Guidance for Industry
INDs — Approaches to Complying with CGMP During Phase 1
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Draft Guidance
This guidance document is
being distributed for comment purposes only.
Comments and suggestions regarding this draft
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of the draft guidance. Submit comments to the Division of Dockets
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availability that publishes in the Federal Register.
For questions regarding this draft document
contact (CDER) Monica Caphart at 301-827-9047 or (CBER)
Christopher Joneckis at 301-435-5681.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
January 2006
CGMP
Guidance for Industry
INDs — Approaches to Complying with CGMP During Phase 1
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Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
January 2006
CGMP
Guidance for Industry
INDs — Approaches to Complying with CGMP During Phase 1
This
draft guidance, when finalized, will represent the Food and Drug
Administration's (FDA's) current thinking on this topic. It
does not create or confer any rights for or on any person and
does not operate to bind FDA or the public. You can use an
alternative approach if the approach satisfies the requirements
of the applicable statutes and regulations. If you want to
discuss an alternative approach, contact the FDA staff
responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number
listed on the title page of this guidance.
This guidance is intended to assist persons
producing drug and biological products (investigational drugs)
for use during phase 1 development (21 CFR 312.21(a)) in complying
with relevant current good manufacturing practice as required by §
501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C
Act). Controls for producing an investigational new drug for use
in a phase 1 study are primarily aimed at ensuring subject
safety. The Agency believes that applying quality control (QC)
principles to the production of investigational products (i.e.,
interpreting and implementing CGMPs consistent with good
scientific methodology) will facilitate the initiation of
investigational studies in humans and protect study subjects. When
finalized, this guidance will replace the
1991 Guideline on the Preparation
of Investigational New Drug Products (Human and Animal)
for the production of IND
products for phase 1 clinical trials described in the Scope
section of this guidance.
This guidance is being issued concurrently
with a direct final rule (and companion proposed rule), which
specifies that the particular requirements in Part 211 (21 CFR
211) need not be met for most investigational drugs manufactured
for use during phase 1 development. Instead, the Agency
recommends the approaches outlined in this guidance for complying
with § 501(a)(2)(B) of the FD&C Act.
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a
topic and should be viewed only as recommendations, unless
specific regulatory or statutory requirements are cited. The use
of the word should in Agency guidances means that something
is suggested or recommended, but not required.
In 1991, the Agency issued the Guideline
on the Preparation of Investigational New Drug Products (Human and
Animal). However, the 1991 document did not discuss all
manufacturing situations, including, for example, small- or
laboratory-scale production of investigational new drugs. In
addition, the 1991 document did not address fully the Agency's
expectation that an incremental approach to
manufacturing controls would be taken during investigational drug
development, which for most products includes a change in
production scale.
This guidance (once finalized) and the
regulation it complements, once finalized, will represent the
Agency's effort to proceed with its plans to formally describe an
approach to aide manufacturers in implementing manufacturing
controls that are appropriate for the stage of development. The
use of this approach recognizes that some controls and the extent
of controls needed to achieve appropriate product quality differ
not only between investigational and commercial manufacture, but
also among the various phases of clinical studies. Consistent
with the Agency's CGMP for the 21 Century initiative,
where applicable, manufacturers are also expected to implement
controls that reflect product and production considerations,
evolving process and product knowledge, and manufacturing
experience.
This guidance describes FDA’s current
thinking regarding controls for special production situations
(e.g., a laboratory setting, exploratory studies, multi-product
and multi-batch testing) and specific types (e.g.,
biological/biotechnology products, aseptically processed products)
of investigational new drug (IND) products manufactured for use
during phase 1 clinical trials as described in the Scope section
of this guidance. As the new rule specifies, the particular
requirements in Parts 211 (21 CFR 211) need not be met for certain
exploratory products manufactured for use during phase 1 clinical
trials.
When finalized, this guidance will replace
the 1991 Guideline on the
Preparation of Investigational New Drug Products (Human and
Animal) for the
production of IND products for phase 1 clinical trials described
in the Scope section of this guidance. Phase 2 and 3
production will continue to be subject to those portions of 210
and 211 that are applicable.
