Assay validation and statistical analysis workshop

5th South East Asia Regional Office of the World Health Organization (SEARO) National Control Laboratory Network "Assay Validation and Statistical Analysis" Workshop, Yangon, Myanmar, 20-24 September 1999

Participants at the Workshop

As part of the curriculum development for the TGA Global Training Network course in Vaccine Regulation, Chris Rolls, Immunobiology Section, TGA Laboratories, with funding from AusAID, assisted the WHO and National Institute for Biological Standards and Control (NIBSC) team presenting the 4th SEARO National Control Laboratory Network "Laboratory Quality Systems" Workshop in Barog, India. In recognition of TGA's contribution, Chris Rolls was invited to the follow-up 5th SEARO National Control Laboratory Network "Assay Validation and Statistical Analysis" Workshop, in Yangon, Myanmar from 20-24 September 1999.

Chris, together with two scientists from NIBSC in the UK, presented three days of interactive lectures and discussion on the theoretical and practical aspects of vaccine QC assay validation, analysis, and monitoring. The Hepatitis B, Diphtheria, and Tetanus vaccine assays, and the problems associated with assaying combination vaccines, were featured and the Biostatistician from NIBSC provided the statistical detail. The 14 participants, from Thailand, Sri Lanka, Myanmar, India, Indonesia, and Bangladesh, all shared their experiences and work in this field.

The final day involved the co-ordinator of the Global Training Network, WHO, Geneva, and a representative from the Vaccine Supply and Quality unit of SEARO, Delhi, facilitating ongoing action plans for the implementation and follow-up training which the workshop had discussed. The subject for the next workshop in the series was discussed, with several suggestions proposed, including a workshop on Lot Release. The member country to host the next workshop has yet to be decided.

Condoms - review of standards to include non latex devices

Current Australian regulatory requirements are that barrier contraceptives be assessed as registrable devices unless there is a recognised standard in place, in which case the device can be considered for listing in the ARTG providing compliance with the standard is demonstrated. Currently the only recognised standard is ISO 4074-1:1996(E) which is referenced by TGO 61 which sets out requirements for male latex condoms. Alternative non-latex devices are currently supplied in some overseas markets. Although some guidelines and local standards exist in various parts of the world, there are no standards in place which are sufficiently comprehensive for standards-based assessment of these emerging technologies. As Australia moves to an internationally harmonised, standards based regulatory framework, the need for adequate standards in this area will become even more important.

TGA recently consulted with industry, testing laboratories and Standards Australia with a proposal to convene a working party to explore options for addressing the deficiency in standardisation needs. Following strong interest in this proposal, the working party convened on 9 December 1999 at TGA.

Gerda Mark's retirement

Dr Gerda Mark of the Biomaterials and Engineering Section, TGA Laboratories retired on 3 September 1999 after 20 years service with the TGA. Gerda will be remembered for her contributions to the field of cytotoxicity.

Gerda Mark with colleagues at her farewell

Head of blood products group awarded professional development award

Albert Farrugia, TGA's Senior Advisor on Blood Products and Head of the Blood Products Group, has been awarded a Professional Development Award for studying blood delivery and regulatory systems in a number of overseas countries. The award will see Dr Farrugia spending three months in the Canadian Blood Safety Council, Health Canada's Blood and Tissues Division, the FDA's Office of Blood, the Paul Ehrlich Institute's Division of Transfusion Medicine and other agencies. Dr Farrugia is expected to take up the award from February to April 2000. This significant resource allocation demonstrates the Department's and TGA's commitment to improving regulatory practice in the blood products sector.

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Influenza vaccines - 2000

The WHO has two meetings a year to recommend the components for the influenza vaccines for the Northern and Southern Hemispheres. The meeting to recommend the formulation of the vaccine for the Southern Hemisphere was held in Nice, France, September 20-22 1999. The committee comprises members from the four WHO Collaborating Centres for Reference and Research on Influenza, the three regulatory authorities (NIBSC, CBER and TGA) and WHO. Dr. Gary Grohmann, Head of Immunobiology, represented TGA at this meeting.

