(s) listing the components
(i.e., reagents, solvents, excipients, catalysts, etc.) used currently in the manufacture
of the investigational drug substance; to include, for each listed agent, its
manufacturer or source, product specifications, and quantity used in the manufacture. (See Example
Drug Master Card.1)
(Note: the Drug Master Card(s) may provide for alternative
manufacturers of inactive components used in the manufacture of the
investigational drug substance.)(Note: for novel components [i.e., non-commercially
available components manufactured specifically for use in the preparation of
the investigational drug substance] additional manufacturing information may
need to be provided.(See Example Drug Master Card.2)
Incorporate Drug Master Card(s) listing
the step-by-step procedures used currently for the manufacture of the
investigational drug substance. (See Example
Drug Master Card.1) 2.4 Acceptable limits
and analytical methods use to assure the identity, strength, quality and purity
of the investigational drug substance
For an investigational drug substance
manufactured in full compliance with the FDA’s current Good Manufacturing Practice
(cGMP) standards:
Specify the acceptable limits of identity, strength, quality
and purity that will form the basis for the release/acceptance of the investigational
drug substance for its use in the preparation of the investigational drug
product. Provide a brief description of the various test (i.e.,
analytical) methods that are (will be) used to establish that the
investigational drug substance meets the defined, acceptable limits of
identity, strength, quality and purity. (Note: Validation procedures/data for the test (i.e.,
analytical) methods are ordinarily not required to be included in the IND
application for the initial stage of drug development; as it is assumed that
the manufacturer will perform such validation procedures consistent with cGMP
compliance.) Provide copies of analytical data verifying that the
manufacturing process results in an investigational drug substance that meets
or exceeds the specified, acceptable limits of identity, strength, quality and
purity. Submit a copy of the “certificate of analysis” that will
form the basis for release/acceptance of the investigational drug substance for
its use in the preparation of the investigational drug product. Alternately, if the cGMP manufacturer of the investigational
drug substance has submitted, or will submit, a respective Drug Master File to
the FDA (or if the manufacturer has in place a FDA-accepted IND for the
investigational drug substance/product), incorporate (i.e., into a referenced
appendix of the IND application) a letter or written notification from the
manufacturer authorizing the FDA to access its Drug Master File (or IND) in
support of the chemistry, manufacturing, and control information required to be
submitted under this IND application. Submit a copy of the “certificate of analysis” that will
form the basis for release/acceptance of the investigational drug substance for
its use in the preparation of the investigational drug product. Alternately, if the investigational drug product is approved
by the FDA for commercial marketing, specify such and incorporate (i.e., into a
referenced appendix of the IND For an investigational drug substance not manufactured in full compliance with the FDA’s
current Good Manufacturing Practice (cGMP) standards:
Specify the acceptable limits of identity, strength, quality
and purity that will form the basis for the release/acceptance of the investigational
drug substance for its use in the preparation of the investigational drug
product. Provide a description of the various test (i.e., analytical)
methods that will be used to establish that the investigational drug substance
meets the defined, acceptable limits of identity, strength, quality and
purity. Summarize the procedures that will be used to verify the
correct operation of the respective analytical equipment. Provide copies of analytical data verifying that the
manufacturing process results in an investigational drug substance that meets
or exceeds the specified, acceptable limits of identity, strength, quality and
purity. Submit a copy of the Drug Master Card(s) outlining the acceptable limits of identity,
strength, quality and purity and corresponding test (i.e., analytical) methods
that will form the basis for release/acceptance of the investigational drug
substance for its use in the preparation of the investigational drug
product. (See Example
Drug Master Card.1) 2.5
Information to support the stability of the investigational drug
substance
Specify the expiry period assigned currently to the investigational
drug substance. (Note: If stability of
the investigational drug substance is continuing to be studied for the purpose
of extending the current assigned expiry period, indicate such and state that
the assigned expiry period may be revised based on the results of the ongoing
stability study.) Provide a brief description of the stability study and the
test (i.e., analytical) methods that were used to monitor the stability of the investigational
drug substance. (Note: The stability study should involve storage of the
investigational drug substance in the final container/closure system specified
in its manufacturing process and under environmental conditions specified in
the product labeling. The extent of the
test methods used to monitor the stability of the investigational drug
substance should be sufficient to verify that the specified, acceptable limits
of identity, strength, quality and purity are retained throughout the assigned
expiry period.) (Note: There is no need to submit the actual stability study
protocol.) Summarize, in tabular or graphical format, the data
supporting the expiry period assigned currently to the investigational drug
substance. (Note: There is no need to submit detailed stability data.) Alternately, if the cGMP manufacturer of the investigational
drug substance has submitted, or will submit, a respective Drug Master File to
