Counterfeit drugs

Previous editions of TGA News have described some of the issues involving the Surveillance Unit's role in combatting counterfeit drugs (also see the article on page 11). Another aspect of TGA's involvement with counterfeit drugs is in the analysis and detection of counterfeits, a task undertaken primarily by the Chemistry Section.

One of the more subtle forms of counterfeiting involves manufacture of an active ingredient by a company not legally permitted to do so, especially when the material is later represented to originate from the legal source. In this case, the material may well comply with the expected quality standards but it may also contain substances which are not specifically covered by the standard, bearing in mind that compendial standards often relate to a specific manufacturing process. The detection of such counterfeiting is a challenge from an analytical perspective and this was discussed among representatives of international regulatory agencies in October last year. Larry Kelly of the Chemistry Section represented the TGA.

The meeting was hosted by the USFDA's National Centre for Forensic Chemistry in Cincinnati. Officers from the FDA, the Canadian Health Authority, the UK Medicines Control Agency and the German regulatory agency attended the meeting to discuss areas of mutual interest and concern. The focus was on analytical techniques which can be used to detect the more subtle forms of counterfeiting. Such techniques include chromatographic and elemental fingerprinting. Each agency presented examples of their work in this area and plans for future collaboration were discussed.

For its part, the Chemistry Section is committed to working on the problem of detecting counterfeit raw material actives and finished products and is working with other sections of the TGA also involved with this area, Surveillance and GMPALS. Also, arrangements are being made to place a senior officer from the Chemistry section with the USFDA laboratory for an extended visit to enhance TGA's technical capabilities.

Interlaboratory trials of candidate reference material for the cytotoxicity testing of device materials

Cytotoxicity testing is a basic screening test for all polymer materials which contact body tissues. The Biomaterials and Engineering Section, TGA Laboratories, has recently participated in an international trial of candidate standard reference materials for cytotoxicity testing, organised by the International Standards Organisation Technical Committee ISO/TC 194, which is preparing a family of standards entitled "Biological Evaluation of Medical Devices". These standards include ISO 10993-5 1992; Part 5: Tests for Cytotoxicity: in vitro methods. There is currently a wide range of tissue culture methods and control materials in use, which make it difficult to compare results between different laboratories. In order to control for this variability there is a need for known standard reference materials which provide benchmarks for testing by different laboratories.

The candidate reference polymers used in these tests were developed by Japanese scientists and include a polyethylene (negative control material); and two polyurethanes (positive control materials) formulated with either 0.1% zinc diethyldithiocarbamate or with 0.25% zinc dibutyldithiocarbamate.

The test protocol required the exposure of L929 cells (a laboratory strain of mouse cells) to serial dilutions of extracts of the test materials and also to direct contact with the materials. Cell counts were performed after 24 and 72 hours contact and compared with blank controls. The mean cell number and the relative cell survival were calculated; and, for the extract dilutions, also the 50% inhibition concentration (IC₅₀). The results of all the participating laboratories will be assessed by the ISO coordinators of the trial.

Another international trial of candidate reference materials for cytotoxicity testing is being organised by the United Kingdom Laboratory of the Government Chemist. The materials to be tested include a negative control material (polyethylene); a positive control material (polyvinyl chloride with organotin stabiliser) and 4 test materials - additive free high density polyethylene; polyvinyl chloride with dioctylphthalate plasticiser; polyvinyl chloride with triocty trimellitate plasticiser and additive free polyurethane. This trial is about to begin, and the TGAL will be a participant.

TGAL's participation in these international cytotoxicity trials as one of a number of competent testing laboratories enables us to actively contribute to the development of these important international standards.

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New appointment

Dr Garry Hopkins has been appointed a Principal Scientific Advisor in the TGA Laboratories Executive Unit. In 1976 Garry received his PhD from the John Curtin School of Medical Research, ANU and built a successful career in medical research in Canada, Flinders Medical Centre (Adelaide) and the Baker Medical Research Institute (Melbourne). Since 1988 he has held senior management positions in the pharmaceutical industry with responsibilities for clinical and regulatory operations. In his new position, Garry will co-ordinate liaison between TGAL and the pharmaceutical industry, national and international organisations, oversee associated collaborative projects and provide scientific advice on Branch operations.

