TO THE EDITOR:
According to the package insert for the Ultra-TechneKow DTE generator (Mallinckrodt Inc., St. Louis, MO) (1), generator eluate should not be used if its appearance is discolored. One of the few unique features that has been implemented with this new generation of 99mTc generators is the placement of a bright orange-color paper disk (13-mm diameter and 1-mm thickness) at the bottom of the column safe hole where the 98Mo column is located. The so-called “molybdenum column integrity pigment disk” turns the eluate a light yellow color if the column is broken, cracked, etc. (2). If such a change in the color of the eluate occurs, this is an indication that the sterility of the generator system has been compromised (2). Therefore, any discolored eluate should be discarded (1).
Although the use of a pigment disk is an interesting idea, it may not be practical because the leaded glass used in either the elution shield or the syringe shield would also appear to be yellow in color. Thus, it would be quite difficult to detect a light yellow appearance of the eluate through the yellow leaded glass.
To facilitate the fractionated elution process, an ergonomically designed elution shield was introduced along with the Ultra-TechneKow DTE generator. Although this elution shield has been fitted with a light source to allow visual inspection of the elution process, the double-layer lead-glass windows (i.e., one layer on the elution shield and the other layer on the window ring of the auxiliary lead shield for the generator) make it difficult to notice any change in the appearance of the 99mTc eluate. If an all-metal canister such as a lead CAP-MAC or tungsten CAP-MAC (Capintec, Inc., Ramsey, NJ) is used to elute an Ultra-TechneKow DTE generator, it would be impossible to note any discoloration of the eluate unless the elution vial is removed from the vial shield. To reduce hand and eye exposure to the operator, both of these CAP-MAC canisters are designed to measure 99Mo or 99mTc without exposing the operator to the unshielded elution vial. If it is necessary to remove the eluate vial from the CAP-MAC shield to observe the coloration of the 99mTc eluate, this undoubtedly defeats the purpose of using the CAP-MAC device.
During the past 4 y in which we have used the Ultra-TechneKow DTE generators in our institution, we have experienced one isolated incident of “yellow eluate.” Because we use the tungsten CAP-MAC device for eluting generators as well as for storing 99mTc eluate, the technologist, in this instance, initially did not notice the yellow coloration of the flawed eluate. However, the technologist was prompted to check the elution vial when the measured radioactivity of the eluate was found to be far less than that anticipated. The total eluted volume (approximately 10 mL) was satisfactory because a 10-mL elution vial was used; however, the eluate was yellow in color. To confirm that the generator eluate was defective (i.e., low activity and yellow appearance), a fractionation elution process (i.e., elution was terminated at approximately 45 s) was conducted using the same generator immediately afterward, and once again the collected eluate (approximately 7 mL) appeared yellow in color.
The generator was then returned to Mallinckrodt for further investigation. According to the report that I received from Mallinckrodt Inc. (R.R. Bartnick, written communication, November 1999), another elution of this generator was conducted at the Mallinckrodt facility, and the eluate obtained was slightly yellow in color. After this generator was dismantled at Mallinckrodt, a pool of yellow eluate was found inside the column safe hole, and it was later determined to be leakage from the generator column that had caused the eluate to turn yellow.
The aforementioned scenario is the only yellow eluate incident that we have noticed in our institution since we began to use the Ultra-TechneKow DTE generators in 1997. On average, we order four to seven new Ultra-TechneKow DTE generators (depending on 99Mo radioactivity amounts) every week. Therefore, in our experience, occurrence of the leakage problem with the Ultra-TechneKow DTE generator is very rare. However, four issues relative to the yellow eluate problem still must be addressed:
What is the incidence rate of yellow eluate since the Ultra-TechneKow DTE generator was first introduced to the United States market in July 1997? On the basis of our own experience, the occurrence rate of yellow eluate from an Ultra-TechneKow DTE generator appears to be very low.
Should visual inspection of each eluate obtained from an Ultra-TechneKow DTE generator be required? Currently, visual inspection of the 99mTc eluate is not listed as a required step either in the Ultra-TechneKow DTE package insert (1) or in the monograph for 99mTc–sodium pertechnetate injection in U.S. Pharmacopeia 24 & National Formulary 19 (3).
