Propofol: Provive and Sandoz propofol 1% emulsion for injection - all sizes and all batches, update 3

Related information

Safety advisory - potential bacterial contamination

7 July 2014

This update includes further details about the TGA's ongoing investigations into potential contamination of some vials of propofol 1% emulsion for injection with Ralstonia species.

Current status

Health professionals, hospitals and health facilities are advised that all sizes and batches of the AFT-distributed Provive and Sandoz Propofol 1% products are no longer under a precautionary supply restriction.

Based on the balance of the information now available, the TGA is confident that supply restrictions are not necessary for Provive 1%, Provive MCT-LCT 1% or Propofol Sandoz propofol 1% emulsion for injection products as listed below. This includes batches A030906 (expiry date 08/15) and A030907 (expiry date 08/15) of Provive MCT-LCT 1% emulsion for injection which were the batches quarantined following the initial notification of a potential problem.

ARTG ARTG Label
118940 Claris Lifesciences Australia Pty Ltd PROVIVE 1% propofol 1000mg/100mL emulsion for injection vial
118938 Claris Lifesciences Australia Pty Ltd PROVIVE 1% propofol 200mg/20mL emulsion for injection vial
162319 PROVIVE MCT-LCT 1% propofol 500mg/50mL emulsion for injection vial
118939 Claris Lifesciences Australia Pty Ltd PROVIVE 1% propofol 500mg/50mL emulsion for injection vial
162320 PROVIVE MCT-LCT 1% propofol 1000mg/100mL emulsion for injection vial
162318 PROVIVE MCT-LCT 1% propofol 200mg/20mL emulsion for injection vial
148870 PROPOFOL SANDOZ propofol 200mg/20mL emulsion for injection vial
148872 PROPOFOL SANDOZ propofol 1000mg/100mL emulsion for injection vial
148871 PROPOFOL SANDOZ propofol 500mg/50mL emulsion for injection vial

The TGA is continuing to work with clinical and microbiological experts to assess the available evidence related to eight reported cases of bacteraemia, including possible links between the cases and potential causes.

Information for consumers

While the investigations into the possible causes of eight reported cases of bacteraemia are continuing, based on current information, TGA is satisfied that the contents of propofol 1% emulsion for injection vials from batches previously identified in relation to this issue are not contaminated.

If you have any questions or concerns about this issue, talk to your health professional.

Testing results update

The TGA and three external laboratories have tested samples from 25 batches of propofol 1% emulsion for injection supplied to Australia and New Zealand for sterility and bacterial endotoxins. Samples from more than 1680 vials from these batches were tested for compliance with sterility requirements and a further 97 vials were tested for the presence of bacterial endotoxins. All samples passed the criteria for the tests for sterility and bacterial endotoxins.

The external surfaces of injection vials, including the outer surface of the rubber stopper and the inner surface of the vial lid, are not required to be sterile and so might not be free from microbial contamination. Nevertheless, one laboratory undertook testing of the outer surface of rubber stoppers and the inner surface of vial lids and reported a positive test result for Ralstonia mannitolilytica from a single test pool of five lids and rubber stoppers. As indicated in the Table, the laboratory has placed several caveats on this test result.

To further investigate this finding the TGA and an external laboratory also tested the outer surface of rubber stoppers and the inner surface of vial lids for microbial contamination. In total, stoppers and lids from 524 vials across 15 batches of propofol 1% emulsion for injection have been tested. While this additional testing has revealed microbial contamination on a low number of lids and rubber stoppers, this contamination did not include Ralstonia mannitolilytica.

Table: Propofol 1 % emulsion for injection - results of microbiological testing

Batch number Laboratory1 Test for Sterility2 (vials tested) Test for Bacterial Endotoxins3
(vials tested)
Microbial Contamination Test4 - vial contents
(vials tested)
Microbial Contamination Test - flip-off lid and rubber stopper external surfaces5
No. positive for bacterial growth/no. tested Bacteria isolated
A030906 A Pass (20) Pass (1) Pass (3) 12/80 Bacillus species, Gram-positive cocci
B Pass (80) Pass (4) - - -
C - - Pass (12) 10/14 pools 6, 7
(total 70 tested)
Bacillus species x 10
Coagulase-negative staphylococci x 3
A030907 A Pass (20) Pass (1) Pass (3) 7/80 Bacillus species, Gram-positive cocci
B Pass (80) Pass (4) - - -
C - - Pass (10) 15/18 pools6, 7
(total 90 tested)
Bacillus species x 10
Coagulase-negative staphylococci x 5
Ralstonia mannitolilytica (1 pool)7
A031266 A - Pass (1) - - -
B Pass (61) Pass (4) - - -
D Pass (20) Pass (1) Pass (20) 0/20 -
A031267 A - Pass (1) - - -
B Pass (61) Pass (4) - - -
D Pass (20) Pass (1) Pass (20) 0/20 -
A040081 A - Pass (1) - - -
B Pass (61) Pass (4) - - -
D Pass (20) Pass (1) Pass (20) 0/20 -
A031282 B Pass (60) Pass (3) - - -
E Pass (20) Pass (2) - - -
A031283 B Pass (60) Pass (3) - - -
E Pass (20) Pass (2) - - -
A030021 A - Pass (1) - - -
B Pass (60) Pass (3) - - -
A030146 A - Pass (1) - - -
B Pass (60) Pass (3) - - -
A030293 A - Pass (1) Pass (3) - -
B Pass (60) Pass (3) - - -
A0308728 B Pass (60) Pass (4) - - -
A0308398 B Pass (40) Pass (4) - - -
A0308408 B Pass (40) Pass (4) - - -
A0309328 B Pass (60) Pass (4) - - -
A0309368 B Pass (60) Pass (4) - - -
A0309378 B Pass (60) Pass (4) - - -
A031027 B Pass (60) Pass (4) - - -
A031069 B Pass (60) Pass (4) - - -
A030504 B Pass (60) Pass (3) - - -
A031202 B Pass (60) Pass (3) - - -
A030288 B Pass (60) Pass (3) - - -
A031203 A - - - 0/5 -
B Pass (60) Pass (3) - - -
A031210 A - - - 1/5 Gram-positive cocci
B Pass (60) Pass (3) - - -
A030085 A - - - 2/20 Bacillus species, Gram-positive cocci
B Pass (60) Pass (3) - - -
A031195 A - - - 1/20 Bacillus species, Gram-positive cocci
B Pass (60) Pass (3) - - -
A031196 A - - - 2/20 Bacillus species, Gram-positive cocci
B Pass (60) Pass (3) - - -
A031256 A - - - 5/18 Bacillus species, Gram-positive cocci
B Pass (60) Pass (3) - - -
A031110 A - - - 4/20 Bacillus species, Gram-positive cocci
B Pass (60) Pass (3) - - -
A020647 A - - - 0/2 -
B Pass (60) Pass (3) - - -
A020648 A - - - 1/19 Bacillus species
B Pass (60) Pass (3) - - -
A030071 A - - - 1/15 Gram-positive cocci
B Pass (60) Pass (3) - - -