the FDA (or if the manufacturer has in place a FDA-accepted IND for the
investigational drug substance/product), incorporate (i.e., into a referenced
appendix of the IND application) a letter or written notification from the
manufacturer authorizing the FDA to access its Drug Master File (or IND or NDA)
in support of the chemistry, manufacturing, and control information required to
be submitted under this IND application. Alternately, if the investigational drug product is approved
by the FDA for commercial marketing, specify such and incorporate (i.e., into a
referenced appendix of the IND For
an investigational drug substance not
manufactured in full compliance with the FDA’s current Good Manufacturing
Practice (cGMP) standards:
Specify the expiry period assigned currently to the investigational
drug substance. (Note: If stability of the investigational drug substance is
continuing to be studied for the purpose of extending the current assigned
expiry period, indicate such and state that the assigned expiry period may be
revised based on the results of the ongoing stability study.) Provide a brief description of the stability study and the
test (i.e., analytical) methods that were used to monitor the stability of the
investigational drug substance. (Note: The stability study should involve storage of the
investigational drug substance in the final container/closure system specified
in its manufacturing process and under environmental conditions specified in
the product labeling. The extent of the
test methods used to monitor the stability of the investigational drug
substance should be sufficient to verify that the specified, acceptable limits
of identity, strength, quality and purity are retained throughout the assigned
expiry period.) (Note: There is no need to submit the actual stability study
protocol.) Summarize, in tabular or graphical format, the data
supporting the expiry period assigned currently to the drug substance. (Note: There is no need to submit detailed stability data.) 3.
Investigational drug product:
3.1 Description of the
investigational drug product
Provide a description of the of the
investigational drug product (i.e., the final formulation of the
investigational drug that will be used in clinical research studies) 3.2 Manufacturer of
the investigational drug product Provide
the name and full address of the manufacturer of the investigational drug
product. Specify if the manufacture of the
investigational drug product was or was not (will or will not be) performed in
full compliance with the FDA’s current Good Manufacturing Practice (cGMP)
standards. If so, include with the
manufacturer’s address, its FDA Drug Establishment Registration Number. 3.3 Components used in the manufacture of the investigational
drug product For an investigational drug product manufactured
in full compliance with the FDA’s current Good Manufacturing Practice (cGMP)
standards:
Provide a list of all components used in the manufacture of
the investigational drug product; including both those components that are
intended to appear in the final product and those components that are not
intended to appear in the final product (i.e., but which were used in the
manufacturing process). For each of the
inactive components, include a reference to its quality specification (e.g., USP , NF (Note: this list may include reasonable alternatives for
inactive components used in the manufacture of the investigational drug
product.) Alternately, if the cGMP manufacturer of the investigational
drug product has submitted, or will submit, a respective Drug Master File to
the FDA (or if the manufacturer has in place a FDA-accepted IND for the
investigational drug substance/product), incorporate (i.e., into a referenced
appendix of the IND application) a letter or written notification from the
manufacturer authorizing the FDA to access its Drug Master File (or IND) in
support of the chemistry, manufacturing and control information required to be
submitted under this IND application. Alternately, if the investigational drug product is approved
by the FDA for commercial marketing, specify such and incorporate (i.e., into a
referenced appendix of the IND For an investigational drug product not manufactured in full compliance
with the FDA’s current Good Manufacturing Practice (cGMP) standards:
Incorporate Drug Master Card(s) listing all of the
components (including the investigational drug substance) used currently in the
manufacture of the investigational drug product; to include, for each listed
component, its manufacturer, quality specification (e.g., USP, NF, ACS), and
quantity used in the preparation. (See Example Drug Master Card.1)
(Note: the Drug Master Card(s) may provide for alternative
manufacturers of inactive components used in the manufacture of the
investigational drug product.)(Note: for novel components [i.e., non-commercially
available components manufactured specifically for use in the preparation of
the investigational drug product] additional manufacturing information may need
to be provided.(See
Example Drug Master Card.2)
Describe the procedures (e.g., inspection of the
“certificate of analysis” provided by the manufacturer, defined identity
test(s)) that will be used to verify that the investigational drug substance
meets acceptable standards of identity, strength, quality and purity for use in
the manufacture of the investigational drug product. Describe the procedures (e.g., inspection of the product
label and/or the “certificate of analysis” provided by the manufacturer) that
will be used to verify that the inactive components used in the manufacture of
the investigational drug product meet or exceed defined quality specifications. 3.4 Quantitative
composition of the investigational drug product For
an investigational drug product manufactured in full compliance with the FDA’s
current Good Manufacturing Practice (cGMP) standards:
Summarize the quantitative composition
of the investigational drug product.
