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Guidance for Industry
Nonclinical Studies for the Safety Evaluation
of Pharmaceutical Excipients
(PDF
version of this document)
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)
May 2005
Pharmacology/Toxicology
Additional copies are available
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Food and Drug Administration
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Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
or
Office of Communication, Training,
and
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Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
(Tel) 800-835-4709 or 301-827-1800
http://www.fda.gov/cber/guidelines.htm
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)
May 2005
Pharmacology/Toxicology
I. INTRODUCTION
IV. RECOMMENDED
STRATEGIES TO SUPPORT MARKETING OF NEW EXCIPIENTS IN DRUG PRODUCTS
Guidance for Industry
Nonclinical Studies for the Safety Evaluation
of Pharmaceutical Excipients
This
guidance represents 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 document provides guidance concerning
development of safety profiles to support use of new excipients as
components of drug or biological products. It is intended for use
by reviewers within both the Center for Drug Evaluation and Research
(CDER) and the Center for Biologics Evaluation and Research (CBER)
and by interested individuals in industry. It is also intended to
foster and expedite the development of new excipients, communicate
to pharmaceutical and excipient manufacturers current CDER and CBER
recommendations on the nonclinical safety data that should be
generated to support excipient development, and increase uniformity
within CDER and CBER as to expectations for the nonclinical safety
evaluation of excipients.
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 this guidance, the phrase new excipients
means any inactive ingredients that are intentionally added to
therapeutic and diagnostic products, but that: (1) we believe are
not intended to exert therapeutic effects at the intended dosage,
although they may act to improve product delivery (e.g., enhance
absorption or control release of the drug substance); and (2) are
not fully qualified by existing safety data with respect to the
currently proposed level of exposure, duration of exposure, or route
of administration. Examples of excipients include fillers,
extenders, diluents, wetting agents, solvents, emulsifiers,
preservatives, flavors, absorption enhancers, sustained-release
matrices, and coloring agents. Within the context of this guidance,
the term excipient applies to macromolecular substances such
as albumin, or substances such as amino acids and sugars that are
used in drug and biological products. It does not, however, apply
to process or product-related impurities (e.g., degradation
products, leachates, residual solvents) or extraneous
contaminants.
Not all excipients are inert substances; some
have been shown to be potential toxicants. The Federal Food, Drug,
and Cosmetic Act of 1938 (the Act) was enacted after the tragedy of
the elixir of sulfanilamide in 1937 in which an untested excipient
was responsible for the death of many children who consumed the
pharmaceutical. The Act required manufacturers to perform safety
testing of pharmaceuticals and submit new drug applications (NDAs)
demonstrating safety before marketing. Since that time, the Agency
has become aware that certain other excipients used in commerce can
cause serious toxicities in consumers of prescription and
over-the-counter (OTC) drug products in the United States and other
countries.
This guidance describes the types of toxicity
data that the Agency uses in determining whether a potential new
excipient is safe for use in human pharmaceuticals. It discusses
recommended safety evaluations for excipients proposed for use in
OTC and generic drug products, and describes testing strategies for
pharmaceuticals proposed for short-term, intermediate, and long-term
use. It also describes recommended excipient toxicity testing for
pulmonary, injectable, and topical pharmaceuticals.
Most, if not all, drug products could not be
made without the use of excipients. Tablets, capsules, suspensions,
and others all require one or more excipients in their
formulations. Excipients may also have functions, for example, in
sustained release preparations or in enhancing drug penetration
through the skin.
It is important to perform risk-benefit
assessments on proposed new excipients in drug products and to
establish permissible and safe limits for these substances. This
requires evaluation of a safety database. With proper planning,
however, it is often possible to assess the toxicology of an
excipient in a relatively efficient manner. For example, sponsors
can develop new excipients concurrently with safety evaluation of
new drug and biological products by adding groups of animals that
receive the excipient to studies that would have been conducted
anyway to develop a drug substance. The Centers recognize that
existing human data for some excipients can substitute for certain
nonclinical safety data, and an excipient with documented prior
human exposure under circumstances relevant to the proposed use may
not require evaluation in the full battery of toxicology studies
outlined in this guidance. For example, the Centers will continue
to consider factors such as use in previously approved products or
GRAS status as a direct food additive. Under some circumstances
(e.g., similar route of administration, level of exposure, patient
population, and duration of exposure) experience associated with the
prior use may adequately qualify an excipient. However, it may be
necessary for the safety database associated with that excipient to
be brought up to current standards (e.g., submission of additional
genetic toxicology data). The available information that supported
the prior use will be considered in light of any proposed new use by
the appropriate review division. It is important to note that the
inclusion of an excipient in a USP/NF monograph or other non-FDA
document is not an indication that the substance has been reviewed
by the FDA and found safe for use.