Epidemiological data were presented at the meeting describing influenza activity in all parts of the globe. H3 strains and B strains predominated but activity was generally low compared to previous years. Very few H1 strains were detected. Serological and genomic data were also presented with information on immune response/protection and genetic variability and evolution.

Novel influenza viruses (H5, H7 and H9 Strains) detected in Hong Kong some years ago in humans and birds were also discussed. Their activity was rare. The committee also recommended downgrading the current level of alertness in the WHO Influenza Pandemic Preparedness Plan from Phase 0 Level 2 (human infection confirmed) to Phase 0 (no indications of any new virus type).

Having considered the information available the WHO committee recommended that vaccines to be used in the 2000 season (southern hemisphere winter) contain the following:

• an A/Moscow/10/99 (H3N2)-like virus
• an A/New Caledonia/20/99 (H1N1)-like virus
• a B/Beijing/184/93-like virus*

or

• a B/Shangdong/7/97-like virus

* The most widely used vaccine virus is B/Yamanashi/166/98

The WHO committee resolved that the specific vaccine viruses used in each country be approved by the national control authorities [Australian Influenza Vaccine Committee (AIVC) in Australia/NZ/South Africa]. National public health authorities are responsible for recommendations regarding the use of the vaccine. As most of the population is likely to have been infected with influenza A(H3N2), influenza A(H1N1) and influenza B viruses, 1 dose of inactivated influenza vaccine should be immunogenic for individuals of all ages except young children. Previously unimmunized children should receive 2 doses of vaccine with an interval between doses of at least 4 weeks.

Recommendations for the composition of vaccines intended for November 2000 to April 2001 (northern hemisphere winter) will be made by WHO in February 2000.

Composition of Australian Influenza Vaccine for the 2000 Winter

The meeting of the AIVC was convened on 7 October 1999. At that meeting the committee decided to adopt the WHO recommendations of an A/Moscow/10/99 (H3N2) like strain, an A/New Caledonia/20/99 (H1N1) like strain and a B/Beijing/184/93 like strain as the vaccine components. The A/Moscow/10/99 strain was endorsed subject to the production of a suitable reassortant. The committee reconvened on 9 November. The data presented indicated that there were no suitable A/Moscow/10/99 high growth reassortants available. It was also clear that the vaccine manufacturers required to know the H3 strain by 12 November in order to produce vaccine for the Southern Hemisphere by 1st March. Since none of the A/Moscow/10/99 reassortants prepared by CSL/WHO (IVR 112, 117,118 and 119 ), CBER (RESVIR15) and NIBSC represent an improvement over the current A/Sydney/5/97 strain, the AIVC recommended A/Sydney/5/97 as a suitable H3N2 vaccine strain.

Having considered the information on international surveillance by WHO and recent epidemiological data and strain characterisation, the Committee decided that the composition of vaccines for year 2000 Season should be as follows:

• A (H3N2): an A/Sydney/5/97 (H3N2) - like strain, 15 µg HA per dose.
• A (H1N1): an A/New Caledonia/20/99 (H1N1) - like strain, 15 µg HA per dose.
• B a B/Beijing/184/93-like strain, 15 µg HA per dose.

It was also determined that the following viruses are suitable vaccine strains:

• A/Sydney/5/97(IVR-108 and RESVIR-13) are A/Sydney/5/97 (H3N2)-like strains
• A/New Caledonia/20/99 (IVR-116) is an A/New Caledonia/20/99 (H1N1)-like strain
• B/Yamanashi/166/98 is a B/Beijing/184/93-like strain.

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Status of standards for sterilization of health care products - ISO Technical Committee 198

Vivienne Christ and Robyn Isaacson of the Microbiology Section, representing Standards Australia, attended the 12th meeting of ISO/TC 198 Sterilization of health care products at the British Standards Institute, London in September. At the meeting joint revisions of International (ISO) and European (CEN) Standards for the development, validation and routine sterilization processes began. The standards under revision include those for moist heat sterilization (ISO 11134, ISO 13683 and EN 554), radiation sterilization (ISO 11137 and EN 552) and ethylene oxide sterilization (ISO 11135 and EN 550). The joint revision process of the ISO and CEN Standards will be based on the format of the draft ISO/EN 14937 Sterilization of health care products - General criteria for characterization of a sterilizing agent and development, validation and routine control of a sterilization process and will result in a single set of medical devices sterilization standards to be used around the world.

