UKRG Handbook RADIOPHARMACEUTICAL DILUENT DIRECTORY
Introduction
Dilution of radiopharmaceuticals is normally undertaken in order to make the volume of the dose injected more amenable to the patient and to facilitate measurement of its radioactivity. However although the practice is commonplace, data to support it are scarce and are almost exclusively based on information obtained from manufacturers either from SPC and/or pack inserts or in the form of verbal advice following telephone inquiries.
Scale of Complexity
The act of dilution may vary from simply drawing the appropriate diluent up into the syringe which already contains the correct activity (but in a volume too small to handle) eg with a paediatric dose of a 99mTc radiopharmaceutical withdrawn from a high activity vial. At the other end of the scale it may be part of the manufacture of a batch of a longer lived radiopharmaceutical involving addition of several components eg 125I Human Serum Albumin.
Dilution and the Medicines Act
Recent advice1 has reiterated that where products are prepared or manufactured outside the commercial manufacturers instructions, the responsibility for the efficacy of the product lies with the unit preparing the product. This would clearly be the case for the second example described above where as a minimum, radiochemical purity, chemical purity and chemical identity of the new diluted product would need to be established throughout its assigned shelf life.
At the other extreme, dilution of a dose in its final presentation form at the point of injection into the patient is clearly part of the process of administration and is not covered by the Medicines Act. The issue affecting radiopharmacies is that most dilution activities falls somewhere within these two extremes, with validated guidance from manufacturers or published data being minimal.
The aim of the following table is to provide information about the most appropriate diluent, the limitations of dilution, and reference source where known. The dilution of radiopharmaceuticals for long term storage as a manufacturing process is not within the scope of this table and radiopharmacy staff are advised to validate each circumstance where this may be attempted.
|
RADIOPHARMACEUTICAL |
DILUENT |
MAXIMUM VOLUME |
REFERENCE |
| 99mTc Kits* | sodium chloride 0.9% | see text |
-
|
| 111In Octreoscan® | sodium chloride 0.9% | 2 - 3ml | Package insert |
| 111In Oncoscint® | Not recommended | inferred from SPC | |
| 111In Calcium DTPA | sodium chloride 0.9% (pyrogen free) | not stated | |
| 123I Sodium Iodide (Bristol-Myers Squibb) | none stated: try sodium chloride 0.9% | not stated | |
| 123I Sodium Iodide (Tyco/Mallinckrodt) | sodium chloride 0.9% | not stated | SPC |
| 123I Sodium Iodide (Amersham Health) | Not recommended (pH critical) | company information | |
| 123I Iomazenil | Not recommended | Ethanol based formulation of product | |
| 123I Ioflupane (DatScanÔ)(Amersham Health) | Not recommended | SPC. Ethanol based formulation of product | |
| 123I Iobenguane (MIBG) (Amersham Health) | |||
| 123I Iobenguane (MIBG) (Tyco/Mallinckrodt) | water for injection or 5% glucose in water | not stated | SPC |
| 123I Iobenguane (MIBG) (Bristol-Myers Squibb) | sodium chloride 0.9% | not stated | Package insert |
| 123I o-Iodohippurate (Tyco/Mallinckrodt) | none stated: try sodium chloride 0.9% | ||
| 123I o-Iodohippurate (Amersham Health) | |||
| 125I Iothalamate | |||
| 125I HSA (Isopharma) | sodium chloride 0.9% & benzyl alcohol 0.9% or albumin 15mg/ml soln. | Not stated | SPC |
| 131I Sodium Iodide oral/IV (all manufacturers) | Any suitable diluent. No incompatibilities known | SPC | |
| 131I MIBG (diagnostic) (Amersham Health) | sodium chloride 0.9% | ||
| 131I MIBG (therapeutic) (Amersham Health) | sodium chloride 0.9% | up to 50ml | Company information |
| 131I MIBG (therapeutic) (Tyco/Mallinckrodt) | glucose 5% in water only | Infused with glucose 5% up to 250ml | SPC |
| 131I MIBG (therapeutic) (Bristol-Myers Squibb) | glucose 5% in water only | Company information | |
| 90Y Yttrium Silicate | Dilution not recommended: pH critical | Company information: colloid may break down if pH falls below pH11 | |
| 32P Sodium Phosphate | Not recommended | Company information | |
| 201Tl Thallous Chloride | None stated: use sodium chloride 0.9% | ||
| 67Ga Gallium Citrate | None stated: use sodium chloride 0.9% | ||
| 59Fe Ferric Citrate | sodium citrate dihydrate 1% and sodium chloride 0.58% | Data sheet: (to avoid precipitation) | |
| 51Cr Edetate (EDTA) | sodium chloride 0.9% and benzyl alcohol 1% | ||
| 51Cr Sodium Chromate | sodium chloride 0.9% | up to 10ml | |
| 18F Fluorodeoxyglucose | sodium chloride 0.9% | ||
| 153Sm Samarium EDTMP QuadrametÔ | Not recommended | SPC | |
| 89Sr Strontium chloride MetastronÔ | Not recommended | SPC |
99mTc Technetium based products* obtained from commercial suppliers normally have a tightly defined volume range eg 1-10ml within which the product has been exhaustively tested for stability. All kits are prepared with sodium chloride 0.9% injection. In the authors experience, it is common practice for further dilution to take place with sodium chloride 0.9% injection to a volume at least twice that of the maximimum described in the package insert. (Nanocoll kit actually allows up to 1:50 in pack insert).
A typical scenario would be one where a large activity but relatively small volume is transferred from the kit vial to a sterile nitrogen filled vial and then diluted to a much larger volume to enable a standardised volume to be used for patient injection. In practice this could be a volume of 0.5ml (from a maximally diluted kit according to the manufacturers instructions) diluted to 2ml in the secondary container. This may then be used by the imaging department as a multi-dose vial for several patients over a period of a few hours.
Conclusion
Dilution of radiopharmaceuticals as part of the process of their production is not well documented as is evident from the gaps in the table. Stability data are lacking whether the product is stored in syringes or in the original vial. Radiopharmaceutical manufacturers are reluctant to give approval to the practice on a large scale, thus the responsibility ultimately rests with the producing department or the person administering the product.
Readers of this paper who are aware of alternative diluents or have further information concerning dilution in general are urged to contact either pmaltby@rlbuh-tr.nwest.nhs.uk or webmaster@ukrg.org.uk.
References
1. Hesslewood SR, Palmer AM and Lazarus CR. Radiopharmaceutical "Kits": use outside the manufacturers' instructions. The Hospital Pharmacist 1998;5:107-8