This guidance
applies to the following:
Investigational new human drug and
biological products (including finished dosage forms used as
placebos) intended for human use during phase 1 development,
including, for example, investigational recombinant and
nonrecombinant therapeutic products, vaccine products,
allergenic products, in vivo diagnostics, plasma derivative
products, blood and blood components, gene therapy products,
and somatic cellular therapy products (including
xenotransplantation products) that are subject to CGMP
requirements of § 501(a)(2)(B) of the FD&C Act.
|
The guidance applies to investigational products whether they are
produced in small- or large-scale environments because such
studies are typically designed to assess tolerability or
feasibility for further development of a specific drug or
biological product. However, if
an investigational drug has already been manufactured by an IND
sponsor for use during phase 2 or phase 3 studies or has been
lawfully marketed, manufacture of such a drug must comply with the
appropriate sections of 21 CFR Part 211 for the drug to be used in
any subsequent phase 1 investigational studies, irrespective of
the trial size or duration of dosing.
This guidance
does not apply to the following:
·
Human cell or tissue products regulated solely under
Section 361 of the PHS Act
·
Clinical trials for products subject to the device
approval or clearance provisions of the Food, Drug, and cosmetic
Act
·
Investigational new drugs manufactured for phase 2
and 3 studies
·
Already approved products that are being used during
phase 1 studies (e.g., for a new indication)
If clarification
on applicability of this guidance to a specific clinical study is
needed, please contact the appropriate center with responsibility
for review of the IND.
We recommend
that this guidance be used as a companion to other guidances
describing the chemistry, manufacturing, and control (CMC)
information submitted and reviewed in an IND application for phase
1 studies (References 1, 2, 3). At this stage of development, in
many cases, manufacture of the active ingredient and the final
investigational product will be accomplished through a series of
steps within a single facility. Producers of new active
pharmaceutical ingredients (also referred to as an API or
drug substance) must also conform with CGMP as required in
§ 501(a)(2)(B) of the FD&C Act. Guidance on CGMP for the
manufacture of new API for some products used in clinical studies
is also available (Reference 4). Such producers should implement
controls appropriate to the stage of development and, thus, may
want to consider the recommendations described in this guidance.
IV.
STATUTORY AND REGULATORY
REQUIREMENTS
Section 501(a)(2)(B) of the FD&C Act requires
drugs, which include investigational new drugs, to comply with
current good manufacturing practice:
A drug...shall be deemed
adulterated...if...the methods used in, or the facilities or
controls used for, its manufacture, processing, packing, or
holding do not conform to or are not operated or administered in
conformity with current good manufacturing practice to assure that
such drug meets the requirements of this chapter as to safety and
has the identity and strength, and meets the quality and purity
characteristics, which it purports or is represented to possess
Certain of the requirements of 21 CFR Parts
211, which implement section § 501(a)(2)(B) of the FD&C Act, were
directed at commercial manufacture of products, typically
characterized by large, repetitive, commercial batch production
(e.g., those that address expiration dating
(§ 211.137(g)), and warehousing (§ 211.142)
and are not relevant to the manufacture of most drugs for
investigational use for phase 1 studies.
This guidance
outlines approaches that sponsors and producers of phase 1
investigational new drugs can use to comply with the requirements
of CGMP under section 501(a)(2)(B) of the FD&C Act. These
recommendations are designed to provide approaches to CGMP that
appropriately address factors associated with the production of
clinical supplies for use in most phase 1 studies. The
recommendations will also help provide an appropriate quality
framework for a variety of investigational new drugs manufactured
in various situations.
During product development, the quality and
safety of investigational drug products are maintained, in part,
by having appropriate quality control (QC) procedures in effect.
Using established or standardized procedures will also facilitate
the production of equivalent or comparable investigational product
for further clinical study as needed.
Adherence to QC procedures during phase 1
development occurs largely through having:
-
Written procedures that are well
defined
-
Equipment that is adequately
controlled
- Data from production, including testing,
that are accurately and consistently recorded
Producers may
have acceptable alternative ways of meeting the objectives
described in this guidance. It is the responsibility of the
sponsors/producers to provide and use such methods, facilities,
and controls to ensure that the investigational drug meets
appropriate standards of safety, identity, strength, quality, and
purity.