The scope of the revisions will be limited to sterilization of medical devices. However, their general applicability to the sterilization of other health care products will be acknowledged. The standards will not define specific requirements for designating devices as "sterile". These requirements and the specification of a sterility assurance level for products labelled as "sterile" will be left to the discretion of national standards developers or regulators. In Australia the requirements for sterility assurance are specified through the adoption of EN 556 Requirements for terminally-sterilised devices to be labelled "Sterile" in the Manufacturing Principles.

ISO and CEN have already published one joint standard on the sterilization of single use devices incorporating animal tissues with liquid chemical sterilants (ISO 14160) and are finalising joint standards on the selection, use and interpretation of biological indicators (ISO/DIS 14161) and on general criteria for sterilization processes (ISO/FDIS 14937). Work is also under way on joint standards for washer-disinfectors, instructions to be provided with resterilizable medical devices, packaging and on standards for aseptic processing including filtration, freeze-drying, isolator-barrier technologies and sterilization- and cleaning-in-place. Future joint revisions are planned for the general standards for biological indicators and chemical indicators.

Of particular interest to Australian manufacturers is confirmation that sterilization by gamma irradiation using 25 kGy requires substantiation using dose verification. Substantial revision of ISO/TR 13409 Sterilization of health care products - Radiation sterilization - Substantiation of 25 kGy as a sterilization dose for small or infrequent production batches has commenced and the revised methodology will be based on the original VDmax approach published by Kowalski and Tallentire¹. This document will form Part 3 of the revised ISO 11137/EN 552 series.

1. Kowalski, J.B., Tallentire, A. Substantiation of 25kGy as a sterilization dose: a rational approach to establishing verification dose. Radiation Physics and Chemistry 1999; 54:55-64.

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TGA satellite seminar at the Australasian Society for Blood Transfusion conference

A successful seminar on the theme "Blood Safety and Supply - Scientific and Regulatory Perspectives" was attended by 100 participants during the October 1999 conference of the ASBT in Melbourne. Opening the Seminar, Terry Slater, National Manager of the TGA, spoke about the TGA's commitment in maintaining best practice in the blood products area. These have included TGA's establishment of a Blood Products Group, TGA's international initiative towards establishing a global blood safety initiative through WHO and TGA's support of the Commonwealth Review of the Australian blood system. The participants heard talks from eminent Australian and overseas experts on a wide range of issues including the delivery of blood services, the regulatory mechanisms involved in fresh blood regulation, current problems such as new variant CJD and the introduction of NAT testing. The Commonwealth Review process was also described by Penny Rogers. Feedback on the Seminar was very positive and it is anticipated that similar events will be held next year.

Liana Harvath of the FDA, Albert Farrugia of TGA's Blood Products Group and Penny Rogers of the Commonwealth Blood Review Secretariat at the TGA Seminar.

TGA to regulate human tissues and tissue products

TGA is proposing a new policy for regulation of human tissues based on risk-management principles. Tissues will be scrutinised according to the degree of manipulation involved in the manufacture. The policy will be considered by the National Consultative Committee for Therapeutic Goods in the near future. Further consultation with stakeholders, including manufacturing centres and the public will be undertaken as part of this process.

These products include whole tissues (bone, skin) subject to little or no manipulation and cell and tissues products which are subject to high levels of manipulation such as blood stem cells and fibroblasts. Manipulation may involve selective culture, expansion and storage, or in some cases the insertion of specific genes (gene therapy).

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Towards global adverse event reporting: activities of Global Harmonisation Task Force (GHTF) Study Group 2

Study Group 2 (SG2) of GHTF was formed in 1995 and is charged with harmonising medical device adverse event reporting and post-market surveillance activities. Dr Jorge Garcia of TGA Laboratories and manager of the Incident Report Investigation Scheme represents TGA on SG2.