I.e., address the quantity of the investigational drug substance and the
quantities of components that are intended to appear in the investigational
drug product. (Note: For components used in the
manufacture of the investigational drug product, but which are not intended to
appear in the final product, describe the manufacturing processes or procedures
that result in the elimination of these components.) Alternately, if the cGMP manufacturer
of the investigational drug product has submitted, or will submit, a respective
Drug Master File to the FDA (or if the manufacturer has in place a FDA-accepted
IND for the investigational drug product), incorporate a letter or written
notification from the manufacturer authorizing the FDA to access its Drug
Master File (or IND) in support of the chemistry, manufacturing and control
information required to be submitted under this IND application. Alternately, if the investigational
drug product is approved by the FDA for commercial marketing, specify such and
incorporate (i.e., into a referenced appendix of the IND For an investigational drug product not manufactured in full compliance
with the FDA’s current Good Manufacturing Practice (cGMP) standards:
Summarize the quantitative composition
of the investigational drug product.
I.e., address the quantity of the investigational drug substance and the
quantities of components that are intended to appear in the investigational
drug product. (Note: For components used in the manufacture of the
investigational drug product, but which are not intended to appear in the final
product, describe the manufacturing processes or procedures that result in the
elimination of these components.) 3.5 Method of
manufacture and final packaging of the investigational drug product For an investigational drug product manufactured
in full compliance with the FDA’s current Good Manufacturing Practice (cGMP)
standards:
Provide a detailed flow diagram of the process for
manufacture and packaging of the investigational drug product. (Note: For sterile investigational drug products, the flow
diagram should address the sterilization process.) (Note: Step-by-step procedures used for the manufacture and
packaging of the investigational drug product are ordinarily not required to be
included in the IND application for the initial stage of drug development; as
it is assumed that the manufacturer will establish such procedures consistent
with cGMP compliance.) Alternately, if the cGMP manufacturer
of the investigational drug product has submitted, or will submit, a respective
Drug Master File to the FDA (or if the manufacturer has in place a FDA-accepted
for the investigational drug product), incorporate a letter or written
notification from the manufacturer authorizing the FDA to access its Drug
Master File (or IND) in support of the chemistry, manufacturing and control
information required to be submitted under this IND application. Alternately, if the investigational
drug product is approved by the FDA for commercial marketing, specify such and
incorporate (i.e., into a referenced appendix of the IND
Incorporate Drug Master Card(s) listing the step-by-step procedures used
currently for the preparation and packaging of the investigational drug product;
to include, for sterile investigational drug products, the procedures for sterilization of
the product. (See Example
Drug Master Card.1)
3.6 Acceptable limits
and analytical methods use to assure the identity, strength, quality and purity
of the investigational drug product For an investigational drug product manufactured
in full compliance with the FDA’s current Good Manufacturing Practice (cGMP)
standards:
Specify the acceptable limits of identity, strength, quality
and purity that will form the basis for the release of the investigational drug
product for human use. Provide a brief description of the various test (i.e.,
analytical) methods that will be used to establish that the investigational
drug product meets the defined, acceptable limits of identity, strength,
quality and purity. (Note: The test [i.e., analytical] methods that should be
submitted will vary according the dosage form of the investigational drug
product. For example, for sterile
products, the sterility and bacterial endotoxin (i.e., pyrogen) test methods
should be submitted.) (Note: Validation procedures/data for the test [i.e.,
analytical] methods are ordinarily not required to be included in the IND
application for the initial stage of drug development; as it is assumed that
the manufacturer will perform such validation procedures consistent with cGMP
compliance.) Provide copies of analytical data verifying that the
manufacturing process results in an investigational drug product that meets or
exceeds the specified, acceptable limits of identity, strength, quality and
purity. Alternately, if the cGMP manufacturer of the investigational
drug product has submitted, or will submit, a respective Drug Master File to
the FDA (or if the manufacturer has in place a FDA-accepted IND for the
investigational drug product), incorporate (i.e., into a referenced appendix of
the IND application) a letter or written notification from the manufacturer
authorizing the FDA to access its Drug Master File (or IND) in support of the
chemistry, manufacturing, and control information required to be submitted