International collaborative studies - Molecular Biology Section, TGAL

TGAL regularly participates in international collaborative studies coordinated either by the UK National Institute for Biological Standards and Controls (NIBSC) on behalf of the WHO, or by the European Pharmacopoeia Commission. This represents part of TGAL's contribution to international harmonisation and is a valuable opportunity to benchmark the quality of our laboratory work against the best in the world. The Molecular Biology Section recently participated in the following studies.

• A WHO-coordinated collaborative study to calibrate candidate International Reference Preparations of Interferon α. The study utilised in vitro antiproliferative and antiviral assays and evaluated various other methods of measuring Interferon α activities. The Section is also preparing to contribute to the establishment of a new Interferon β international reference preparation.
• A WHO collaborative study to assess the suitability of a proposed international standard for Human Parathyroid Hormone. This standard which is intended for use in physicochemical assays, immunoassays and bioassays was defined in terms of mass and biological activity using immunoassays (ELISA) and reverse phase HPLC.
• An international collaborative study of recombinant Erythropoietin which is being co-ordinated by the European Pharmacopoeia Commission. This study should lead to the replacement of isoelectric focusing with capillary electrophoresis as a technique to resolve erythropoietin isoforms. This type of analysis provides more consistent resolution of isoforms and will be used for monitoring batch-to-batch variations.

Microbial limits for non-sterile pharmaceuticals

The need to retain Australian regulatory requirements for non-sterile pharmaceutical products has been under discussion since publication of guideline limits in the 1996 Addendum to the British Pharmacopoeia (BP). The Therapeutic Goods Administration contends that, in some respects, the BP limits, formulated by the European Pharmacopoeial Commission, do not provide for adequate patient safety. The case for retention of TGA guidelines is based on laboratory investigation into the microbial quality of product groups on the Australian market and an assessment of the risk to patients of microbial contamination in pharmaceutical products which are not manufactured as sterile.

The April and November 1997 meetings of the Therapeutic Goods Committee (TGC) considered submissions from the Microbiology Section of TGA Laboratories and comment from industry on revised TGAL Guidelines for Assessing the Results of Microbiological Tests on Non-sterile Pharmaceuticals for Human Use. The TGC also considered the current international situation, and the pharmacopoeial proposals for international harmonisation of microbial limits.

As a result, the TGC has recommended retention, for the present, of the current TGAL Guidelines, ratified by TGC in 1994 and updated in 1995 to include a new category for herbal teas. The situation will be further reviewed within two years, pending the outcome of the harmonisation process.

The Microbiology Section is continuing input into the harmonisation process, via comment to the USP and the EP. The Section's Principal Microbiologist, Shelley Tang, attended as an observer the meeting of the EP Group of Experts 1CM, which formulated the EP/BP guidelines. The meeting was held in Strasbourg, France, on March 3, 1998. Ms Tang's paper entitled Microbial Limits Reviewed - the Basis for Unique Australian Regulatory Requirements for Microbial Quality of Non-sterile Pharmaceuticals will be published in the PDA Journal of Pharmaceutical Science and Technology expected in the next few months.

A new era in sterility testing: the end of unique Australian requirements

The Microbiology Section has been active in the international harmonisation process for the pharmacopoeial sterility test over the past few years. Publication of the paper "The Incubation Period in Sterility Testing" (1993) resulted in recognition of the TGA's views on the 14 day sterility test. Since then, Chief Microbiologist, Vivienne Christ, has participated at the Interpharmacopoeial Open Conference under the International Committee for Harmonisation (ICH) and as convenor of the Pharmaceutical Inspection Convention/Co-Operation Scheme (PIC/S) working group preparing the guidelines "Recommendations on Sterility Testing".

As a result, the TGA supports the harmonised sterility test as described in the EP Third Edition Supplement 1998 which became effective in Europe on January 1, 1998.

