Counterfeit drugs - meeting of international regulatory authorities in Ottawa, Canada 10-12 May 1999

Larry Kelly of the Chemistry Section, TGA Laboratories attended an inter-agency meeting on anti-counterfeiting held in Ottawa in May. Representatives from the regulatory agencies in the USA, UK, Germany, Canada, Netherlands, Italy, Belgium and Brazil were present. The meeting split into two groups - one dealing with enforcement issues and the other covering laboratory detection methods. The laboratory group discussed developments in analytical methodology and techniques related to the detection of counterfeit and sub-standard pharmaceuticals. Examples from the respective jurisdictions including TGA, were described and information not normally available by other methods was shared. Methods for identifying the manufacturing source of the active ingredient were described. The forum provides a very good example of practical collaboration between agencies.

International Standards Organisation (ISO): biological evaluation of medical devices

Shirley Bolis of the Biomaterials & Engineering Section attended the annual meeting of ISO Technical Committee 194 (TC 194) in Helsingør, Denmark in May 1999. The TC 194 Biological Evaluation of Medical Devices is concerned with the standardisation of approaches to the evaluation of biological safety of medical devices and materials and applicable test methodology. TC 194 is responsible for ISO Standards 10993 Biological Evaluation for Medical Devices and 14155 Clinical Investigations of Medical Devices.

Thirteen of the total of fifteen Working Groups in TC 194 met in Denmark to workshop technical and editorial issues. The Working Groups addressed various safety issues relating to the use of medical devices, including cytotoxicity, carcinogenicity, local implantation effects, reproductive toxicity, irritation and sensitization and degradation of materials in biological fluids.

The Task Force on Immunotoxic effects of medical devices established in 1998 to address the necessity for inclusion of immunotoxic testing in evaluation of medical device safety has produced a draft Guidance document including strategies for testing and relevant methodology. The document was considered at the meeting and recommended for inclusion in ISO 10993.

There are ongoing problems with lack of consistency between the various Parts of ISO 10993 and this has been a major focus of TC 194 activities in the last year. Proposed mechanisms to overcome this were reported to the TC meeting and will be investigated in the coming twelve months by all participants.

TC 194 has released a questionnaire on the use of ISO 10993 and problems associated with its interpretation. This has been sent to manufacturers, notified bodies, regulatory agencies and other interested parties and is also available on the Internet (http://www.nni.nl via "Online producten" and "Option ISO/TC 194 WG15 questionnaire"). All users are encouraged to comment on their experiences with ISO 10993 by the closing date of 30 November 1999.

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Professor Seitz visits TGA

In March 1999, TGA hosted a visit by Professor Rainer Seitz, the head of the Transfusion Medicine Division of the Paul Ehlrich Institute, Germany. Professor Seitz is also a member of the European Pharmacopoeia Commission and the Biotechnology Working Party of the Committee for Proprietary Medicinal Products (CPMP). He gave talks on the European Regulatory system for blood products and current safety issues associated with these products.

Professor Rainer Seitz, Dr Albert Farrugia and Dr Leonie Hunt

Reverse osmosis as a basis for production of water for injection

In March 1999, TGA's Shelley Tang attended a Scientific Workshop in Strasbourg, organised by the European Department for the Quality of Medicines, to consider whether the European Pharmacopoeia should include Reverse Osmosis (RO) as an allowable method for the production of Water for Injection. The Workshop provided an excellent opportunity for debate with background papers presented by speakers from the European Pharmacopoeia, the Joint CPMP/CVMP* Quality Working Party, United States Pharmacopoeia and FDA, and the views presented from producers and users of RO water, as well as those of regulators and inspectors.

The Workshop recommended that RO water not be included as an acceptable method for production of Water for Injection at the present time, pending collection of more data. The Workshop's Chairman, Professor D Calam, expressed disappointment at the lack of data from producers and users of RO systems. The same lack of data led the workshop to conclude that there was insufficient evidence to demonstrate that RO systems could consistently produce water of a quality at least equal to that of distilled water.

However, the European Pharmacopoeia (EP) will keep the matter open, and encourages the submission of data on the quality of RO water as compared to that of distilled water. Data published in a refereed scientific journal is preferred; information on test results should include the details of the methods used for testing.

During the Workshop it also became evident that there was general confusion on the use of water in accordance with the two monographs in the EP. This confusion needs to be addressed, and a third monograph was proposed for grades of water not already covered in the EP. There was also general agreement that the microbiological test method for water in the EP needs revision, and this recommendation was passed to the Group of Experts responsible for microbiological matters.

*CPMP is the Committee for Proprietary Medicinal Products. CVMP is the Committee for Veterinary Medicinal Products.

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Sterility testing - a matter of interpretation

In December 1998 Therapeutic Goods Order Number 11 Standard for Sterile Therapeutic Goods was revoked and the British Pharmacopoeia 1998 (BP 98) was adopted. Since then manufacturers have been required to comply with the sterility test of the BP 98 or the identical test in the 1998 Supplement to the Third Edition of the European Pharmacopoeia (EP 98). The TGA Guidelines on sterility testing of therapeutic goods were also published in December 1998 to provide guidance to industry and laboratories on sterility testing in accordance with the BP/EP 98.