Producers of investigational products should consider
carefully how to best ensure the implementation of standards,
practices and procedures that conform to CGMP for their specific
product and production operation.
A number of technologies and resources are
available for use that can facilitate conformance with CGMP and
help streamline product development. Some examples include:
·
Use of disposable equipment and process aids, which
can reduce cleaning burden
·
Use of prepackaged Water For Injection (WFI) and
presterilized containers, which can eliminate the need for
additional equipment or qualifying existing equipment
·
Use of process equipment that is closed (i.e.,
product not exposed to the environment during processing), which
can alleviate the need for stricter room classification for air
quality
·
Use of contract or shared production facilities and
testing laboratories, for production and testing (including
specialized services) of investigational product. Some academic
institutions have developed shared production and testing
facilities that can be used by institutional sponsors.
Because the sponsor is responsible for
important aspects of the clinical investigation, we recommend that
sponsors and producers consider carefully the risks from the
production environment that might adversely affect the resulting
quality of an investigational product, especially when the
investigational product is produced in laboratory facilities that
are not expressly or solely designed for their production. For
example, of particular importance is the susceptibility of a
product to contamination or cross contamination with other
substances (e.g. chemicals, biological substances,
adventitious agents) that may be
present from previous or concurrent research or production
activities.
We recommend
the following:
·
A formal evaluation
of the production environment to identify potential hazards
·
Taking of
appropriate actions prior to and during production to minimize
risks and safeguard the quality of the investigational product
Some recommendations pertaining to specific
areas of CGMP follow. Consistent with the
statute
(§ 501(a) (2)
(b)), CGMP must be in effect for the production of each
investigational drug batch used in clinical trials. The following
recommendations provide for flexibility to allow producers to
implement controls appropriate for their specific situation and
application. Producers should establish production controls based
on a risk assessment for the product and manufacturing process and
follow good scientific and quality control principles when
implementing specific practices and procedures for CGMP.
All personnel should have the education,
experience and training or any combination thereof to enable that
person to perform the assigned function. In particular, personnel
should have the appropriate experience to prepare the
investigational product and be familiar with QC principles and
acceptable methods for complying with the statutory requirement of
CGMP, such as the recommendations outlined in this guidance.
We recommend that every producer establish a
QC plan and document that plan in writing. For example, a sound
QC plan should provide for the following functions:
-
Responsibility for examining the various components used in the
production of a product (e.g., containers, closures, in-process
materials, packaging materials, and labeling) to ensure that
they are appropriate and meet defined, relevant quality
standards
-
Responsibility for review and approval of production procedures,
testing procedures, and acceptance criteria
-
Responsibility for releasing or rejecting each clinical batch
based upon a cumulative review of completed production records
and other relevant information (e.g., procedures were followed,
product tests performed appropriately, acceptance criteria met)
-
Responsibility for investigating and initiating corrective
action if unexpected results or errors occur during production
We also recommend that QC responsibilities be
performed independently from production responsibilities. When
activities such as testing, commonly performed by dedicated QC
personnel in commercial manufacture, are performed by production
personnel, adequate controls should be in place (e.g., segregation
of testing from production so as to not contaminate testing or
negatively affect test results).
However, in limited circumstances, depending
on the size and structure of an organization, all QC functions
could be performed by the same individual. For example, in some
small operations, it may be justified to have the same individual
perform both production and QC functions, including release or
rejection of each batch. Under such circumstances, we recommend
that another qualified individual not involved in the production
operation carry out an additional, periodic review of production
records. It is important to note that quality should be the
responsibility of all personnel involved in manufacturing
Any facility, including a laboratory, used
for production of investigational drugs for use in phase 1 studies
should have adequate work areas and equipment for the intended
task:
- Sufficient
space, clean environment, appropriate construction
- Appropriate
lighting, ventilation, and heating
- Appropriate
cooling, plumbing, washing, and sanitation
- Appropriate
air handling systems (e.g., laminar flow hoods) to aid in
preventing contamination and cross-contamination of product
- Appropriate
equipment that will not contaminate the product or otherwise be
reactive, additive, or absorptive with the product and that is
properly maintained, calibrated, cleaned, and sanitized at
appropriate intervals following written procedures
We recommend
that all equipment used for a particular process be identified and
documented in the production record. We also recommend that the
provisions in section VI.D, Sterile Products/Aseptically Processed
Products, be followed for investigational products prepared using
aseptic processing.
