TGA laboratory information bulletin
Volume 6, Number 1 (September 1994)
Contents
- A microbiological investigation of Turbuhaler(R) products
- Sunscreens under the legislative umbrella
- Determination of Sulindac in pharmaceutical dosage form by HPLC
- HPLC and TLC examination of Aconite herbal material
- Comparison of selected reversed-phase HPLC columns for application in pharmaceutical analysis
- Microbiological quality of herbals teas
- Investigations of the hydrolysis of erythromycin succinate
- Other publications by staff of the Laboratories
A microbiological investigation of Turbuhaler(R) products
Turbuhaler( (Astra Pharmaceuticals Pty Ltd Australia) products are breath-activated metered-dose powder inhalers free from propellants, preservatives, lubricants, carrier substances or other additives. Actives can either be Terbutaline Sulfate (marketed in Australia as Bricanyl) or Budesonide (Pulmicort). Testing was carried out following a complaint received by the TGA concerning visual mould contamination of a Pulmicort unit after a period of use. To obtain used or partially used units for testing a questionnaire was prepared and taken to retail pharmacies and the Thoracic Clinic at Woden Valley Hospital, ACT. The questionnaire was to be given to patients with a Turbuhaler( and returned with the used device at the end of use. The report contains comments from Dr. Greg Pearce, Astra's Scientific Affairs Manager.
Conclusion:
The results suggest that the growth of mould and bacteria on the mouthpiece of Turbuhaler® devices during normal use may be frequent but highly variable. The contamination appears to be caused by micro-organisms endogenous to the patient and the potential risk of infection is low. Revised cleaning instructions and possible modifications to the device may minimise the extent of contamination. Company response included comments to the effect that the sample tested was small (15) and very selective compared with the numbers sold in Australia since its launch (3.6 million). The addition of a desiccant to the Pulmicort Turbuhaler® had reduced incidences of complaint received by Astra and that units which did exhibit high levels of mouthpiece contamination had either been subject to incorrect use or cleaning (such as washing) or did not contain a desiccant.
Sunscreens under the legislative umbrella
Since the arrival of the Therapeutic Goods Act 1989, all sunscreen products of SPF4 and above have been designated as therapeutic goods. In 1989 the major industry associations agreed with the proposition that licensing of sunscreen manufacturers would commence about two years after the start of the legislation, with compliance with good manufacturing practices (GMP) a condition of the licence. A specific code of GMP was developed as a cooperative industry/TGA effort. Following adoption of the 1989 Act, the Microbiology and Pharmaceutical Chemistry Sections instituted programs of testing to examine the standard of sunscreen products available on the Australian market. It was intended that representative products from a variety of Australian manufacturers and suppliers be tested to ensure their compliance with the TGA recommendations on microbial contents of non-sterile pharmaceutical products and to assess the chemical composition of the products before and after storage at 40(C for 12 months.
Conclusion:
The results suggest that the introduction of the Therapeutic Goods Act 1989 has resulted in the improvement of product quality and that the standard of sunscreens is now generally acceptable. Guidelines for Stability Testing of sunscreens have been published. It now a requirement of listing on the ARTG that sunscreens carry an expiry date and that the expiry date be supported by stability testing data.
Determination of Sulindac in pharmaceutical dosage form by HPLC
A reliable, specific and simple high performance liquid chromatographic (HPLC) method for the analysis of sulindac in pharmaceutical dosage forms has been developed. The method uses a C8 reversed-phase column with a binary solvent system consisting of acetonitrile and 0.05M potassium dihydrogen phosphate (60:40) as the mobile phase.
HPLC and TLC examination of Aconite herbal material
Aconites, the dried root stocks of the various species of plants which form the genus Aconitum, are characterised by the presence of one or more C19-diterpinoid-ester alkaloids including aconitine, mesaconitine and hypaconitine. It is the presence of these alkaloids that provide the plants with the properties that are exploited in many traditional herbal medicines. In carefully prepared doses, aconite is traditionally used as a treatment for joint or abdominal pain and as an anaesthetic. However, due to the extreme toxicity of the alkaloids and the often unknown quality of the raw material, accidental poisoning can easily occur. Following a suspected case of aconite poisoning TGA examined samples of herbal material. High pressure liquid chromatographic and thin layer chromatographic methods were employed in the identification process.
Comparison of selected reversed-phase HPLC columns for application in pharmaceutical analysis
The chromatographic behaviour of certain octyl (C8) and octadecyl (C18) reversed-phase columns marketed in Australia is compared with uBondapak( C18 (Waters) column. Chromatographic conditions employed were chosen from in-house HPLC methods with column performance measured in terms of efficiency (N), capacity factor (k') and symmetry factor (f). Theoretical calculations use the procedures detailed in Appendix D, 'Guidelines for Laboratory Instrumentation' of the Australian Code of Good Manufacturing Practice for Therapeutic goods and Medicinal products.
Microbiological quality of herbals teas
In 1990 TGA Laboratories (TGAL) published guidelines that recommend microbial limits for non-sterile pharmaceuticals. The guidelines are used by TGAL in assessing the significance of contamination detected in pharmaceutical and herbals products. The guidelines recognise that different limits are appropriate for different product categories. They also recognise that products that contain materials of plant and animal origin may naturally harbour larger numbers of micro-organisms than products with substances derived through chemical synthesis.
TGAL has published results of microbiological tests on a variety of herbal products. The results suggest that the TGAL Guidelines may need to be reviewed in relation to dried herbals products, such as teas. A further study was carried out to provide more information on the microbial qualities of herbal teas on the Australian market and to investigate the need for a special category within the TGAL Guidelines.
Investigations of the hydrolysis of erythromycin succinate
Erythromycin ethylsuccinate (EES) is used in the formulation of extemporaneous oral dosage products such as tablets and as granules in the preparation of oral mixtures. EES is biologically inactive, being hydrolysed in vivo to the therapeutically active parent compound erythromycin. The purpose of the project was to confirm whether or not the two hour preliminary in vitro hydrolysis step at room temperature nominated by the British Pharmacopoeia 1993 for the microbiological assay of EES is adequate to convert EES to the active erythromycin. Incomplete hydrolysis of EES causes underestimation of the erythromycin potency of products containing EES.
Other publications by staff of the TGA Laboratories
Journal of Parenteral Science and Technology, Vol. 47, No. 5, September 1993
The Incubation period in Sterility Testing
Sterility test results gathered over a ten year period have been analysed to determine the effects of the incubation period. Overall there was no difference between the membrane filtration test and direct inoculation in the time required for visible growth of contaminants. Growth occurred earlier if products contained no preservatives or antimicrobial substances. However, use of the membrane filtration method did not significantly enhance the efficiency of detection at seven days incubation. Regardless of the nature of the product or the method of test an unacceptable proportion of contaminants would be missed by limiting incubation to seven days.