International visitors & training

Over the past few months, the TGA has hosted a number of short-term visits by delegations from regulatory agencies in Malaysia, Japan, Canada, Indonesia, China and East Timor.

The TGA also provided training programs, on a cost recovery basis or with financial sponsorship from AusAID, in the areas of non-prescription medicines regulation, medical device regulation and GMP on medicinal products for government officials from Indonesia, Hong Kong, Malaysia, Singapore and Thailand.

GHTF study group 2

April 2005

Abstract

Study Group 2 of the Global Harmonization Task Force (SG2) has now completed work on comprehensive guidance for medical Devices Vigilance Systems. SG2 has also established a system for exchange of vigilance information between Competent Authorities (National Regulatory Agencies). The group is now completing consolidation work on related vigilance guidance documents. The article describes final SG2 Guidance, discusses current and future work for the SG2 and describes the implementation of SG2 Guidance in Australia.

Introduction

Medical device regulation is about abating the risk associated with the use of medical devices. Some of the risk is addressed through pre-market conformity assessment and the residual risk is addressed using post-market vigilance and surveillance. The term post-market vigilance relates to systems for the reporting and investigation of adverse events associated with the use of medical devices. Investigation of events leads either to remedial action or to dissemination of information that could be used to prevent or alleviate the consequences of any future events. The term post-market surveillance is broadly used to describe the range of pro-active activities undertaken by both medical device manufacturers and national regulators to ensure the ongoing safety, effectiveness, performance and compliance of medical devices in the market. Such activities may include testing, surveys, surveillance audits, and clinical studies.

Comprehensive guidance on vigilance

Study Group 2 (SG2) of the Global Harmonization Task Force (GHTF) has developed a series of documents¹, which together represent comprehensive guidance on post-market vigilance (see Table 1).

¹ http://www.ghtf.org

Table1 - Schedule of GHTF SG2 Guidance on Vigilance

Guidance Ref	Guidance Title
Adverse Event Reporting by Manufacturers
SG2-N21R8	Adverse Event Reporting Guidance for the Medical Device Manufacturer or its Authorized Representative
SG2-N31R7.2	Proposal for Reporting of Use Errors with Medical Devices by their Manufacturer or Authorized Representative
SG2-N36R7	Manufacturer's Trend Reporting of Adverse Events
SG2-N32R3.1	Universal Manufacturer Report Format
SG2-N33R11	Timing of Adverse Event Reports
National Competent Authority Report Exchange
SG2-N20R10	National Competent Authority Report Exchange Criteria
SG2-N9R11	Global Medical Device Competent Authority Report
SG2-N8R4	Guidance on How to Handle Information Concerning Vigilance Reporting Related to Medical Devices

Vigilance systems rely on users of medical devices to report incidents to the manufacturer and/or to regulatory authorities. When a medical device manufacturer becomes aware that an adverse event that is associated with their device has occurred, they must first determine whether the event must be reported to a regulatory authority. Guidance in this regard is provided in SG2-N21R8 (see Table 1). This document provides a definition of what constitutes a reportable event. Even if an event is not reportable, the manufacturer must record the event in the company complaint file. Events that are not normally reportable become reportable if a change in trend (usually an increase in frequency) is identified. Guidance in this regard is provided in SG2-N36R7. Guidance regarding timeframes for reporting and what amount of information constitutes a complete report are provided in documents SG2-N33R11 and SG2-N32R3.1 respectively.

SG2-N8R4 provides guidance on how vigilance information should be handled by National Regulatory Agencies. In addition, SG2 has established a National Competent Authority Reporting (NCAR) program. The program is used by National Regulatory Authorities to exchange information about issues of public health safety or concern. Documents SG2- N9R11, and N20R10 outline both the type of information and the procedures to be used during these exchanges.

Vigilance is not enough

Vigilance alone cannot detect all problems associated with the use of all devices. Moreover, Vigilance is an inappropriate strategy for the detection of problems with some types of medical devices. For example, vigilance is poor at identifying problems with in-vitro diagnostics and biocompatibility problems other than those that are manifested quickly. Detection of those types of problems requires the application of pro-active post-market measures.