under this IND application. Alternately, if the investigational drug product is approved
by the FDA for commercial marketing, specify such and incorporate (i.e., into a
referenced appendix of the IND Submit a copy of the “certificate of analysis” that will
form the basis for release/acceptance of the investigational drug product for
use in the clinical research study. For an investigational drug product not manufactured in full compliance with the FDA’s
current Good Manufacturing Practice (cGMP) standards:
Specify the acceptable limits of identity, strength, quality
and purity that will form the basis for the release of the investigational drug
product for use in the clinical research study. Provide a description of the various test (i.e., analytical)
methods that will be used to establish that the investigational drug product
meets the defined, acceptable limits of identity, strength, quality and purity. Summarize the
procedures that will be used to verify the correct operation of the respective
analytical equipment. (Note: The test (i.e., analytical) methods that should be
submitted will vary according the dosage form of the investigational drug
product. For example, for sterile
products, the sterility and bacterial endotoxin (i.e., pyrogen) test methods
should be submitted.) Provide copies of analytical data verifying that the
manufacturing process results in an investigational drug product that meets or
exceeds the specified, acceptable limits of identity, strength, quality and
purity. Submit a copy of the Drug Master Card(s) outlining the acceptable limits of identity,
strength, quality and purity and corresponding test (i.e., analytical) methods
that will form the basis for release of the investigational drug product for
human use. (See Example Drug Master
Card.1)
3.7 Information to
support the stability of the investigational drug product For
an investigational drug substance manufactured in full compliance with the
FDA’s current Good Manufacturing Practice (cGMP) standards:
Specify the expiry period assigned currently to the
investigational drug product. (Note: If
stability of the investigational drug substance is continuing to be studied for
the purpose of extending the current assigned expiry period, indicate such and
state that the assigned expiry period may be revised based on the results of
the ongoing stability study.) Provide a brief description of the stability study and the
test (i.e., analytical) methods that were used to monitor the stability of the
investigational drug product. (Note: The stability study should involve storage of the
investigational drug product in the final container/closure system specified in
its manufacturing process and under environmental conditions specified in the
product labeling. The extent of the test
methods used to monitor the stability of the investigational drug product
should be sufficient to verify that the specified, acceptable limits of
identity, strength, quality and purity are retained throughout the assigned
expiry period.) (Note: There is no need to submit the actual stability study
protocol.) Summarize, in tabular or graphical format, the data
supporting the expiry period assigned currently to the investigational drug
product. (Note: There is no need to submit detailed stability data.) Alternately, if the cGMP manufacturer of the investigational
drug product has submitted, or will submit, a respective Drug Master File to
the FDA (or if the manufacturer has in place a FDA-accepted IND for the
investigational drug substance/product), incorporate (i.e., into a referenced
appendix of the IND application) a letter or written notification from the
manufacturer authorizing the FDA to access its Drug Master File (or IND or NDA)
in support of the chemistry, manufacturing, and control information required to
be submitted under this IND application. Alternately, if the investigational drug product is approved
by the FDA for commercial marketing, specify such and incorporate (i.e., into a
referenced appendix of the IND For
an investigational drug substance not
manufactured in full compliance with the FDA’s current Good Manufacturing
Practice (cGMP) standards:
Specify the expiry period assigned currently to the
investigational drug product. (Note: If stability of the investigational drug product is
continuing to be studied for the purpose of extending the current assigned
expiry period, indicate such and state that the assigned expiry period may be
revised based on the results of the ongoing stability study.) Provide a brief description of the stability study and the
test (i.e., analytical) methods that were used to monitor the stability of the
investigational drug product. (Note: The stability study should involve storage of the
investigational drug product in the
final container/closure system specified in its manufacturing process and under
environmental conditions specified in the product labeling. The extent of the test methods used to
monitor the stability of the investigational drug product should be sufficient
to verify that the specified, acceptable limits of identity, strength, quality
and purity are retained throughout the assigned expiry period.) (Note: There is no need to submit the actual stability study
protocol.) Summarize, in tabular or graphical format, the data
supporting the expiry period assigned currently to the investigational drug product.
