Report on European RAPS Conference

The Third European Conference of the Regulatory Affairs Professionals Society was held in France in April 1997. The conference was attended primarily by regulatory affairs officers from North American and European manufacturers and representatives from the WHO and European Regulatory Authorities. The conference was organised as three concurrent streams - Devices, Drugs and Biologicals. A representative of TGAL attended the Biologicals stream.

Registration of Biologicals in Europe is in a process of change. On 1 January 1995 centralised European registration through the European Agency for the Evaluation of Medicinal Products (EMEA) was implemented. Centralised registration has been required for biotechnology products (including those produced using recombinant DNA technology) since its implementation. However, other biologicals can currently be registered centrally through the EMEA or through the mutual recognition procedure once a company has gained approval for a product in one member country. From January 1998 only centralised registration will be available.

International collaboration in disinfectant regulation

Ms Karen Longstaff, Senior Microbiologist with the Microbiology Section, TGA Laboratories (TGAL) recently visited the laboratory of Dr Syed Sattar at the University of Ottawa, Canada, to gain further practical experience in microbial efficacy testing of disinfectants. Considerable practical training was received in the first tier of the new quantitative sporicide carrier test that the laboratory has developed for the US Environmental Protection Agency (EPA). This training will enable TGAL to participate in the second tier collaborative studies for the quantitative sporicide carrier test.

The visit also enabled Ms Longstaff to spend time with officers from the FDA Office of Device Evaluation, Washington, where she was able to study in some depth, the evaluation process for 510 (k) applications (premarket notification submissions) for sterilants and high level instrument grade disinfectants. Training was provided by both the University of Ottawa and the FDA in the interests of international harmonisation and in recognition of the potential input from TGA to scientific aspects of disinfectant regulation.

Constructive discussions were also held and useful contacts made with the EPA in regard to microbial efficacy testing of hospital, commercial and household grade disinfectants; Health Canada regarding current Canadian and Australian requirements for regulation of disinfectants and the US Pharmacopoeial Convention in regard to microbial limits for non-sterile pharmaceuticals.

The visit provided an invaluable opportunity to establish relationships with a laboratory that enjoys an international reputation for quality in the field of disinfectant testing and to further cement existing relationships with our regulatory counterparts. It has significantly increased the knowledge and expertise within the Microbiology Section to enable TGA to more effectively achieve the Government's objectives in regard to regulation of disinfectants.

Electronic submission of dossiers for evaluation has commenced in the USA, as an augmentation to paper submission. However, it is anticipated that electronic only submissions would be in place in Europe and the USA by the middle of the next decade. The majority of the trade displays at the conference were on computer systems for preparation and lodgement of electronic applications. There was discussion of the ICH proposal for development of a "Common Technical Document" format for data submission to the USA, Japan and Europe.

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Pharmaceutical Benefits - listing cut off dates

The process of listing a product with the Pharmaceutical Benefits Scheme includes the provision of a sample for analysis by the TGA Laboratories. To assist in meeting listing deadlines an agreement has been reached with sponsors whereby samples will be supplied no later than one month prior to the closing date for those samples where chemical testing is required and no later than six weeks prior to the cut-off date for samples involving microbiological testing.

The following table sets out the dates by which samples should be provided to the laboratories for analysis prior to listing as pharmaceutical benefits.

Publication Date	Chemistry Deadline	Microbiology Deadline
November 1997	22 July 97	8 July 97
February 1998	22 October 97	8 October 97
May 1998	22 January 98	8 January 98
August 1998	22 April 98	8 April 98
November 1998	22 July 98	8 July 98
February 1999	22 October 98	8 October 98

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Near Infra-Red Spectrometry (NIRS) guidelines

Near infra-red spectrometry (NIRS) is a technique which may be used for confirming the identity of a substance. It has been used in the food and grains industries for a number of years and is becoming increasingly popular in the pharmaceutical industry.

Working with the APMA, and through consultation with international agencies, TGA staff have developed a set of guidelines for the use of NIRS by pharmaceutical manufacturers. The guideline document addresses administrative issues, instrument performance requirements and GMP aspects. In particular, the document describes the circumstances under which use of NIRS may be regarded as a self-assessable change, as opposed to one requiring prior approval, together with the data requirements needed by the TGA to support the changes.

In broad terms, the sponsor will need to seek TGA approval where replacement of an approved method by NIRS is proposed. Once the TGA has approved the use of NIRS for a particular material or group of materials and an SOP for future extensions has been agreed, the sponsor may extend the use of the technique to other materials where certain conditions are met.

