Rubber stopper quality and technical issues: a global perspective.
Many issues are common among these regions, but their focus may be different. Typically, an issue arises in one region, and then migrates to another.
One issue related to worldwide pharmaceutical distribution is that of regional compendial testing. These are basic tests that must be conducted on materials that will be used for pharmaceutical stoppers. This basic testing is necessary for regulatory submissions and each region has its own documentation requirements and protocol demands.
United States: Testing specific to stoppers in the United States Pharmacopoeia (USP) is in Section 381: Physicochemical Series and Sections 87 and 88: Biological Testing.
Europe: For submissions to Europe, closures must be qualified through a series of tests from the Pharmacopoeia of Europe (Ph. Eur. Section 3.2.9). This testing includes physicochemical testing and functional testing of the rubber closures.
Japan: For submission to Japan, the Japanese Pharmacopoeia (JP), Section 59, lists physicochemical and biological series testing.
The test series for each region have few similarities. The tests are typically wet chemical methods that have been used for years and do not use any advanced analytical techniques common to the pharmaceutical and analytical industries.
However, these are not the only regional compendial tests. Almost every country has its specific test series, but over the years, as industry has tried to harmonize, the USP, Ph. Eur. and JP have become the most common standards for stoppers.
Currently, the USP is evaluating a change to harmonize with the Ph. Eur. physicochemical series for rubber stoppers by January 2006. The Ph. Eur. has specifications for each test while the USP does not have specifications for Section 381 testing.
The high-profile stopper issues are discussed below.
The Food and Drug Administration (FDA) is requesting that a quality agreement be put in place between all pharmaceutical and biotech companies and their key suppliers. These quality agreements should be the overarching guidelines defining the expectation and relationship between the supplier and the customer. They typically cover issues such as change control and customer notification, CGMPs and validation issues.
Drug Master Files (DMFs)
DMFs are an essential element of the chemistry, manufacturing and controls (CMC) section of the drug and biologic application submission process in the United States and Canada. Both the FDA and Health Canada have Drug Master File systems.
A Drug Master File is a voluntary submission to the FDA or Health Canada's Therapeutic Products Directorate that contains confidential trade, patent or proprietary information relevant to a drug, biologic or medical device application that the DMF holder does not wish to disclose to the application's owner.
A Letter of Authorization (LOA) is issued by the DMF holder to the regulatory agency granting permission to reference the DMF.
Extractables are chemical species that migrate from packaging or other components under exaggerated solvent, temperature and time conditions. Leachables are chemical species that migrate from packaging or other components under normal conditions of use or during stability studies.
The extractables/leachables issue has been a growing concern in the U.S. and has also been seen emanating from the regulatory authorities in Europe. From a regulatory standpoint, it is imperative that the drug manufacturer has a clear understanding of what is in the drug product--even if there seems to be no negative effect on efficacy.
Leachables testing is quite different from compendial testing and involves the use of optimized methods to look for individual species.
Ready-to-sterilize stoppers are becoming an industry trend. This process replaces the normal stopper washing and preparation process that had been done at the pharmaceutical manufacturer's facility. A ready-to-sterilize process should be fully validated by pharmaceutical GMP standards and the manufacturing should be conducted under CGMP standards.
Current Good Manufacturing Practices (CGMP)
In the United States, the Code of Federal Regulations (CFR) section 210 and 211 guide the pharmaceutical industry in the production of pharmaceutical and biopharmaceutical products. The FDA will audit pharmaceutical manufacturing facilities to these standards and has also made it clear that the pharmaceutical/biotechnology industry needs to audit their suppliers to the same standards. Therefore, aspects of the closure manufacturing process are to meet applicable CGMPs. In the area of stopper processing, the FDA has made it clear that this process is to be fully CGMP compliant.
Silicone oil (polydimethylsiloxane fluid) has been used by drug manufacturers as an aid to help rubber closures flow through their stoppering equipment. It has been used sparingly and, in many cases, newer alternatives have been used in order to totally avoid some of the problems associated with silicone oil, namely inconsistency in its application. This leads to problems in machining and can also cause issues such as droplets in solution and hazing upon reconstitution of lyophilized products. One trend to minimize the risk associated with this issue is to use closures coated or laminated with fluorocarbon film.
The compatibility of the closure design with the glass vial for each application is critical. If the two items are not complementary, potential problems with pop-up or seal integrity may emerge.
Additionally, there can also be lyophilization problems with stoppers sticking to the shelves within the lye chamber once they are used to push the closure into the vial. This often leads to significant down time and clean-up issues within the lye chamber. Films applied to the top of the stopper can mitigate this problem.
BSE/TSE (Mad Cow Disease)
Bovine Spongiform Encephalopathy (BSE) and Transmissible Spongiform Encephalopathy (TSE) are diseases derived from cow or pig tallow. Since some animal derived raw materials are used as ingredients in rubber closures, there has been much industry concern, primarily driven from Europe to other regions of the world, in relationship to this issue.
The European Medicines Agency (EMEA) has recently given clear direction on this issue in relationship to pharmaceutical packaging. Their concern is only for primary packaging components, those that are in direct contact with the drug, not secondary components.
Acceptable Quality Levels (AQLs)
Typically, the closure industry has used AQL levels via the most recent American National Standard document on Sampling Procedures and Tables for Inspection by Attributes. There has been a trend, most notably emanating from Japan, away from the use of AQLs to a zero-defect mentality. In the U.S. and Europe this is manifesting itself another way--through final inspection of the finished packaged drug product.
In Europe and Asia specifically, there seems to be a movement away from the use of vials towards the use of prefilled syringe systems. The prefilled syringe systems typically offer one major advantage--they are user friendly.
A syringe brings with it certain functionality needs that are in addition to those of a vial. The break loose and extrusion forces of the plunger over the shelf-life of the syringe system are critical. The fact that syringe systems are typically filled via aseptic processes versus terminal sterilization processes may also have implications on sterility.
Another functionality issue that relates most directly to how the product will be used in the field is fragmentation or coring of a rubber closure. Coring is the generation of rubber particles from the insertion of the needle through the rubber. The drug applicant needs to understand how a product will typically be used. What types of needles will be used? Will a spike be used to access the medicament? Will multiple punctures be necessary? These considerations are important to evaluate the correct rubber formulations and the correct configuration or "shape" of the stopper.
Stoppering line speeds for 300 vials per minute or higher are typical. At these speeds, stoppers are expected to be uniform from a dimensional standpoint and a lubricity standpoint, so as to track well in the equipment. Again, alternatives to the traditional silicone oil coating have been able to help address this issue, especially in new applications.
Another issue relates to stopper tackiness and the ability for stoppers to twin or clump following sterilization processing, leading to manufacturing issues. It is important that the pharmaceutical industry realize that their processing cycles/conditions can have a tremendous impact on this characteristic of the rubber.
--Frances L. DeGrazio
Vice President, Quality Assurance and Regulatory Affairs, Americas West Pharmaceutical Services, Inc.