Use of procedural controls in an appropriate
facility promotes orderly production and aids in preventing
contamination, cross contamination and mix-ups (see Section VI.B).
We recommend there be written procedures
describing the handling, review, and acceptance and control of
components used in the production of an investigational product.
Components should be controlled (e.g., segregated, labeled) until
they have been examined or tested, as appropriate, and released
for use in production. It is important to handle and store
components in a manner that prevents degradation or
contamination. We recommend keeping a record (e.g., log book)
containing relevant information on all components. Information to
record would include receipt date, quantity of the shipment,
supplier's name, component lot number, investigational product
batch number, storage conditions, and corresponding expiration
date.
We recommend establishing acceptance criteria
for specified attributes on each component. For some components,
all relevant attributes or acceptance criteria may not be known at
this stage of product development. However, attributes and
acceptance criteria selected for assessment should be based on
scientific knowledge and experience for use in the specific
investigational drug. The component attributes and acceptance
criteria will be reviewed in the IND application (Ref 1-3).
We recommend that the certificate of analysis
(COA) and/or other documentation on each lot of component be
examined to ensure that it meets established acceptance criteria
for specified attributes. For some materials (e.g., human and
animal derived), documentation should include information on
sourcing and/or test results for adventitious agents, as
appropriate. If documentation for a component is incomplete,
testing for the incomplete attribute of the component is
recommended. For each batch of the drug substance (or API), we
strongly recommend performing confirmatory identity testing,
regardless of whether documentation has been provided.
We recommend that production of
investigational products follow written production procedures that
provide the following:
- A record of
laboratory testing and production data that details the
components, equipment, and procedures used. We recommend that
sponsors retain documentation sufficient to replicate the
production process. Similarly, if production of a clinical
batch is initiated but not completed, we recommend that the
record include an explanation of why production was terminated.
- A record of
changes in procedures and processes used for subsequent batches
along with the rationale for any changes
- A record of the microbiological controls
that have been implemented (including written procedures) for
the production of sterile processed investigational new drugs
that are covered by this guidance. We also recommend the use of
aseptic techniques and the control of in-process components
designed to prevent microbial and endotoxin contamination (see
Section VI.D, Sterile Products/Aseptically Processed Products).
Analytical tests used in production (e.g.,
testing of components, in-process material, packaging, drug
product) should be scientifically sound (e.g., specific,
sensitive, and accurate) and reproducible for the specified
purpose. We recommend that tests be performed under controlled
conditions and follow written procedures describing the testing
methodology.
Laboratory testing of the investigational
product to evaluate identity, strength, potency, purity, and
quality attributes should be performed, as appropriate. Specified
attributes should be monitored, and acceptance criteria applied
appropriately. For known safety-related concerns, specifications
should be established and met. For some product attributes, all
relevant acceptance criteria may not be known at this stage of
product development. This information will be reviewed in the IND
submission (References 1, 2, 3).
We recommend that laboratory equipment be
calibrated at appropriate intervals and be maintained according to
established written procedures to ensure reliability of test
results. We recommend that personnel verify that the equipment is
in good working condition when samples are analyzed (e.g., systems
suitability).
We further
recommend that a representative sample from each product batch be
retained. When feasible, we recommend that the sample consist of
twice the quantity necessary to conduct release testing (excluding
any testing for pyrogenicity and sterility). We recommend that the
samples be appropriately stored and retained for at least 2 years
following study termination, or withdrawal of the IND
application.