For products marketed under OTC drug
monographs, 21 CFR 330.1(e) requires: “The product contains only
suitable inactive ingredients which are safe in the amounts
administered and do not interfere with the effectiveness of the
preparation or with suitable tests or assays to determine if the
product meets its professed standards of identity, strength,
quality, and purity. Color additives may be used only in accordance
with section 721 of the act and subchapter A of this chapter.” It
is the manufacturer’s responsibility to comply with these
requirements and to have appropriate supporting data in its files.
The provisions of § 330.1(e) do not apply to OTC products marketed
under NDAs or abbreviated new drug applications (ANDAs). Some
excipients used in NDA-approved drug products may not be safe for
use in OTC products (e.g., some toxic excipients used in cancer
chemotherapeutics).
Requirements for submitting safety information
on excipients in ANDAs for generic products are stated in 21 CFR
314.94(a)(9). Under this regulation, drug products intended for
parenteral, ophthalmic, or otic use should contain the same
excipients in the same concentrations as the reference listed drug
product, with the exception of buffers, antioxidants, and
preservatives, provided that the applicant identifies and
characterizes the differences and provides information demonstrating
that the differences do not affect the safety of the proposed drug
product. For other routes of administration (e.g., topical dermal,
oral), there is no requirement that the excipients in the final
formulations be the same as those in the reference listed drug
product, although the applicant must demonstrate that the inactive
ingredients do not affect the safety or efficacy of the proposed
drug product (21 CFR 314.94(a)(9)(ii)). However, we recommend that
the applicant identify and characterize the differences in
excipients and provide information demonstrating that the
differences do not affect the safety of the proposed drug product.
Consideration should be given to the prior indication and patient
population for which use of the excipient was previously deemed
safe. Alternatively, new or additional information to support the
proposed new use should be referenced.
It is important that a new or inadequately
qualified inactive ingredient proposed for use in any product to be
marketed pursuant to an NDA, biologics license application (BLA), or
ANDA be supported by adequate data. These data can be placed in the
application directly or in a drug master file (DMF). This guidance
describes the nonclinical data we recommend be submitted to verify
that a proposed excipient is safe in the amounts administered if
relevant prior human use cannot be adequately documented.
We may request additional safety data if we
determine that the proposed conditions of use are not fully
supported by the available data. We may request a pharmacokinetic
profile for excipients that are extensively absorbed or
biotransformed. When applicable, drug-excipient interaction studies
may also be requested. The proposed conditions of use of a new
excipient (e.g., use in pediatric patients)
may affect the need for toxicology data. The sponsor is encouraged
to contact the appropriate review division for guidance.
We recognize that every excipient is unique and
that scientifically valid reasons may exist for modifying and
deleting certain preclinical
studies listed in this guidance for a given combination of excipient
and proposed use. For example, it may be justifiable for the safety
evaluation of excipients deemed necessary for the delivery of
lifesaving therapies to be abbreviated (relative to the evaluation
of excipients for use in products for low morbidity indications) or
completed post-approval. As another example, excipients that are
large polymers that differ from previously characterized excipients
only in molecular weight (chain length) can be adequately
characterized in an abbreviated manner using less safety data,
provided that the new excipient and the previously studied excipient
are sufficiently similar with regard to physical state,
pharmacokinetics, and levels of unreacted monomers and other
impurities. We will consider such excipients on a case-by-case
basis. The sponsor is encouraged to contact the appropriate review
division to receive specific guidance when necessary.