SG2 has had extensive discussions about what constitutes Post-market Surveillance and what differentiates it from Post-market Vigilance (see definition in the Introduction). The SG2 has also considered the activities being undertaken by regulatory agencies and manufacturers around the world which fit the description of Surveillance. In doing so the SG2 concluded that in the vast majority of those activities harmonisation was either not possible, not desirable, or another group such as ISO Technical committees had already undertaken the harmonisation work.

National Competent Authority reports

For some time now, National Competent Authorities participating in the GHTF SG2 have been exchanging post-market information through a process known as National Competent Authority Report (NCAR) exchange. The process, which originated as a pilot and now continues formally and indefinitely, is governed by the criteria set down in guidance document GHTF SG2 N20R10. NCARs are not reports of individual adverse events, they are reports about safety related issues, which may have led to or is likely to lead to market action such as recall. The information exchanged may be confidential.

The SG2 envisages that as more Competent Authorities establish medical device regulations, they may also wish to join the NCAR Exchange Program. The Group has now produced GHTF SG2 N38R14: Application Requirements for Participation in the GHTF National Competent Authority Report Exchange Program. The document is in its final stages of being accepted as a final guidance document. Organisations wishing to participate in the GHTF's NCAR Exchange Program will have to receive the training and agree to the commitments described in GHTF SG2 N38.

Current SG2 work

The SG2 is now working to consolidate related guidance into fewer documents. For example, work is currently under way to consolidate documents 21, 31, 36, 32 and 33 into a single document. The original SG2-N21R8, now a 5-year-old document, is being revised during the consolidation process. The resulting document will be SG2-N54: Global Guidance for Adverse Event Reporting for Medical Devices. Similar consolidation work is being carried out on GHTF SG2 N9 and N20.

Some national regulations require that medical device adverse events be reported to their national regulatory agency regardless of where in the world the events took place. Other national regulations require reports only if the events occurred within their own national boundaries. This means that depending on where in the world a reportable event took place, reports may have to be submitted to more than one regulatory agency. The SG2 has been considering what advice may be given about this problem. The discussion has raised the idea of a global database for adverse event reporting. However this idea has some way to go before workable guidance can be agreed upon, and even then it would take some time to implement. In lieu of producing guidance on this area, the SG2 is in the final stages of producing a status document, GHTF SG2 N68, which summarizes the regulatory requirements of the five GHTF member countries in relation to reporting events that occurred abroad.

In addition to these projects, the SG2 is working on a harmonized electronic protocol for manufacturer's adverse event reports, and on a uniform content that product advisory notices should contain.

Implementation of GHTF SG2 Guidance in Australia

Most GHTF recommendations (pre and post market) were incorporated into the new Australian regulatory system for medical devices that came into force on 5 October 2002.

In brief, Section 41MP of the Therapeutic Goods Act states that adverse events must be reported to the TGA, while Medical Device Regulation 5.7 stipulates the timeframes within which a report about an adverse event must be submitted to the Therapeutic Goods Administration (TGA). TGA's Guidance Document 11 provides a "Plain English Interpretation" of the Act and the Regulations and describes general exemptions from the requirement to report. Medical Devices Guidance 11 also provides a reporting form which reflects the recommendations of GHTF SG2 N32. <http://www.tga.gov.au/docs/html/devguid11.htm>

The reader should note that while the recommendations in the guidance documents produced by the GHTF SG2 have been largely implemented in Australia, there are some small but important differences. The two most important are:

1. Timeframes for reporting are slightly different to those described in GHTF SG2 N33 R11.
2. Adverse events caused by use error must be reported to the TGA.

The reader should refer to the Therapeutic Goods Act, the Medical Devices Regulations and Guidance 11 for complete details.

Dr Jorge Garcia
TGA Laboratories
Secretary, GHTF SG2

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International meetings - Tissue regulation

Dr Shirley Bolis, a senior scientist from the Biocompatibility area of TGA Laboratories, attended the FDA and the New Paradigm for Tissue Regulation meeting in Dallas, USA, 31 January-3 February 2005. The FDA ran a workshop regarding the final ruling on the new regulations for good tissue practices for human cells, tissues and cell and tissue based products (HCT/Ps). There were just over 500 participants mostly from USA organisations involved in recovery of cells and tissues, tissue banks, processors and distributors of HCT/Ps. Both industry and the FDA presented seminars as well as running workshops on issues such as donor eligibility, quality systems, validation and reporting.