We recommend
that sponsors initiate a stability study using representative
samples of the investigational new drug to monitor the stability
and quality of the product during the clinical investigation
(i.e., date of manufacture through date of last administration).
As indicated
in previous sections, we recommend that sponsors keep complete
records relating to the quality and operation of the production
processes, including:
·
Equipment maintenance and calibration
·
Production records and related analytical test records
·
Distribution records
·
All quality control functions
·
Component records
Under the applicable IND regulations,
sponsors must retain records for at least 2 years after a
marketing application is approved for the drug, or if an
application is not approved for the drug, until 2 years after
shipment and delivery of the drug for investigational use is
discontinued and the FDA is notified.
A screening study, which is performed under an exploratory
IND application, is intended to compare the properties of related
active moieties to screen for the preferred compound or
formulations for additional clinical development under a
traditional IND application (Reference 5). Screening studies
involve single-dose or short-term (e.g., <7 days of dosing)
studies in humans of up to 5 chemically or pharmacologically
related new chemical entities.
Microdose
studies are defined as studies in which participants are
administered a single dose of less than 1/100th of the
dose calculated to yield a pharmacological effect of the test
substance based on primary pharmacodynamic data obtained in vitro
and in vivo (typically doses in, or below the low microgram range)
and at a maximum dose of £
100 micrograms.
These types of
investigational studies are often performed in small-scale
laboratories or research organizations.
In such cases, special considerations are warranted. For example,
when the same area or room is used for both the production of
investigational products and research, we recommend that the
sponsor segregate the operations sufficiently to
- Promote the
orderly handling of materials and equipment
- Avoid
contamination of equipment and product by other substances,
personnel, or environmental conditions
- Prevent
mix-ups
Reagents and
components used for investigational product production may be
stored safely in the same area as those used for research as long
as they are properly labeled and organized in a manner that avoids
mix-ups or unintended use.
Finally, we
recommend that equipment be used for a single purpose (i.e.,
research only or production only) at any given time.
Ideally, we
recommend that one product be produced in an area or room at any
given time separate from unrelated activities. However, the same
area or room could be used for multiple purposes, including
production of other investigational products or laboratory
research, provided that appropriate cleaning and control
procedures are in place to ensure that there is no carry-over of
materials or products or mix-ups. We recommend that in such
cases, the design or layout of an area promote the orderly
handling of materials and equipment, the prevention of mix-ups,
and the prevention of contamination of equipment or product by
substances, previously produced products, personnel, or
environmental conditions.
Additional
controls could include procedures for clearing the room of
previous product materials, product segregation, component
segregation, and use of unique identifiers. We recommend that the
implemented controls be assessed periodically to evaluate their
effectiveness. Appropriate corrective action should be taken as a
result of this assessment, or when other events warrant.
Some biological and biotechnology
investigational products, including those made from pathogenic
microorganisms, spore-forming microorganisms, transgenic animals
and plants, live viral vaccines, and gene therapy vectors, warrant
additional containment considerations. We encourage early
discussions with the applicable Agency center (i.e., product and
facility group with responsibility for the product) prior to
engaging in the production of such IND products.
The production process is critical to
ensuring the correct composition and safety of biological and
biotechnology products. For these products, it can be difficult
to distinguish changes in quality attributes, or predict the
impact of observed changes in quality attributes on safety. This
is especially true for phase 1 studies where knowledge and
understanding of an investigational new drug is limited and where
comprehensive product characterization is often unavailable,
especially for products that are difficult to characterize.
Therefore, it is critical, beginning with phase 1 studies, to
adequately control and document the production process in
conjunction with appropriate testing to reproduce comparable IND
product as necessary. Retained samples (e.g., drug substance,
drug product, intermediate, in-process material) that can be
subsequently analyzed for comparison, can provide important links
in reproducing comparable biological and biotechnological
products.
We recommend that appropriate equipment
qualification and controls in production be in place to ensure
that units with safety-related functions (e.g., viral clearance,
virus/toxin attenuation, pasteurization) will perform as
intended. Specific testing may also serve to complement these
functions. We recommend that testing for safety-related purposes
such as viral loads, bioburden, detoxification of bacterial
toxins, virus clearance or inactivation, and clearance of
substances (e.g., antibiotics, chemicals) be used in production
and that adventitious agent testing be established as
appropriate.
