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RUBBER PARTICLES IN INJECTIONS WHAT ABOUT THE PATIENT?

(Sandy Lunoe)
It is generally recognized that particles in injections may result in serious
complications for patients. The potential serious adverse events resulting from
the use of a sterile injectable product with particles by the intravenous route
include embolic, thrombotic and other vascular events (e.g., phlebitis).
Complications in connection with the subcutaneous route may include foreign
body granuloma, local injection site reactions, and increased immunogenicity (1)
There are therefore official requirements for manufacturers to provide
documentation to health authorities concerning particulate matter in injectable
products (2)
Many years ago I worked in the sterile department of a public hospital in Norway.
In connection with quality control of injections one of my jobs was to count
particles in injections with an automatic counter and to identify them
microscopically prior to release of each batch.
Particles identified were for example glass, crystals, fibres from filters, or rubber
particles from the stoppers. The latter may have been released during the
sterilisation process, heating in autoclaves under high temperature and pressure.
I was often present on the wards when patients were given injections after the
rubber stoppers on injection vials had been punctured prior to withdrawal of the
doses.
For interest, I sometimes counted and identified particles in injections both
before and after puncturing the stoppers. There were, as expected, more rubber
particles after puncturing and the numbers were higher for thicker needles and
several punctures.
I contacted Food and Drug Administration (FDA) and asked if there is a
requirement for manufacturers of injections including vaccines to produce
documentation concerning particulate matter after puncture of rubber stoppers.
The complete reply from FDA is posted below (3).
It is surprising and disconcerning to learn from the answer received :
TO THE BEST OF MY KNOWLEDGE, THERE IS NO SPECIFIC REQUIREMENTFOR
THE MANUFACTURER TO COUNT AND IDENTIFY PARTICLES AFTER VACCINE
STOPPERS ARE PUNCTURED .
If there was a requirement for this, it would undoubtedly result in more
awareness from the manufacturers regarding the quality choice of rubber
stoppers, an aspect which surely should be considered in connection with
patients health and safety.
(1) http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHu
manMedicalProducts/ucm227225.htm
(2) http://www.usp.org/pdf/EN/USPNF/PF35(5)_StimArticle-3.pdf

(3) Reply from FDA:


Thank you for your follow-up inquiry. FDA expects purity of all products in
single-dose or multi-dose vials.
To the best of my knowledge, there is no specific requirement for the
manufacturer to count and identify particles after vaccine stoppers are
punctured.
Title 21 of the Code of Federal Regulations (CFR), Part 610.13
(http://edocket.access.gpo.gov/cfr_2010/aprqtr/pdf/21cfr610.13.pdf),
states, in part, "Products shall be free of extraneous material except that
which is unavoidable in the manufacturing process described in the
approved biologics license application". In Title 21 CFR, Part 600.3(r),
purity is defined as the "relative freedom from extraneous matter in the
finished product, whether or not harmful to the recipient or deleterious to
the product". This regulation can be found at the following web address:
http://edocket.access.gpo.gov/cfr_2010/aprqtr/pdf/21cfr600.3.pdf.
We hope this information is helpful.
Center for Biologics Evaluation and Research
Food and Drug Administration