Guidance
Expiration Dating of Unit-Dose Repackaged Drugs:
Compliance Policy Guide
(PDF copy
of this document)
DRAFT GUIDANCE
This guidance document
is being distributed for comment purposes only.
Comments and suggestions regarding this draft
document should be submitted within 90 days of publication in the
Federal Register of the notice announcing the availability
of the draft guidance. Submit comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852. All comments should be
identified with the docket number listed in the notice of
availability that publishes in the Federal Register.
For questions regarding this draft document
contact Barry Rothman, 301-827-9026.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
May 2005
Compliance
Additional copies are available
from:
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
May 2005
Compliance
Guidance
Expiration Dating of Unit-Dose Repackaged Drugs:
Compliance Policy Guide
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draft guidance, when finalized, will represent the Food and Drug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 it 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.
Sec. 480.200 (CPG 7132b.11)
Many companies repackage solid and liquid oral
dosage form drug products into unit-dose containers. This guidance
states the circumstances under which the Food and Drug
Administration (FDA) intends to exercise its enforcement discretion
and does not intend to take enforcement action against such
repackagers for failure to conduct stability studies to support
expiration dates for these unit-dose repackaged products.
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.
Unit-dose packaging systems are widespread in
health care. Some unit-dose containers are available directly from
manufacturers and repackagers; some drug products are repackaged
into unit-dose containers by hospital or community pharmacies or
shared service establishments. A shared service repackaging
operation is one that exclusively serves one or more hospitals
and/or related institutions, each having separate or no pharmacy
services and each having responsibility for restricting distribution
of the drug products received from the shared service
establishment.
The nature of drug dispensing within hospitals
in particular has made such unit-dose packaging useful and
convenient in helping to ensure that medications are properly
administered to patients. However, questions have arisen concerning
the appropriate expiration dating for drug products repackaged into
unit-dose containers.
FDA’s current good manufacturing practice (CGMP)
regulations for finished pharmaceuticals, 21 CFR Part 211, include
§ 211.137 on “Expiration dating.” Section 211.137(a) requires that
each drug product bear an expiration date determined by appropriate
stability testing, as described in § 211.166. Under § 211.137(b), a
drug product’s expiration date must be related to any storage
conditions stated on the labeling, as determined by stability
studies described in § 211.166. Samples used for stability testing
must be in the same container-closure system as that in which the
drug product is marketed (§ 211.166(a)(4)). This is to ensure the
drugs’ safety and efficacy over their intended shelf life.
The U.S. Pharmacopeia (USP) contains standards
on expiration dating and beyond-use dating in its General Notices
and Requirements section.
The USP directs dispensers of prescription drug products to place on
the label of the prescription container a suitable beyond-use date
to limit the patient’s use of the product. The beyond-use date
cannot be later than the expiration date on the manufacturer’s
container. The USP states:
For nonsterile solid and liquid dosage
forms that are packaged in single-unit and unit-dose containers, the
beyond-use date shall be one year from the date the drug is packaged
into the single-unit or unit-dose container or the expiration date
on the manufacturer’s container, whichever is earlier, unless
stability data or the manufacturer’s labeling indicates otherwise.
FDA has considered the USP beyond-use standard
and believes that similar conditions are appropriate for FDA’s CPG
7132b.11 for expiration dating. FDA believes that under certain
specified conditions, it may be possible to assign appropriate
expiration dating without conducting new stability studies on the
nonsterile solid and liquid oral dosage forms repackaged into
unit-dose containers. Therefore, FDA does not intend to take action
against any nonsterile unit-dose repackaging firm (including shared
services repackaging operations) or drug product in a unit-dose
container solely on the basis of the failure of the repackaging firm
to have stability studies supporting the expiration dates used,
provided that the repackager meets all other regulations applicable
to repackaged drug products and:
1. The expiration date does not exceed (a) 1 year from the
date of repackaging or (b) the expiration date on the container of
the original manufacturer’s product, whichever is earlier, unless
stability data or the original manufacturer’s product labeling
indicates otherwise.
2. If the drug product repackaged is in solid oral dosage
form, the formed unit-dose container complies with the Class A
standard described in the USP, General Chapter <671>
Containers—Permeation, “Single-Unit Containers and Unit-Dose
Containers for Capsules and Tablets.”
3. The original bulk container of drug product has not been
opened previously and the entire contents are repackaged in one
operation.
4. The repackaging and storage of the drug product are
accomplished in a controlled environment that is consistent with the
conditions described in the labeling for the original drug product
and the repackaged drug product. Where no temperature is specified
in the labeling of the original drug product, a controlled room
temperature (as defined in the General Notices and Requirements
section of the USP) should be maintained during repackaging and
storage of both solid and liquid oral dosage form drug products.
Where no humidity is specified in the labeling of the original drug
product, the relative humidity should not exceed 75 percent at 23
degrees Celsius for the repackaging and storage of solid oral dosage
forms.
This CPG applies only to nonsterile solid and
liquid oral dosage forms in unit-dose containers. Sterile products
and other types of dosage forms and packages pose sterility and/or
stability concerns that this CPG would not adequately address.
Thus, this CPG does not apply to sterile products, other dosage
forms, and other types of packages.
Liquid oral dosage forms should not be
repackaged unless suitable materials are used and precautions are
taken to prevent evaporation or solvent loss.
This CPG does not apply to nitroglycerin
sublingual tablets or any other solid or liquid oral dosage form
drug product known to have stability problems that preclude the
product from being repackaged. This group of products generally
would include any drug known to be oxygen sensitive or that exhibits
extreme moisture or light sensitivity. In deciding whether a
particular drug product is suitable for repackaging, the repackager
should take into consideration any available information from the
manufacturer, published literature, the USP, and FDA.
FDA’s intent to exercise enforcement discretion
concerning stability studies for repackaged products does not apply
to any other requirements of Parts 210 and 211.
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Date created: May 27, 2005 |