We recommend that all pivotal toxicology
studies be performed in accordance with state-of-the-art protocols
and good laboratory practice regulations. The following
recommendations are primarily intended for excipients for which
adequate prior human exposure has not been documented.
We recommend that all potential new excipients
be appropriately evaluated for pharmacological activity using a
battery of standard tests (see ICH guidance S7A).
These evaluations can be performed during the course of toxicology
studies or as independent safety pharmacology studies. It is useful
for these data to be obtained at an early point during the safety
evaluation of an excipient, since, if the excipient is found to be
pharmacologically active, this information can influence subsequent
development. Appropriate regulatory guidance can be given by the
responsible review division.
We recommend
that the safety evaluation of potential new excipients that are
intended for use in products that are limited by labeling to
clinical use of 14 or fewer consecutive days per treatment episode
and are infrequently used include at least the following:
- Acute
toxicology studies performed in both a rodent species and a
mammalian nonrodent species by the route of administration
intended for clinical use (see CDER guidance for industry
Single Dose Acute Toxicity Testing for Pharmaceuticals). It
is not necessary to determine the LD50 of an excipient.
It may be appropriate to omit acute toxicology studies from the
safety evaluation of a new excipient under certain circumstances.
For example, if repeat-dose toxicology studies are performed in
which the high dose is the limit dose (e.g., 2 g/kg or 2
percent of the diet) and little or no toxicity is observed at that
dose, it can be assumed that the acute toxicity has been
adequately evaluated. In some cases, a dose-escalation study is
considered an acceptable alternative to a single-dose design (see
ICH guidance M3).
- It is recommended that the absorption,
distribution, metabolism, and excretion of the excipient be
studied following administration by the clinically relevant routes
to the same species that are used in the nonclinical safety
studies (see ICH guidelines S3A and S3B).
- It is recommended that excipients be
evaluated in the standard battery of genetic toxicology studies
discussed in ICH guidance S2B.
- It is recommended that 1-month repeat-dose
toxicology studies be performed in both a rodent species and a
mammalian nonrodent species by the route of administration
intended for clinical use. It is important that the studies
include complete clinical pathology, histopathology, and
toxicokinetic analysis.
- It is recommended that the reproductive
toxicology of the excipient be evaluated as discussed in ICH
guidelines S5A and S5B,
including: (1) assessment of potential to affect fertility or
early embryonic development to implantation; (2) teratology in
both a rodent species and a mammalian nonrodent species; and (3)
effects on prenatal and postnatal development, including maternal
function. The most efficient way to address these different
developmental landmarks is use of a single-study rodent
assay (as defined in ICH guidance S5A) to assess all phases of
reproductive toxicity, in conjunction with a teratology study in a
nonrodent species, provided that the available data predict the
excipient has minimal toxicity.
We recommend that the nonclinical safety
evaluation of potential new excipients that are intended for use in
drug products that are labeled for clinical use of more than 2 weeks
but less than or equal to 3 months per treatment episode include at
least the following:
- All studies from Section IV.A. and B. in
this guidance, with the exception of the 1-month toxicology
studies. Note: If toxicity or significant biological activity is
observed in short-term studies, 1-month toxicology studies may be
useful for establishing dosages to be used in 3-month studies.
- We recommend that 3-month repeat-dose
toxicology studies be performed in both a rodent species and a
mammalian nonrodent species by the appropriate route of
administration. It is important that the studies include complete
clinical pathology, histopathology, and toxicokinetic analysis.
- We may ask for additional studies (e.g.,
studies involving parenteral administration). This request is
usually driven by questions raised in the completed studies.
We recommend that the safety evaluation of
potential new excipients that are intended for use in drug products
labeled for clinical use of more than 3 months in a given patient
(either as a single treatment episode or as a result of multiple
courses of therapy to treat a chronic or recurrent condition)
include at least the following:
- All studies from Section IV.A., B., and C.
of this guidance. Note that 1-month and 3-month toxicology
studies are not essential, but may provide useful dosage selection
data.
- We recommend that a 6-month repeat-dose
toxicology study be performed in a rodent species by the
appropriate route. It is important that the study include
complete clinical pathology, histopathology, and toxicokinetic
analysis. We recommend that studies that involve excipients of
low toxicity in general use the limit dose as the highest dose for
testing.