(Note:
There is no need to submit detailed stability data.) 4. Investigational
drug product labels and labeling For
an investigational drug product manufactured in full compliance with the FDA’s
current Good Manufacturing Practice (cGMP) standards:
Submit a mock-up or printed
representation of the label that will be attached to the container of the
investigational drug product. (Note: the product container label
should contain, at a minimum, the name and address of the manufacturer; the
identify of the investigational drug substance; the quantity of the
investigational drug substance per unit (e.g.,capsule or tablet) or volume; the
assigned batch or lot number; the specifications of “sterile” and
“pyrogen-free” (if applicable); the conditions for appropriate storage of the
product; the expiration date; and the statement, “Caution: New Drug – Limited
by Federal (or United States) law to investigational use.”) Submit, if applicable, any additional
labeling materials that will be provided to the investigators involved in
clinical studies of the investigational drug product. (Note: The labeling of the
investigational drug product shall not bear any statement that is false or
misleading and shall not represent that the product is safe or effective for
the purposes for which it is being investigated.) Alternately, if the cGMP manufacturer
of the investigational drug product has submitted, or will submit, a respective
Drug Master File to the FDA (or if the manufacturer has in place a FDA-accepted
IND for the investigational drug product), the product container label information
may be addressed by incorporating (i.e., into a referenced appendix of the IND
application) a letter or written notification from the manufacturer authorizing
the FDA to access its Drug Master File (or IND or NDA) in support of chemistry,
manufacturing and control information required to be submitted under this IND
application.) Alternately, if the investigational drug product is approved
by the FDA for commercial marketing, specify such and incorporate (i.e., into a
referenced appendix of the IND For an investigational drug product not manufactured in full compliance
with the FDA’s current Good Manufacturing Practice (cGMP) standards:
Submit a mock-up or printed
representation of the label that will be attached to the container of the
investigational drug product. (Note: the product container label
should contain, at a minimum, the name and address of the manufacturer; the
identity of the investigational drug substance; the quantity of the
investigational drug substance per unit (e.g.,capsule or tablet) or volume; the
assigned batch or lot number; the specifications of “sterile” and
“pyrogen-free” (if applicable); the conditions for appropriate storage of the
product; the expiration date; and the statement, “Caution: New Drug – Limited
by Federal (or United States) law to investigational use.”) Submit, if applicable, any additional
labeling materials that will be provided to the investigators involved in clinical
studies of the investigational drug product. (Note: The labeling of the investigational drug product
shall not bear any statement that is false or misleading and shall not
represent that the product is safe or effective for the purposes for which it
is being investigated.) 5. Placebo:
composition, manufacture, and control information (Incorporate only if applicable)
Provide a description of the placebo that will be used in
the clinical research study (studies) including its physical, chemical (e.g.,
chemical identity and/or structure), or biological characteristics. Identify the manufacturer of the placebo product; to include
the manufacturer’s full address. Specify
if the manufacture of the placebo product was or was not (will or will not be)
performed in full compliance with the FDA’s current Good Manufacturing Practice
(cGMP) standards. If so, include with
the manufacturer’s address, its FDA Drug Establishment Registration Number. For a placebo product manufactured in
full compliance with the FDA’s current Good Manufacturing Practice (cGMP)
standards:
Summarize the quantitative composition of the placebo
product. I.e., address the quantity of
the placebo substance and the quantities of any components that are intended to
appear in the placebo product. For any components used in the manufacture of the placebo
product, but which are not intended to appear in the final product, describe
the manufacturing processes or procedures that result in the elimination of
these components. Specify the acceptable limits of quality and purity of that
will form the basis for the release of the placebo product for human use; and
provide a description of the various test (i.e., analytical) methods that will
be used to establish that the placebo product meets these defined limits. (Note: The test (i.e., analytical) methods that should be
submitted will vary according the dosage form of the placebo product. For example, for sterile placebo products,