Of particular importance in evaluating the
environment to be used for production (see section V) is the
susceptibility of biotechnology and biological products to
contamination with biological substances including microbial
adventitious agents (e.g., bacterial, viral, mycoplasm) that may
remain from previous research or production activities.
In addition to the recommendation in section
VI.B, we recommend that multi-product facilities have cleaning and
testing procedures in place that ensure prevention and/or
detection of contamination by adventitious agents. To the extent
possible, dedicated equipment and/or disposable parts (e.g.,
tubing) is recommended. For multi-product areas, we recommend
that procedures be established to prevent cross-contamination and
that demonstrate removal of the previously manufactured product
from shared equipment and work surfaces, especially if live viral
and vector processing occurs in a production area.
Due to the wide variety and unique production
aspects of investigational gene and cellular therapy products,
producers should consider the appropriateness of additional or
specialized controls. Although we recommend that investigational
cell and gene therapy products be produced following the
recommendations in this guidance, we recognize that it may not be
possible to follow each recommendation. For example, with some
cellular products, it may be impossible to retain samples of the
final cellular product due to the limited amounts of material
available. We recommend that reasons for adopted approaches be
included in the records on the investigational product.1.
We are aware that, in some cases,
investigational biological and biotechnology products covered by
this guidance may be produced as frequently as one batch per
subject in phase 1 studies (e.g., therapeutic vaccines, cell
therapies, gene therapies). Production of multiple batches will
allow additional production and testing information to accumulate
in an accelerated manner as compared to more conventional
products. It is also important to have and adhere to appropriate
control procedures that enable the consistent manufacture of
comparable drug substance and drug products.
When producing multiple batches of the same
investigational product, we recommend that producers periodically
conduct and document internal performance reviews. We recommend
that such a review assess the control and consistency of the
production process and overall product quality. This review would
fall outside of routine production operations and would be
conducted to assess procedures, practices, and information,
including data generated from production and investigational new
drug testing. Based on the review, appropriate modifications and
corrective actions can be taken to control procedures and
production operations. The data generated with each batch can
also allow the producer to establish and/or refine acceptance
criteria as experience and knowledge permits and, therefore, to
achieve more consistent investigational new drug production.
We recommend that special precautions be
taken for investigational new drugs intended to be sterile.
Thorough consideration
should be given to controls for aseptic processing. The following
examples are recommendations that should be considered:
·
Conducting aseptic manipulation in an aseptic
workstation under laminar flow conditions (e.g., an air
classification of Class 100). Some
examples of workstations include a laminar air flow workbench,
biosafety cabinets, or barrier isolator system.
·
Disinfecting the entire aseptic workstation as
appropriate (e.g., before aseptic manipulation, or between
different operations during the same day)
·
Ensuring that items within a laminar airflow aseptic
workstation not interrupt the airflow.
·
Disinfecting gloves or changing them frequently when
working in the laminar flow hood.
·
Disinfecting the surface of nonsterile items (e.g.,
test tube rack, and the overwrap for sterile syringes and filters)
with sterile disinfectant solution before placing them in the
laminar flow hood.
·
Performing manipulations of drug or components
subsequent to a sterilizing step under appropriate conditions.
·
Documenting and following all procedures intended to
maintain the sterility of the components, in-process materials,
and final product.
·
Qualifying sterility tests (e.g., USP <71>) to
demonstrate that the test article does not interfere with the
test.
·
Employing aseptic technique and control of
microbiological impurities in components designed to prevent
microbial and endotoxin contamination.
·
Training personnel using aseptic techniques in those
techniques.
·
Qualifying for use equipment used for sterilization;
performing appropriate calibration; keeping maintenance records.
·
Creating documentation to support the use of sterile
components and disposable equipment (e.g., filters, bags,
containers) in the form of Sterilization/certification of
analysis, or demonstration that the sterilization method is
validated.