International meetings - TSE conference

Dr. Gary Grohmann, Head of the Immunology/Vaccines group in TGA Laboratories, attended the international scientific meeting on transmissible spongiform encephalopathies (TSEs) in Washington, USA, 13-15 February 2005, where the latest results from research and epidemiology were presented. Topics included:

• the nature and behaviour of TSE agents
• pathology
• advances in diagnostics
• prevention
• treatment
• inactivation
• prion clearance studies
• prion safety evaluation.

Advances had been made in all areas, especially in the pathology of these diseases, diagnostics and inactivation, making it now possible for sponsors to include prion clearance studies in registration submissions.

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International standards - Changes to the BP/EP and USP sterility testing

Background

Currently, sterile products supplied in Australia are required to be tested for sterility using the method contained in the 2003 Edition of the British Pharmacopoeia (BP), which is the same as that published in the European Pharmacopoeia (EP) 4th Edition 2002.

The TGA does not currently accept the United States Pharmacopoeia (USP) 27 <71> Sterility Test because there are several areas where it is significantly different from the BP/EP test. These include:

• The BP/EP requires a significantly shorter incubation period for challenge organisms for the media growth promotion test and method validation. It specifies 3 days for bacteria and 5 days for fungi. The USP specifies 5 days for all organisms for the growth promotion test and 7 days for all organisms for method validation.
• The USP allows a 7 day incubation period for products terminally sterilised by steam.
• The USP criteria for invalidation of the sterility test are far less specific than the EP/BP.

Changes to the compendia

The BP 2004 version of the Appendix XVI A, Test for Sterility contains some changes from the previous BP 2003 version. Changes have also been made to the USP 28 <71> Sterility Tests, and it specifically states that portions of the general chapter have been harmonized with the corresponding texts of the EP and/or the JP. The discrepant areas of the USP test method listed above are now in line with the BP 2004 test method as detailed below.

Many changes in the current BP and USP sterility test methods are minor or just variations of the way in which the same information is conveyed to the user. However, the following changes are significant and may affect how sterility tests are performed on sterile preparations intended for distribution in Australia.