Is the yellow appearance of eluate obtained from an Ultra-TechneKow DTE generator always associated with an amount of 99mTc radioactivity that is much less than that anticipated? If so, it may only be necessary to check the color of the eluate when the measured 99mTc activity is far below the normal value.
In the event that yellow eluate were used inadvertently in the preparation of a radiopharmaceutical for patient studies, would the pigment material used in the disk have any adverse effect on the patients involved, other than compromising the sterility of the 99mTc drug product (2)?
REPLY:
We thank Dr. Hung for his comments regarding Mallinckrodt’s Ultra-TechneKow DTE generator (99mTc generator) and note his concerns over the appearance of the “yellow eluate” from one of the generators shipped to his facility.
Mallinckrodt Inc. is dedicated to providing products to the nuclear medicine community that are safe for both the customer and the patients that benefit from them. In this regard, Mallinckrodt’s Ultra-TechneKow DTE generator is designed with features that ensure the delivery of a sterile drug product for either direct patient administration or use in an approved 99mTc radiopharmaceutical kit from various vendors. One of these features, as specified by Dr. Hung, is the inclusion of a dye-impregnated disk that is placed under the generator column in its shielding. The purpose of the disk is to provide the customer with a visual indicator in the event that the integrity of the sterile generator column has been compromised.
Should there be a loss of integrity in the column seals, generator eluate leaking out of the column would come in contact with the disk, extract the yellow-orange dye, and produce a colored solution. During the elution step, this colored solution would be drawn back into the generator column through the break in the seal and be collected in the eluate vial. When colored eluate is observed in the collection vial, it is an indication that the generator eluate has bypassed the sterile confines of the generator assembly and should no longer be considered to be a sterile drug product. The Mallinckrodt Ultra-TechneKow DTE generator is unique in this design, and we are unaware of a similar feature in 99mTc generators from other vendors.
Responses to the specific issues raised by Dr. Hung follow:
According to our records, the incidence rate of the yellow eluate appearing in Mallinckrodt’s Ultra-TechneKow DTE generator since its 1997 launch in the United States has been <0.02%. As construed by Dr. Hung, the incidence of the yellow eluate is indeed very rare and affirms the overall integrity of this product for customer use.
It is true that visual inspection of the generator eluate is not specifically listed as a required step either in the Ultra-TechneKow DTE package insert (1) or in the monograph for 99mTc–sodium pertechnetate injection in U.S. Pharmacopeia 24 & National Formulary 19 (2). As Dr. Hung pointed out, the package insert does state under the elution directions that the generator eluate should not be used if its appearance is discolored, which does imply that some type of visual check must be performed on the eluate before its use. Furthermore, according to the U.S. Pharmacopeia monograph for 99mTc–sodium pertechnetate injection (2), the material is expected to meet the requirements listed in the general chapter on injections, which specifies that all products intended for injection should be free of foreign matter and inspected for such. Good pharmacy practice and adherence to the ALARA (as low as reasonably achievable [radiation exposure]) principle may appear to be in conflict in this situation; yet, an inspection procedure that satisfies both the requirements for injectable materials and the ALARA principle can be readily implemented (e.g., by the use of mirrors behind lead shielding). In solution, the dye exhibits fluorescence under ultraviolet light, so an ultraviolet lamp may be useful to visualize the presence of the dye in the generator eluate.
The appearance of a yellow color in the generator eluate is not entirely indicative of a low 99mTc yield. A low 99mTc yield may occur in conjunction with a discolored generator eluate if, during the elution process, solution in contact with the dye disk outside the column is drawn into the generator fluid path to a greater extent than generator eluent is drawn through the column that contains the 99Mo/99mTc load. Conversely, a normal 99mTc yield can occur with a discolored generator eluate if the generator eluent is drawn through the column to a greater extent than dye-containing solution is drawn into the generator system. Furthermore, it is known that low 99mTc yields can occur in generator eluates that are clear and colorless because such losses are chemical in origin and may be related to the oxidation state of the 99Mo/99mTc on the generator column.
The toxicity of the dye in the pigment disk is unknown; therefore, any solution containing this dye should not be administered to humans.
In conclusion, we believe the addition of the dye-impregnated disk in Mallinckrodt’s Ultra-TechneKow DTE generator is an important safety feature for this product, which helps ensure that patients receive a drug product that is safe.