ABSTRACT
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Closures that form part of the container-closure system are an important component in the packaging of sterile products. Container-closures
maintain the sterility of parenteral pharmaceuticals and prevent ingress of contamination when a needle is inserted into a
vial. This article describes important aspects to consider in the manufacture of closures for pharmaceutical preparations,
as well as the various physical, chemical, and biological assessments required to ensure that these closures are fit for purpose.
Parenteral products are designed, formulated, and packaged to be sterile and to maintain sterility. One of the most important
parts of the packaging of sterile drug products is the container-closure mechanism. This article examines the use of closures,
for products intended for injection, in the pharmaceutical industry. The article considers the most important aspects relating
to the manufacture of closures and the different physical and biological assessments required to ensure that the closures
are "fit for purpose." The article does not address caps or other types of seals.
Closures form part of the "container-closure system." Container-closures function to keep the contents of pharmaceutical preparations
sterile (e.g., by providing a barrier between the neck of a vial and the vial contents) and to prevent ingress of contamination
into a vial once a needle is inserted (e.g., by enabling resealing of the vial after the needle is withdrawn). The closure,
together with a crimp that creates the container-closure, and the vial itself form the primary packaging or packaging component
(i.e., the material that first envelops the product and holds it) (1). The ideal container-closure will have low permeability
to air and moisture and a high resistance to aging (2).
Therefore, the manufacturers and users must have confidence in the quality control and validation of closures. It is an important
part of pharmaceutical manufacturing that all information on the composition and manufacturing processes for each component
type must be understood.
CLOSURES
Pharmaceutical closures, also known as stoppers or bungs, are an important part of the final packaging of pharmaceutical preparations,
particularly those that are intended to be sterile. The most commonly used type of stopper is the elastomeric closure. An
elastomer is any material that is able to resume its original shape when a deforming force is removed, which is known as viscoelasticity
(3).
For the manufacturing of closures, the elastomer is either natural or, as is more common, a synthetic rubber, such as butyl
rubber or chlorobutyl rubber. The advantage of synthetic rubbers is that the materials are strongly resistant to permeation
by oxygen or to water vapor (4).
In terms of the specification for closures and the testing and sterilization requirements, the following documents are useful
as starting points:
- FDA, Guidance for Industry: Container Closure Systems for Packaging Drugs and Biologics (Rockville, MD, May 1999).
- European Commission, Guideline on Plastic Immediate Packaging Materials (Brussels, May 2005).
-
USP, General Chapter <381> Elastomeric Closure for Injections.
-
European Pharmacopeia. Chapter 3, Materials for Containers and Containers.
The FDA Code of Federal Regulations (CFR) part 21 211.94 stipulates that container-closures must provide adequate protection to the product over the product shelf-life.
Before using a closure in a vial or bottle with a drug product, the closure must be assessed to determine if it is suitable
for use with the product that will be filled into the glass container. The pharmaceutical manufacturer should consider the
following questions relating to product compatibility, in conjunction with the manufacturer of the closure:
- Is the product absorbed by the rubber?
- Does the rubber react with the product and leach out impurities?
- At which temperature range is both closure and product stable?
- How effective is the seal integrity?
- What happens when the product and stopper are stored together over time?
Once these questions have been satisfactorily answered, the pharmaceutical manufacturer can work with the manufacturer of
the closure to design the optimal closure for the vial type and product.