Changes to compliance testing

The Biomaterials & Engineering Section tests medical devices as part of routine sampling programs, and in response to incidents with devices reported to the Incident Reporting and Investigation Scheme maintained by Medical Devices Section. Changes have been made to the types of safety related compliance tests that will be conducted to allow a greater number of devices to be included in the routine sampling programs. These changes will double the present number of samples that can be tested.

For example, condoms will now be routinely tested for holes, artificially-aged inflation, packaging and labelling. Examination gloves will be tested for leakage and labelling, and surgical gloves for leakage, labelling and sterility. Aproportion of these devices will continue to be tested to all the requirements of the relevant standard.

Sponsors are reminded that all condoms, examination gloves and surgical gloves supplied into Australia must comply with all the requirements of the relevant TGO, and also that all batches of condoms supplied into Australia must be tested and a certificate of conformance to TGO 39 must be obtained prior to supply.

Adoption of pharmacopoeial standards

One of the recommendations to arise from the recent review of the TGA was that there should be greater flexibility in the adoption of pharmacopoeial standards used to ensure safety and quality of medicinal products. The BP is the official standard under the Therapeutic Goods Act 1989, but adoption of USP monographs should facilitate access for consumers to a wider range of quality medicinal products. As part of this initiative, the TGA has been liaising closely with industry and has offered manufacturers of prescription, non-prescription and complementary medicines the option of using a USP monograph where a company demonstrates that safety, quality or efficacy will not be compromised. In the case of a biological, a company will also need to demonstrate that concurrent availability of alternative products conforming to different standards will not cause ambiguity.

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New policy initiative contributes to assuring the safety and supply of medicinal products derived from plasma

Australia pursues a policy of self sufficiency in products derived from human blood and plasma. The Australian Red Cross Blood Service assures Australia has sufficient cellular components of human blood derived from volunteer blood donors. In relation to plasma products, TGA supports this policy through Appendix 19 of the Australian Guidelines for the Registration of Drugs, which states that

One Australian manufacturer, under sole contract to the Commonwealth Government, fractionates the plasma collected by the Red Cross. Thus shortfalls in the supply of these essential products would need to be met by the emergency supply of unevaluated products, with the potential of contamination with infectious agents and other deleterious effects.

The Health Services Development Division has therefore contracted the TGA to establish a list of evaluated products from a range of suitable alternative suppliers. Interested manufacturers may contact Albert Farrugia on (02) 6232 8539 for details regarding the data which TGA will require for evaluation with a view to inclusion in the list. This policy is described in the following addition to Appendix 19 of the AGRD:

Potential sponsors of alternative products may still elect to register these in the standard fashion by submitting data to the TGA which supports the imported products' superiority over local products.

Trans-Tasman standard for Factor VIII

Human blood collected in Australia and New Zealand for the manufacture of coagulation Factor VIII must meet international requirements for quality, particularly in relation to potency. The efforts of blood collection centres to meet these standards are hampered by a lack of

• the chromogenic assay of Factor VIII potency required by the British Pharmacopoeia and
• an appropriate national reference standard which often necessitates the use of inadequately calibrated local plasma pools.

The Molecular Biology Section of TGAL has been collaborating with the Auckland Regional Blood Service to calibrate a proposed Australasian Reference Standard for the measurement of Factor VIII related activities in plasma. In these studies, the potency assigned to the standard was confirmed against a range of international and in-house standards. The preparation was then used to compare two different methods of determining Factor VIII potency - the chromogenic assay required by the TGA and the one-stage coagulation assay used by the blood centres.

The results showed a high level of correlation (r=0.86, P<0.001) suggesting that blood centres could use the chromogenic assay with confidence. Furthermore, a single point determination from a 3-point standard curve fell within the 95% confidence interval calculated from the more involved parallel line method, suggesting that methodology and equipment in the blood centres could be used to perform the chromogenic assay without excess additional costs.

The results of this study will be submitted for approval to the Quality Managers' Forum at the Australasian Society for Blood Transfusion meeting to be held in Auckland in October 1997. Approval will lead to the establishment of an Australasian Standard for measuring Factor VIII activity in plasma. The manufacture of the preparation by the Auckland Blood Centre and the calibration and standardisation by the TGA serves as a practical example of Trans-Tasman collaboration in the regulation of blood products.