BP Sterility Test Section	BP 2003 and EP 4th edition 2002	BP 2004 and EP 5.1	USP 28 (2005)
Culture media/ Culture media and incubation temperatures	The fluid thioglycollate (THIO) recipe includes Glucose monohydrate 5.5g	The fluid thioglycollate recipe includes Glucose monohydrate/anhydrous 5.5g/5.0g	The fluid thioglycollate recipe includes Glucose monohydrate/anhydrous 5.5g/5.0g as per the BP 2004
	States that the thioglycollate media should be placed in suitable containers which provide a ratio of surface to depth of medium such that not more than the upper third of the medium has undergone a colour change indicative of oxygen uptake at the end of the incubation period.	States that the thioglycollate media should be placed in suitable containers which provide a ratio of surface to depth of medium such that not more than the upper half of the medium has undergone a colour change indicative of oxygen uptake at the end of the incubation period.	States that the thioglycollate media should be placed in suitable containers which provide a ratio of surface to depth of medium such that not more than the upper half of the medium has undergone a colour change indicative of oxygen uptake at the end of the incubation period as per the BP 2004.
	The Soya-bean casein digest (SCD) recipe includes Glucose monohydrate 2.5g	The Soya-bean casein digest recipe includes Glucose monohydrate/anhydrous 2.5g/2.3g	The Soya-bean casein digest recipe includes Glucose monohydrate/anhydrous 2.5g/2.3g as per the BP 2004.
Growth promotion test of aerobes, anaerobes and fungi	Does not specify that each batch of medium should be tested.	States to test each batch of ready-prepared and prepared medium.	States to test each batch of ready-prepared and prepared medium as per the BP 2004.
	States that 10-100CFU of a minimum of one aerobic bacteria and one anaerobic bacteria for THIO and one fungi and one aerobic bacteria for SCD should be used. Gives indication of relevant species for each medium in table 16A-1.	States that not more than 100CFU of each of C. sporogenes, P. aeruginosa and S. aureus should be used for THIO and NMT 100CFU of each of A. niger, B. subtilis and C. albicans should be used for SCD.	States that not more than 100CFU of each of C. sporogenes, P. aeruginosa and S. aureus should be used for THIO and NMT 100CFU of each of A. niger, B. subtilis and C. albicans should be used for SCD as per the BP 2004.
	States to incubate not more than 3 days for bacteria and not more than 5 days for fungi.	States to incubate not more than 3 days for bacteria and not more than 5 days for fungi.	Has been amended to include incubation of not more than 3 days for bacteria and not more than 5 days for fungi as per the BP 2004.
Table of organisms suitable for use in the growth promotion and validation test	Includes the following organisms and strains: Aerobic bacteria: S. aureus - ATCC 6538, CIP 4.83, NCTC 10788, NCIMB 9518 B. subtilis - ATCC 6633, CIP 52.62, NCIMB 8054 P. aeruginosa - ATCC 9027, NCIMB 8626, CIP 82.118 Anaerobic bacteria: C. sporogenes - ATCC 19404, CIP 79.3 Fungi: C. albicans - ATCC 10231, IP 48.72, ATCC 2091, IP 1180.79. A. niger - ATCC 16404	Includes the same organisms and strains except the table also includes: C. sporogenes - NCTC 532 or ATCC 11437 C. albicans - NCPF 3179 A. niger - IP 1431.83, IMI 149007 Removed from the table are the strains: C. albicans ATCC 2091 and IP 1180.79	Includes the same organisms and strains as the BP 2004.
Validation Test	States that the THIO should be inoculated with 10-100CFU of the aerobic and anaerobic organisms indicated in Table 16A-1. The SCD should be inoculated with the fungi indicated in Table 16A-1.	States to use NMT 100 CFU of the same organisms as those used for the growth promotion test.	States to use NMT 100 CFU of the same organisms as those used for the growth promotion test as per the BP 2004.
	States to incubate not more than 3 days for bacteria and not more than 5 days for fungi.	States to incubate all containers for not more than 5 days.	States to incubate all containers for not more than 5 days as per the BP 2004.
Test for Sterility of the product to be examined	For filtration, the total volume washed through one single membrane should not exceed 1000 mL, unless otherwise justified and authorised.	Filtration must not exceed a washing cycle of 5 times 200 mL.	Filtration must not exceed a washing cycle of 5 times 200 mL as per the BP 2004.
Observation and interpretation of results	Products that render the medium turbid are to be subbed into fresh medium and the original and transfer containers incubated for a further 7 days.	Products that render the medium turbid are to be subbed (not less than 1 mL) after 14 days incubation into fresh medium and the original and transfer containers incubated for not less than 4 days.	Products that render the medium turbid are to be subbed (not less than 1 mL) after 14 days incubation into fresh medium and the original and transfer containers incubated for not less than 4 days as per the BP 2004.
Table - Minimum number of items to be tested	Table 16A-3 is in the Annex for guidelines for using the test for sterility.	Table 2.6.1-3 is located in the 'observation and interpretation of results' section. The table also includes a new specification of a minimum of 6 containers to be tested for Pharmacy bulk packages of antibiotics (greater than 5 g).	Table 3 is the same as Table 2.6.1-3 in the BP 2004, except for the following additions: large volume parenterals - 2% or 10 containers, whichever is less; antibiotic bulk packages <5g - 20 containers; not more than 100 devices - 10% or 4 items, whichever is the greater; more than 100, but not more than 500 devices - 10 items; and more than 500 devices - 2% or 20 items, whichever is less.
Annex - Guidelines for using the test for sterility	Does not include guidance on the use of condition d) for the observation and interpretation of results.	Includes an extra section on "observation and interpretation of results" which states that if condition d) is to be used as the sole criterion for invalidating a sterility test, it may be necessary to employ sensitive typing techniques to demonstrate that an organism isolated from the product test is identical to an organism isolated from the test materials and/or testing environment. It explains that routine microbiological/biochemical identification techniques may not be sufficiently sensitive or reliable enough to provide unequivocal evidence that two isolates are from the same source. More sensitive tests, eg molecular typing with RNA/DNA homology may be necessary to determine that organisms are clonally related and have a common source.	Does not include guidance on the use of condition d) for the observation and interpretation of results.