- It is important that a chronic toxicology
study be performed in a mammalian nonrodent species by the
appropriate route. If toxicity and pharmacologic effect were
absent in state-of-the-art subchronic studies, a 6-month study may
be sufficient. When toxicity is detected in shorter duration
studies, or in rodents, a chronic study in nonrodents of 9 to12
months may be appropriate. The sponsor is encouraged to contact
the appropriate review division for guidance.
- If appropriate (see ICH guideline S1A),
one of the following approaches may be used to evaluate
carcinogenic potential:
a.
Two-year carcinogenicity bioassays in two appropriate species by the
relevant routes.
b. A
2-year carcinogenicity study in one rodent species plus an
alternative study (e.g., appropriate use of neonatal or
transgenic animals) in a different rodent species. We encourage
discussion with the appropriate review division of the usual choice
for that alternative assay.
c.
Submission of documentation providing scientific justification that
carcinogenicity data are not necessary. For example, based on
negative genetic toxicology data (see ICH guidance S2B for
recommended assays), limited systemic exposure, absence of
accumulation based on nonclinical and clinical pharmacokinetic data,
negative histopathology data from chronic toxicology studies
performed at the maximum feasible dose (MFD) (absence of
preneoplastic lesions and other toxicologic effects), and knowledge
of other excipients in the same class, it may be reasonable to
forego carcinogenicity testing. Decisions concerning the adequacy
of this approach would be made on a case-by-case basis, using a
weight-of-evidence approach. In other cases, adequately performed
cell transformation assays or one 2-year bioassay in the rat or one
transgenic assay, if negative, may be sufficient to
contribute to the weight-of-evidence assessment to address the
carcinogenic potential of the excipient. It is strongly encouraged
that application of the approach described herein be undertaken in
consultation with appropriate review division staff.
We recommend that the safety evaluation of
potential new excipients that are intended for use in injectable,
topical (dermal, intranasal, intraoral, ophthalmic, rectal, or
vaginal), or pulmonary drug products include the following:
- All studies from Section IV.A., B., C., or
D., as appropriate, using the appropriate route of administration.
Studies that include the to-be-marketed formulation of the drug
product are preferred, if this information is available at the
time of excipient evaluation.
- Sensitization study (e.g., guinea pig
maximization study or murine local lymph node assay). Consult
CDER guidance for industry Immunotoxicology Evaluation of
Investigational New Drugs for more information.
- For excipients intended for injectable use,
the following considerations may be appropriate:
- An in vitro hemolysis study could be
performed at the intended concentration for I.V. administration
(bolus and/or infusion) to determine the hemolytic potential.
- The plasma concentrations of creatinine
kinase determined at the intended excipient concentration for
I.M. or S.C. administration can provide information on potential
muscle damage.
- An evaluation of protein binding in
relation to local site tolerability could be done.
- Excipients intended for topical use may need
support from toxicology studies by both the intended clinical
route and the oral or parenteral route if clinical pharmacokinetic
studies conducted under conditions of maximum exposure show
patients would experience systemic exposure to the excipient or
its metabolite, particularly if limited systemic exposure were
observed in nonclinical studies conducted by the clinical route of
administration. The developer of a potential new excipient is
invited to contact the appropriate review division to discuss
whether or not this is appropriate for a specific excipient.
- For topical dermal products and ophthalmic
products, it may be appropriate to conduct an ocular irritation
study.
We recommend that excipients be evaluated
regarding the need for photosafety testing as described in the CDER
guidance for industry Photosafety Testing. Either the
excipient or the complete drug product could be tested. We
encourage consulting the appropriate drug review division prior to
initiation of studies.
Acknowledging the need to develop new
excipients, we have proposed a flexible approach that attempts to
consider both the type of use the excipient will have in approved
products and the biological activity and physical properties of the
molecular entity. It is recognized that during the course of data
evaluation, the reasons for additional data or the potential to
eliminate some studies may become apparent. In such cases, we
recommend consultation with appropriate review division staff to
avoid delays in use of the excipient.
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Date created: May 18, 2005 |
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