Notes

  1. Laboratories
    1. TGA
    2. Manufacturer
    3. External laboratory7
    4. External laboratory
    5. External laboratory
  2. The Test for Sterility is a standard pharmacopoeial batch release test for an injectable medicine. A 'Pass' result means that no microbial contamination was detected in the portion of the samples that were tested. Each test uses 20 vials.
  3. The Test for Bacterial Endotoxins is a standard pharmacopoeial batch release test for an injectable medicine. A 'Pass' result means that bacterial endotoxins were not detected in the portion of the samples that were tested.
  4. The Microbial Contamination Test is not applicable to a sterile medicine. It was performed only as an adjunct test to estimate the level of microbial contamination should vial contents be contaminated. A 'Pass' result means that no microbial contamination was detected in the portion of the samples that were tested.
  5. Flip-off lid and rubber stopper external surface swab tests were performed to assess bacterial contamination on these surfaces.
  6. Testing was performed on pooled samples. Each pool contained the flip-off lids and swabs from the external surface of rubber stoppers from 5 vials.
  7. Laboratory C has placed the following caveats on their test results:
    • The laboratory holds accreditation for testing of human diagnostic samples and for testing of clinical, non-human specimens for investigation of nosocomial infections in outbreaks and/or individuals, e.g. gastrointestinal endoscopes, vascular catheter tips and transfusion bags. The laboratory has limited accreditation for environmental testing
    • Testing of the flip-off lids and external surface of the rubber stoppers included testing of the entire flip-off lid after disinfection of the outer surface of the lid with 70% alcohol. Aseptic techniques were used; however, removal of vial lids was difficult and adventitious contamination might have been introduced during the sampling and testing processes, e.g. the detection of coagulase-negative staphylococci in some pools. Isolation of Bacillus species from some pools might reflect lack of sporicidal activity of 70% alcohol used for disinfection of external surfaces of vial lids.
    • Test methods were adapted in-house. Test methods have not been fully validated and results should be interpreted accordingly.
    • Ralstonia mannitolilytica was isolated from 1 of 32 pools. Ralstonia species are rarely recognised as contaminants in this laboratory.
  8. These batches were not supplied to Australia or New Zealand
  9. Where a laboratory did not perform a test as part of the investigation the cell has a hyphen and is shaded.

Additional considerations

The TGA has conducted a detailed review of Claris Lifesciences Ltd's processes for manufacturing propofol 1% emulsion for injection products and has not found any deviations from approved processes.

It is estimated that approximately 7800 vials of propofol 1% emulsion for injection manufactured by Claris Lifesciences Ltd are used across Australia and New Zealand each day. Given the large number of patients receiving the product, there have been very few cases of Ralstonia bacteraemia reported to the TGA.

The exterior surfaces of injection vials are not intended to be sterile. Most protective lids do not guarantee sterility of the outer surface of a vial rubber stopper/aluminium crimp seal. This lid is intended to act as a shield for the rubber stopper and to keep dust and other physical contaminants away from it.

Noting this, health professionals are reminded that proper aseptic technique must be strictly followed when administering intravenous injections to a patient. This includes wiping the outer surface of the rubber stopper and its injection site with a suitable disinfectant wipe/swab and allowing it to dry before inserting any device into the vial. Further information about the importance of aseptic handling of propofol injections to minimise opportunities for infections in patients is contained in the Product Information supplied by the product sponsors Claris and Sandoz:

Reporting problems

Consumers and health professionals are encouraged to report problems with medicines or vaccines. Your report will contribute to the TGA's monitoring of these products.

The TGA cannot give advice about an individual's medical condition. You are strongly encouraged to talk with a health professional if you are concerned about a possible adverse event associated with a medicine or vaccine.