At their November 1997 meeting, the Therapeutic Goods Committee accepted the proposal that the TGA adopt the BP/EP harmonised Test for Sterility in lieu of Therapeutic Goods Order Number 11, with a revised Appendix C to be retained as a guideline document. The revised Appendix C, renamed TGA Guidelines on Sterility Testing of Therapeutic Goods to indicate its new role as a stand-alone guidance document, is intended to assist companies by providing the practical details that the BP/EP Test for Sterility lacks. It contains additional points to align it with the draft PIC/S document "Recommendations on Sterility Testing" (which has now been accepted by the working group and regulatory member bodies of PIC/S). Devices are not mentioned in the EP test and the TGA Guidelines on Sterility Testing of Therapeutic Goods includes sampling schedules for devices, based on those proposed for the harmonised test in the US Pharmacopoeia; however, the basic test methodology is that of the EP, in line with EU directives.

The TGC recommended that the draft guideline document be circulated with the new EP test to peak industry organisations for comment, and if there was general agreement, that the new EP test could be adopted. Comments have been received from the major industry organisations and some individual companies and, to date, there has been no objection in principle to adoption of the EP sterility test.

We must emphasise that there are no unique Australian mandatory requirements. Compliance with the BP/EP Test for Sterility will be the minimum standard expected of manufacturers when this test is adopted.

Companies should note that the interpretation of test results is the only substantial change and is in fact more stringent than that previously required by the TGA. A repeat sterility test will be permitted only if the first test is invalidated for strictly limited reasons; if the identity of microbial isolates is used to justify invalidation, then molecular typing techniques such as RNA/DNA homology would be required to demonstrate that isolates were identical.

The proposed date for adoption, 1 February 1998, has not been practicable but early adoption, ie, before mid 1998, is still intended. A phase-in period of 6 months is proposed for companies to modify procedures to comply.

1. HG Bathgate, D Lazzari, HA Cameron and D McKay "The Incubation Period in Sterility Testing", J Parenteral Science and Technology Vol 47 No 5: 254-257.

World Health Organization Workshop on Drug Supply Management and Drug Quality Assurance for Pacific Island Countries

Dr Elaine Walker, Head of TGA's designated WHO Collaborating Centre on Drug Quality Assurance, was invited to attend a recent Workshop on "Drug Supply Management and Drug Quality Assurance for Pacific Island Countries". She spoke on quality assurance, describing simple procedures to detect substandard or counterfeit drugs at the workshop, organised by the WHO Regional Office for the Western Pacific and held in Fiji last November. Twenty-one Pacific Island nations were represented. The objectives of the Workshop were to discuss various models of drug procurement, tender requirements and procedures and quality assurance of drug supply systems relevant to the Pacific Island Countries. Delegates also discussed use of the "WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce" and possibilities for exchange of technical information on pharmaceutical matters.

An important outcome of the meeting was the establishment of a network for the exchange of information on drug supply and quality. An initial survey of drug usage has been performed to identify high use products where testing by TGAL could make a significant contribution to the quality of drugs used in Pacific Island countries. TGAL's contribution to the workshop and the initial product testing was made possible by funding from WHO and a grant from the Australian Agency for International Development, AusAID.

World Health Organization Global Network for Training in Vaccine Quality Control

Last February Dr Walker represented the TGA at the third annual meeting of the WHO's Global Network for Training in Vaccine Quality Control (GTN). The Network co-ordinates training provided to National Control Agencies (NCAs) which regulate vaccine manufacture and/or procurement in order to build the six critical control functions of NCAs. These critical functions are defined by the WHO as: written criteria for licencing of vaccines, use of clinical data in licencing decisions, lot-by-lot release of vaccines, laboratory facilities for final product tests, regular inspections for compliance with GMP, and postmarketing surveillance for vaccine-related adverse events and efficacy.

The TGA is one of ten accredited training centres around the world which contribute to the GTN. Over the past year, staff from TGAL and the GMP Audit and Licensing Section of the Conformity Assessment Branch have provided numerous consultancies and workshops in vaccine supply, regulatory functions, quality assurance and Good Manufacturing Practice to NCAs and manufacturers in Vietnam, Thailand, Philippines and China. Training courses have also been conducted at TGA for WHO Fellows from designated countries from the Western Pacific region. A further five workshops and courses are planned for 1998. TGA's contribution to the GTN and the development of training curricula is made possible by funding from WHO and grants from AusAID.