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In addition to the variations included in the above table, the table included in the Test for Sterility for the recommended minimum quantities of the product being examined has been amended in the BP 2004 version as follows:

BP 2004 - Table 2.6.1.2 - Minimum quantity to be used for each medium

Quantity per container	Minimum quantity to be used for each medium unless otherwise justified and authorised
Liquids less than 1 mL 1 - 40 mL Greater than 40 mL and not greater than 100 mL Greater than 100 mL Antibiotic liquids Other preparations soluble in water or in isopropyl myristate	The whole contents of each container. Half the contents of each container but not less than 1 mL. 20 mL 10% of the contents but not less than 20 mL 1 mL The whole contents of each container to provide not less than 200 mg.
Insoluble preparations, creams and ointments to be suspended or emulsified	The whole contents of each container to provide not less than 200 mg.
Solids less than 50 mg 50 mg or more but less than 300 mg 300 mg to 5 g Greater than 5 g	The whole contents of each container. Half the contents of each container but not less than 50 mg. 150 mg 500 mg
Catgut and other surgical sutures for veterinary use	3 sections of a strand (each 30cm long)

The USP 28 Table 2 - Minimum quantity to be used for each medium is the same as that for the BP 2004 except it also includes the following recommendations for devices:

• Surgical dressing/cotton/gauze (in packages) - 100 mg per package;
• Sutures and other individually packaged single-use material - The whole device;
• Other medical devices - The whole device, cut into pieces or disassembled.

These recommendations are also consistent with those listed in the TGA Guidelines for Sterility Testing of Therapeutic Goods (2002) <http://www.tga.gov.au/docs/html/sterilit.htm>.

Status of pharmacopoeial texts

Overall, the BP 2004 sterility test method has changed only slightly from the BP 2003 version. However, the USP 28 sterility test method has changed significantly so that it is now essentially the same as the BP 2004 method. Previous differences between the BP/EP and USP are no longer an issue for sterility testing of preparations for distribution in Australia.

The TGA recently subjected the BP 2004 to industry consultation with a view to adoption as the edition of that document as defined under the Therapeutic Goods Act 1989. When adoption of the BP 2004 occurs in the near future, sterility testing of finished product for the Australian market in accordance with BP 2004, EP 5.1, or USP 28, will be acceptable.

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Internatinal standards - United States Pharmacopoeia convention

Dr Larry Kelly, Acting Director of TGA Laboratories, attended the USP Convention held in Washington 9-13 March 2005. The purpose of holding the Convention every five years, among other things, is to review progress made by the USP against resolutions determined at the previous Convention and to define activities for the next five-year cycle. Approximately 250 members attended the Convention, as well as 50 observers. The membership is drawn from a range of organisations including government, industry and numerous professional and trade associations.

The 2005-2010 resolutions give some insight into the priorities of the USP for the next five years. The resolutions addressed issues such as the need to update monographs and to add new ones; the balance between monographs for innovator products and generic products; and, the continuing role of USP in the international harmonisation process. The resolutions can be viewed on the USP website <http://www.usp.org>.

World Health Organization activities - Influenza vaccines

Dr. Gary Grohmann attended the WHO committee meeting on influenza vaccines, in Geneva, 8-10 February 2005, which determined the composition of influenza vaccines for the Northern Hemisphere for 2005/2006 season. The meeting reviewed worldwide influenza activity, antigenic characterisation of influenza viruses, research, standards and immunity of populations. They also reviewed the vaccine composition and its efficacy for the Southern Hemisphere (2004). The meeting brought together regulators and vaccine manufacturers from the USA, Japan, Australia and Europe.

The committee recommended that vaccines to be used in the 2005-2006 season (northern hemisphere winter) contain the following:

• an A/New Caledonia/20/99(H1N1)-like virus
• an A/California/7/2004(H3N2)-like virus
• a B/Shanghai/361/2002-like virus

A meeting with National Authorities and Representatives of Influenza Vaccine Manufacturers followed on 13 February. At this meeting the WHO influenza committee members explained the scientific reasons for the committee's decision on influenza strains by presenting and summarising data submitted from influenza centres around the world. The regulatory authorities also presented information on strain availability and standardisation. The committee also discussed pandemic preparedness and the latest issues with H5N1 bird flu. The results of these meetings are now published on the WHO website <http://www.who.int/csr/disease/influenza/vaccinerecommendations/en/> and in Weekly Epidemiological Report.

World Health Organization activities - Vaccine production quality

Dr Drew Meek, from the Immunology/Vaccines group in TGA Laboratories is on secondment to the WHO for 12 months to assist with projects for the Ministry of Health, Iran. During his time there he will be based in Tehran providing expert scientific knowledge to help set up better systems for the regulation and testing of vaccines.