the sterility and bacterial endotoxin (i.e., pyrogen) test methods should be
submitted.) Provide copies of analytical data verifying that the
manufacturing process results in a placebo product that meets or exceeds the
specified, acceptable limits of identity, strength, quality and purity. Submit a copy of the “certificate of analysis” that will
form the basis for release of the placebo product human use. Provide a copy of the labeling that will be assigned to the
placebo product. (Note: the placebo product container label should address,
at a minimum, the name and address of the manufacturer; the identity of the
placebo product; the assigned batch or lot number; the specifications of
“sterile” and “pyrogen-free” (if applicable); the conditions for appropriate
storage of the product ;and the expiration date.) Alternately,
if the cGMP manufacturer of the placebo product has submitted, or will submit,
a respective Drug Master File to the FDA (or if the manufacturer already has in
place a FDA-accepted IND that addresses the placebo product), incorporate (i.e.,
within a referenced appendix to the IND application) a letter or written
notification from the manufacturer authorizing the FDA to access its Drug
Master File (or IND) in support of the chemistry, manufacturing, and control
information for the placebo product. Submit a copy of the “certificate of analysis” that will form
the basis for release of the placebo product human use. Alternately,
if the placebo product is FDA-approved for commercial marketing, specify
such. No additional information is
required For a placebo product not
manufactured in full compliance with the FDA’s current Good Manufacturing
Practice (cGMP) standards:
Provide a flow diagram of the process for manufacture and
packaging of the placebo product; and incorporate a list of the components (including
quality specifications and quantities) used in the manufacturing process. (Note: For a sterile placebo product, the flow diagram
should address the sterilization process.) (Note: Alternately, incorporate Drug Master Card(s) that
list the components [including quality specifications and quantities] and
step-by-step procedures used in the preparation of the placebo product.) Summarize
the quantitative composition of the placebo product. I.e., address the quantity of the placebo
substance and the quantities of any components that are intended to appear in
the placebo product. For any components used in the manufacture of the placebo
product, but which are not intended to appear in the final product, describe
the manufacturing processes or procedures that result in the elimination of
these components. Specify
the acceptable limits of quality and purity of that will form the basis for the
release of the placebo product for human use; and provide a description of the
various test (i.e., analytical) methods that will be used to establish that the
placebo product meets these defined limits. (Note: The test (i.e., analytical) methods that should be
submitted will vary according the dosage form of the placebo product. For example, for sterile placebo products,
the sterility and bacterial endotoxin (i.e., pyrogen) test methods should be
submitted.) Summarize the procedures that will be used to verify the
correct operation of the respective analytical equipment. Provide
copies of analytical data verifying that the manufacturing process results in a
placebo product that meets or exceeds the specified, acceptable limits of
identity, strength, quality and purity. Submit
a copy of the “certificate of analysis” that will form the basis for release of
the investigational drug product human use. (Note: Alternately, submit a copy of the Drug Master Card(s) outlining the acceptable limits of identity,
strength, quality and purity and corresponding test (i.e., analytical) methods
that will form the basis for release of the placebo product for human use.) Provide
a copy of the labeling that will be assigned to the placebo product. (Note: the placebo product container label should address,
at a minimum, the name and address of the manufacturer; the identity of the
placebo product; the assigned batch or lot number; the specifications of
“sterile” and “pyrogen-free” (if applicable); the conditions for appropriate
storage of the product; and the expiration date.) 6. Claim for categorical exclusion from or
submission of an environmental assessment Incorporate the following statement, as
written, unless there is a reason to believe that the distribution and use of
the investigational drug product could have an environmental impact The
submission of this IND
Adapted from Guidance for Industry: Content and Format of Investigational New Drug
Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized,
Therapeutic , Biotechnology-Derived Products; Center for Drug Evaluation
and Research (CDER) and Center for Biologics Evaluation and Research, U.S. Food
and Drug Administration; November, 1995.
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