Surgery – Radioactive substance applied to body for therapy – Radioactive substance placed within body
Reexamination Certificate
2002-02-17
2004-02-17
Gilbert, Samuel G. (Department: 3736)
Surgery
Radioactive substance applied to body for therapy
Radioactive substance placed within body
Reexamination Certificate
active
06692426
ABSTRACT:
The present invention relates to sterile radioactive seeds, and to a dry heat method for sterilising seeds. It is particularly concerned with sterile loose seeds which may be presented in a closed container, where the sterilisation method used is dry heat.
Radioactive seeds are radioactive permanent implants for the treatment (brachytherapy) of various clinical conditions, such as cancer, particularly prostate cancer, or restenosis. Such seeds comprise a radioisotope (typically
125
I or
103
Pd) sealed within a biocompatible container (typically titanium or stainless steel). Each patient dose is individually calculated depending on the size of the tumour, but is typically in the range 50-120 seeds per patient when treating prostate cancer. The seeds are implanted in a three-dimensional matrix according to calculated dosimetry. The seeds are sufficiently small to be loaded into implantation needles.
The radioactive-isotope of choice is
125
I. This isotope has a half life of 60 days, short enough to permit implanted seeds to be left permanently in a patient's body without inflicting excessive long term damage.
125
I emits low energy X-rays (30 KeV), which ensures that the volume of treated tissue is mainly confined to the locality of an implanted seed, i.e. the tumour.
In one currently available radioiodine seed, iodine-125 is adsorbed on to a silver rod and encapsulated in a welded titanium capsule. The silver rod acts as an X-ray marker. The seeds are cylindrical, 4.5 mm long and 0.8 mm diameter, designed to fit into a needle or catheter with an internal diameter of 1 mm. Such seeds are described in U.S. Pat. No. 4,323,055. These radioiodine seeds are commercially available. They are designed and manufactured to meet temperature test 5 of ISO 2919: 1999(E). This test involves holding the seeds at −40° C. for 20 minutes; at +600° C. for one hour; and subjecting the seeds to thermal shock from +600° C. to +20° C. It may be noted that these tests are designed simply to assess product safety performance when subjected to various stresses. Designs which do not release radioactivity pass the test. Hence such tests are not part of routine seed manufacture, but form part of the validation of a given seed design. Consequently, any deterioration in performance of the seed product as a result of the test, is not measured.
Brachytherapy seeds are commercially available in three forms:
a) loose, non-sterile, supplied in a screw cap vial;
b) sterile in a flexible suture;
c) sterile in a stiffened suture.
The last product (sold under the RapidStrand trademark) comprises an initially flexible elongated bio-absorbable material having seeds incorporated therein at regular intervals. The strand is subsequently heated which makes it less flexible, to aid the process of implanting in or around a tumour. As noted in U.S. Pat. No. 5,460,692, this RapidStrand product is marketed in a sterile state by virtue of having been treated with a chemical sterilising agent. However, chemical sterilisation is problematic as discussed below and is not suitable for loose seeds.
It may be noted that, despite being radioactive, the radioiodine seeds are not self-sterilising. This is because the radiation dose at the surface of the seed is insufficient to cause the required degree of killing of micro-organisms. Customers who buy non-sterile loose radioiodine seeds need to sterilise them before use. An instruction leaflet accompanying the seeds teaches the use of steam sterilisation and specifically advises against the use of dry heat or chemicals to sterilise the seeds. However any unnecessary manipulation of radioactive seeds by a customer is inherently undesirable. Since the seeds contain a volatile radioiodine isotope, any handling operation that involves heating is particularly undesirable. Moreover regulations in Europe do not permit the sale of radioactive seeds in a non-sterile form if they are to be permanently implanted in the human body. There is thus a need for a supply of loose sterile radioactive seeds. This invention addresses that need.
In one aspect the invention provides a method of sterilising one or more radioactive seeds. The method comprises subjecting the radioactive seeds to dry heat for a time sufficient to effect sterilisation; and subsequently cooling the radioactive seeds. The temperature of the dry heat sterilisation process should be at least 140° C., preferably 150-200° C., most preferably 160-165° C. The term ‘dry heat’ is used in the field of sterilisation, and denotes that the heating is achieved without contacting the seeds with either boiling water or steam, ie. in contrast to moist heat. The term ‘cooling’ encompasses both a passive process (eg. removing or switching off the source of heat) so that the seeds cool slowly to ambient temperature, and a more active process (eg. moving the seeds to a cooler area, or application of a cooling means such as a fan), so that the seeds cool more quickly.
In another aspect the invention provides a product prepared by the above dry heat sterilisation process. The product comprises one or more radioactive seeds in a sterile condition, preferably in a closed container, wherein the seed(s) have been sterilized by dry heat.
In another aspect, the invention provides a product comprising a closed container containing one or more radioactive seeds in a sterile condition, wherein the radioactive seeds are free of moisture and of chemical residues characteristic of chemical sterilisation, and wherein the product is free of degradation characteristic of sterilisation by gamma irradiation.
The dry heat process of the present invention may be carried out by use of a variety of heating means capable of achieving the required substantial absence of moisture and temperature control for the required time, such as ovens (heated by conventional means such as electricity, gas or solid fuel); radiant heat (eg. from hot wire filaments); immersion in a bath of heated high-boiling organic solvent (eg. an oil such as silicone); flames; or infra-red radiation. Heating techniques which require an additional step, such as the removal of residual high-boiling solvent or surface combustion deposits are less preferred. It is preferred to use ovens, which may be electrically or gas heated, and deliver heat via hot air, and which have a temperature-controlled environment. Microwave ovens not suitable, since such heating is not safe for metallic objects such as seeds, potentially risking rupture of the seed. Also, microwave heating would deliver heat to the inside of the seed, whereas the present invention requires that the outer surface of the seed is heated to sterilise that part of the seed which would be in contact with the human body. Ovens suitable for use in the present invention are commercially available in a variety of forms and sizes, and are preferably heated electrically and designed for laboratory use.
The dry heating of the present invention should preferably be carried out in an atmosphere which contains oxygen, and is preferably and conveniently carried out in air. The presence of oxidation facilitates the destruction of micro-organisms by an oxidative process. When the heating means is an oven, hot air is used to transfer the heat to the seeds to be sterilized. Hence, when the seeds are sterilized in a closed container, the headspace gas above the seeds in the container should contain oxygen, and is preferably and conveniently air at atmospheric pressure.
Whichever heating means is used, it is necessary to have adequate temperature control around the zone in which the seeds are to be heated. This temperature control may be achieved either manually, eg. by adjustment of the heat in response to temperature readings, or is preferably achieved automatically via a thermostatically controlled heating means, preferably as part of a temperature-controlled oven. The temperature at specific locations within the heating means used (eg. different areas or shelves within an oven), should be validated prior to use to show that the temperature
Faulkner Ian D.
Rogers Thomas J.
Amersham PLC
Cai Li
Gilbert Samuel G.
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