In recent discussions between TGA and representatives from industry and the Australian Pharmaceutical Manufacturers Association (APMA) it was acknowledged that confusion exists regarding the sterility test interpretation. TGA agreed that further clarification by way of this article might result in fewer questions if sponsors were to provide the following information with their initial applications for registration.

• A statement that the method used for the sterility test is the harmonised test as published in the 1998 supplement to the Third Edition of the EP or in the BP 1998.
• An explicit statement of the in-house interpretation of the four conditions (a) to (d) listed in the EP/BP 98 one or more of which must be met to allow invalidation and hence a repeat test.
• A statement of the circumstances in which condition (d) may be used as the sole criterion to invalidate the initial sterility test result, including a description of the test methods used to confirm that isolates are identical.

Under condition (d), the initial sterility test may be declared invalid and the test repeated, if the organisms found in the product test containers and in the environment or on the operator are identical. The probability of this circumstance occurring is low. However, in a situation where this condition is to be used as the sole criterion for invalidating a particular sterility test, it is necessary to employ sensitive typing techniques to demonstrate that a microorganism isolated from the product is identical to a microorganism isolated from the materials and/or the environment. While routine biochemical/phenotypical identification techniques can demonstrate that two isolates are not identical, these methods are not sufficiently sensitive or reliable enough to provide unequivocal evidence that two isolates are from the same source. Suitably sensitive tests are those accepted by microbiologists conducting epidemiological studies to determine that organisms isolated in an outbreak of disease are clonally related and have a common origin.

Examples of sensitive typing techniques include:

• Pulsed-Field Gel Electrophoresis of whole chromosomal DNA (PFGE);
• Repetitive element PCR (Rep-PCR), a genomic fingerprinting technique using strain specific patterns from PCR amplification of repetitive DNA elements;
• Amplified fragment length polymorphism (AFLP), a genomic fingerprinting technique based on selective amplification of DNA fragments;
• Ribotyping, ribosomal RNA gene fingerprinting, based on highly conserved rRNA sequences present as multiple copies in bacterial genomes.

Other techniques or approaches that are not mentioned above may be acceptable, and details should be submitted with the registration application. In most cases, sponsors will need to ensure that a particular technique is suitable for their purposes. A useful approach would be to collect profiles of organisms recovered from products and the manufacturing and testing environments, which could include Gram positive cocci, Gram negative bacteria, and species of Bacillus. During this process, the laboratory can confirm that the technique provides the detail needed to determine if two isolates are identical.

An informative Minireview has been recently published: Principles and Applications of Methods for DNA-Based Typing of Microbial Organisms, J. Clin. Microbiol., 37, June 1999, pp 1661-1669.

As stated in the December 1998 TGA News, the TGA has determined that it is not necessary at this stage for specialist laboratories contracted to perform such identifications to be GMP licensed. However, manufacturers must ensure that external laboratories are adequately equipped to undertake the work contracted to them.

TGA to regulate fresh blood products

At its meeting on 21 April 1999 the Australian Health Ministers' Advisory Committee (AHMAC) recommended that TGA regulate fresh blood components manufactured in Australian Blood agencies. It is anticipated that the relevant changes to the Therapeutic Goods regulations will be introduced over the next twelve months. TGA currently regulates pooled plasma products manufactured into blood products through licensing of certain Australian Red Cross Blood Service blood collection centres. The rest are the responsibility of the State Health Authorities. It is intended that the current responsibility of the State Health Authorities for fresh blood components will be transferred to TGA. A working group has been set up involving TGA, Health Services Division (HSD) and the Australian Red Cross Service to formulate a strategy for the implementation of this policy. The Blood and Blood Products Committee of AHMAC will oversee the process.

WHO vaccine regulators' course

Course participants

The TGA Laboratories and the International Services Branch recently organised a training course on vaccine regulation for staff from other National Control Authorities (NCAs). The trainees were selected by the World Health Organization (WHO) as representatives of NCAs that require assistance in strengthening the regulation of vaccines. The curriculum was developed by staff from the TGA Laboratories, the Drug Safety and Evaluation Branch and the GMP Audit and Licensing Section of the Conformity Assessment Branch and has been accredited by the WHO Global Training Network (GTN). The GTN coordinates training that is designed to achieve worldwide vaccine quality and supply and is comprised of representatives of the six WHO regional offices, twelve training institutes and two regulatory authorities, including the TGA.

The training course was held from May 5-12, 1999 at the TGA. WHO-sponsored Fellows from NCAs in China, Thailand, Philippines, Singapore and Brazil attended six days of lectures and interactive workshops. The course was structured around the six critical control functions identified by the WHO as being essential for any NCA engaged in regulation to ensure the safety, quality and efficacy of vaccines produced in, or procured for use in, the country of responsibility. Training modules were presented on Essential Functions of a Vaccine NCA, Licencing of Vaccines, Laboratory Facilities for Final Product Testing, Batch Release of Vaccines, Compliance with Good Manufacturing Practice and Post-marketing Surveillance of Vaccines. The course concluded with an Implementation Workshop in which trainees discussed the organisation and functions of the NCAs in their home countries and formulated plans to implement changes when they returned home. These changes were identified during the course, on a country-by-country basis, as having the potential to strengthen the capacity of their NCAs to ensure vaccine quality. The development of the curriculum and presentation of the course was made possible by funding from the WHO and Australia's Overseas Aid Agency, AusAID.