SG2 has produced the document Adverse Event Reporting Guidance for the Medical Device Manufacturer or its Authorised Representative. This guidance is a consensus approach towards adverse event reporting by GHTF members - the U.S., European Union, Japan, Canada and Australia and paves the way for globally harmonised adverse event reporting systems. At a meeting in Bethesda, Maryland in July, the regulatory authorities participating in SG2 agreed to develop plans for implementing the recommendations in the guidance as part of their own local reporting programs.

For Australia, implementation of the guidelines will take place as part of the development of the new harmonised regulatory system for medical devices, which was announced in September 1999. The European Union will also look to implementation of the Guidance by way of revision of the current EU guidance document to incorporate the GHTF agreements.

According to the Guidance, three basic criteria determine whether the manufacturer should report an adverse event to national regulatory bodies (known as "National Competent Authorities" or NCAs):

1. An event has occurred;
2. the manufacturer's device is associated with the event; and
3. The event led to either the death or serious injury of a patient or other person, or was a "near miss" which indicates a death or serious injury could result if the event recurs.

Any event that satisfies all three criteria is deemed to be a "reportable event". The guidance clarifies the three criteria at some length, defines some key terms and contains a large list of examples of events that would be considered to be reportable.

Reporting Exemptions

The Guidance lists eight generic exemption rules which may reduce the number of reports that manufacturers would otherwise be compelled to report:

1. Deficiency of a new device that would always be found by the user prior to its use (this is sometimes known as "out-of-box failure");
2. Adverse events caused solely by patient conditions;
3. Adverse events caused solely by the product having exceeded its documented end of service life;
4. Events where a protection against a fault worked correctly and no death or serious injury occurred;
5. Events which could lead, but have not yet led to a death or serious injury but have been determined to have a remote likelihood of causing death or serious injury by a documented risk analysis;
6. Adverse events associated with expected and foreseeable side effects which are identified in the product's labelling and/or have a certain functional or numerical predictability;
7. Adverse events that occur after a manufacturer has issued an advisory notice (such as a recall or an alert); and
8. Adverse events subject to specific exemptions by an NCA.

It is important to note that the Guidance allows for NCAs to require the reporting of incidents relating to issues of public health concern irrespective of the general exemptions. Similarly, adverse events that are subject to an exemption become reportable to the NCA if a change in trend (usually an increase in frequency) or pattern is identified.

No Consensus on Use Error Reporting

Despite much debate, SG2 has not reached consensus on whether manufacturers should be compelled to report adverse events involving use error. The guidance simply states that "The reportability of adverse events involving use error is not globally harmonised. Reportability is subject to regulatory requirements of the relevant NCA". In the absence of consensus, it is likely that Australia and the other regulatory agencies will continue to require reporting of events irrespective of whether or not there was use error.

Global Exchange of Vigilance Reports

Having developed a globally applicable reporting guidance, SG2 is now contemplating the possibility of a single, global adverse reporting scheme.

At present, some jurisdictions require that all adverse events, regardless of where in the world they occurred, must be reported. This often requires manufacturers to submit more than one report about the same event, a phenomenon known as "echo reporting". Other jurisdictions require adverse event reports that have occurred within their national boundaries.

SG2 is exploring the possibility of manufacturers submitting adverse event reports to the NCA where the event occurred and for significant events to be shared between NCAs through a vigilance exchange scheme. Such a scheme is currently under pilot with participation from all GHTF members. For the pilot, SG2 has developed some broad reporting parameters intended to focus exchanges on high-risk problems where there is some element of decision on regulatory action. The pilot and other SG2 work may one-day result in the development of a global vigilance database, whereby vigilance information is exchanged passively between NCAs. However, the participants are adamant that a system where vigilance information is actively exchanged would be very useful.

Future Plans

SG2 is currently formulating recommendations in regards to timeframes for certain types of reports. Consensus is developing around a maximum of 30 days by which an adverse event report, including the results and conclusions of the manufacturer's investigation must be submitted to the relevant NCA. The group is discussing a much shorter timeframe for the reporting of "issues of significant public health concern".

The group is also developing a global data set for adverse event reporting. This will be the information required from a manufacturer when an adverse event report is submitted. This work is almost complete.