·
Ensuring that release of the final product by the QC
unit, or person, include an acceptable review of production
records demonstrating that aseptic procedures and precautions were
followed.
·
Ensuring that final products are not released until
acceptable results of sterility testing are known. We understand
that products with a short shelf-life (e.g., radiopharmaceuticals,
cellular products) may have to be released while results of the
sterility test are pending based on results from other relevant
tests (e.g., assessment of sterile filtration by bubble point
filter integrity test, cell product — a negative gram stain, or
other rapid microbial detection test and negative endotoxin
test)). We recommend that positive results from sterility
or other relevant tests result in an investigation to determine
the cause of contamination followed by corrective action if
warranted.
Acceptance
Criteria - numerical limits, ranges, or other suitable
measures for acceptance of test results that the drug substance or
drug products or materials at other stages of their manufacture
should meet
Active
Pharmaceutical Ingredient (API) (or Drug Substance) -
any substance or mixture of substances intended to be used
in the manufacture of a drug (medicinal) product and that, when
used in the production of a drug, becomes an active ingredient of
the drug product. Such substances are intended to furnish
pharmacological activity or other direct effect in the diagnosis,
cure, mitigation, treatment, or prevention of disease or to affect
the structure and function of the body.
Batch - a specific
quantity of a drug or other material intended to have uniform
character and quality, within specified limits, and produced
according to a single production order during the same cycle of
manufacture
Component - any ingredient intended
for use in the manufacture of a drug product, including those that
may not appear in such drug product
Contamination
- the undesired introduction of impurities of a chemical
or microbiological nature, or of foreign matter, into or onto a
raw material, in-process material, or IND product during
production, sampling, packaging, or repackaging, storage or
transport
Cross-Contamination - contamination of a material or IND
product with another material or product
Drug product - a finished dosage form
(e.g., tablet, capsule, solution) that contains an active drug
ingredient generally, but not necessarily, in association with
inactive ingredients. The term also includes a finished dosage
form that does not contain an active ingredient, but is intended
to be used as a placebo.
In-process material - any material
fabricated, compounded, blended, or derived by chemical reaction
(e.g., intermediate) that is produced for, and used in, the
preparation of the drug product
Investigational new drug (IND product) -
a new drug or biological drug that is used in a clinical
trial. The term also includes a biological product that is used
in vitro for diagnostic purposes.
Microdose
studies - studies in which participants are
administered a single dose of less than 1/100th of the
dose calculated to yield a pharmacological effect of the test
substance based on primary pharmacodynamic data obtained in vitro
and in vivo (typically doses in, or below the low microgram range)
and at a maximum dose of £
100 micrograms.
Production -
all operations involved in the preparation of an IND product from
receipt of materials through distribution including processing,
storage, packaging, labeling laboratory testing and quality
control
Screening study - a study that is performed under an
exploratory IND application, is intended to compare the properties
of related active moieties to screen for the preferred compound or
formulations for additional clinical development under a
traditional IND application.
Sponsor - person who takes
responsibility for and initiates a clinical investigation
Quality Units - an organizational unit
that fulfills quality control responsibilities. This can be in
the form of separate QC units or a single individual or group,
depending upon the size and structure of the organization.
1. FDA 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.
2.
FDA Draft Guidance for Industry Instructions and Template
for Chemistry, Manufacturing, and Control (CMC) Reviewers of Somatic
Cellular Therapy Investigational New Drug Applications (INDs),
August 15, 2003
3.
FDA Guidance for Industry Instructions and Template for
Chemistry, Manufacturing, and Control (CMC) Reviewers of Human Gene
Therapy Investigational New Drug Applications (INDs), November
8, 2004.
4.
FDA Guidance for Industry Q7A Good Manufacturing Practice
Guidance for Active Pharmaceutical Ingredients, Section 19
This guidance has been
prepared by an Agency working group with representatives from
the Center for Drug Evaluation and Research (CDER), Center for
Biologics Evaluation and Research (CBER), and the Office of
Regulatory Affairs (ORA), at the Food and Drug Adminstration.
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Date created: January 12, 2006 |