20th NRL Workshop on Serology

The 20th NRL Workshop on Serology will be held on 13-15 August 2003 at the Surfers Paradise Marriott Resort in Queensland.

Prominent international guests have been invited and national speakers will offer the Australian context.

For more information see the NRL website <http://www.nrl.gov.au>.

21st TGC meeting

The 21st meeting of the Therapeutic Goods Committee was held on 10-11 February 2003.

Key recommendations from the meeting <http://www.tga.gov.au/docs/html/tgc/tgc21.htm> can be found on this website. The recommendations of the Therapeutic Goods Committee are yet to be considered by the TGA.

It is expected that the next meeting of the Therapeutic Goods Committee will be held in June 2003.

Fees for assessment of overseas manufacturers GMP compliance

The 2002 Review of the TGA's Good Manufacturing Practice Audit and Licensing program proposed a set of fees for assessment of evidence of GMP compliance of overseas manufacturers ('preclearance'). The proposal was discussed with the industry organisations Medicines Australia, Australian Self-Medication Industry, Complementary Healthcare Council of Australia and Medical Industry Association of Australia and the following set of fees have been agreed to.

1. A fee for assessment of evidence of GMP compliance of an overseas manufacturer ($240). This fee is payable every 3 years.
2. A fee for obtaining GMP evidence from an overseas regulatory authority ($210). This is in addition to the assessment fee of $240 and is applicable only if the TGA is requested to obtain GMP evidence of manufacture from European Mutual Recognition Agreement GMP inspectorates or the US FDA. The fee will apply to every application with such a request.
3. A reinstatement fee of $750 - to apply to approval of an overseas manufacturer that has been allowed to expire and a subsequent application for assessment is made. It has been agreed that the TGA will notify manufacturers at least 3 months before expiry to allow time for the manufacturers to take appropriate action and provide further GMP evidence of manufacture for assessment.

It is anticipated that these fees will be effective from 1 July 2003. The TGA also anticipates that revision of the Guidelines on Standard of Overseas Manufacturers (12th Edition) will be finalised by July 2003.

If you have any questions regarding the fees outlined above, please contact Dr Udomsri Low on phone 02 6232 8622, fax 02 6232 8785, or email gmp@tga.gov.au.

Haematopoietic progenitor cell products standards

The TGA has established an Expert Working Group, under the auspices of the Therapeutic Goods Committee, to develop a Therapeutic Goods Order (TGO) to define standards for Haematopoietic Progenitor Cell (HPC) products. The new standards will cover HPC products harvested from bone marrow, peripheral blood, placental and umbilical cord blood.

The current standard for HPC products is included in the Council of Europe's Guide to the Preparation, Use and Quality Assurance of Blood Components (8th edition) which is mandated in Therapeutic Goods Orders No. 66 and No. 66A Standards for Blood Components. The new edition of the Council of Europe's Guide (9th edition), anticipated to be adopted later this year, will not include reference to HPC product standards so it is essential that alternative standards covering HPC products be in place. Accordingly, the TGA proposed that there be two TGOs in place: one for HPC product standards and the other adopting the 9th edition of the Council of Europe's Guide.

The proposed Therapeutic Goods Orders will be considered by the TGC for adoption in mid-2003.

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Microbiological update

International harmonisation

Under the International Committee for Harmonisation (ICH), the Pharmacopoeial Discussion Group (PDG) works towards consensus and harmonisation of general methods and selected monographs in the United States Pharmacopeia (USP), the Japanese Pharmacopoeia (JP) and the European Pharmacopoeia (EP). Harmonisation is formally defined by the PDG in process Stages 1 to 7.

The PDG has agreed in principle to sign off on the harmonised sterility test (Stage 5) to be published in the three pharmacopoeias with eleven footnotes, which outline minor differences remaining between the texts. The PDG reached consensus on the removal of major differences, such as the USP's 7-day incubation for terminally steam sterilized product. The document proceeds to the next stages of adoption (Stage 6) and implementation (Stage 7) by each pharmacopoeia.

The pharmacopoeial expert committees have discussed the harmonisation proposal for microbial limits test methods and microbial contamination limits for non-sterile product classes. TGA Laboratories' Chief Microbiologist is participating in these discussions as an observer on the EP Group of Experts No. 1 (Microbiology). Although there are still a significant number of differences to be resolved, it is expected that the proposed Stage 4 documents will be published in each of the pharmacopoeial journals for official inquiry over the next few months.

Preservative efficacy testing

The EP has aligned the diluent used to prepare the suspensions of challenge organisms used for the inoculum in the preservative efficacy test with the USP. The addition of 1g/l of peptone to 9g/l solution of sodium chloride has been deleted to avoid interactions experienced between peptone and some preservatives. This amendment will be published in Supplement 4.4 to the EP and will flow on to the next edition of the British Pharmacopoeia (BP).

Sponsors are reminded that all sterile and non-sterile multidose dosage forms are now required to comply with the preservative efficacy requirements of the BP. Acceptance of the USP Antimicrobial Effectiveness Test was revoked at the 15th meeting of the Therapeutic Goods Committee in 1999. Preservative efficacy data for formulations which were originally tested according to the USP requirements should be reviewed to ensure that the formulations comply with BP requirements.

Preservative efficacy testing should be carried out on the finished product at expiry to demonstrate the stability of the preservative system. End of shelf life data may not be available for initial registration, however, during product development, it should be established that product formulated with the preservative at the lowest limit at the end of shelf life specification is also capable of satisfying preservative efficacy requirements. It is not sufficient to assess preservative efficacy on the basis of chemical concentration alone because, as stated in EMEA document CPMP/CVMP/QWP/115/95 Note for Guidance on Inclusion of Antioxidants and Antimicrobial Preservatives in Medicinal Products, microbiological efficacy testing should be carried out "even if no evidence of degradation of the antimicrobial preservative . is observed on storage, as other chemical and physical changes in the finished product may influence the efficacy of the antimicrobial preservative."

The stability of the preservative over the proposed open shelf life should also be demonstrated. To support an open shelf life period for multidose injectable and ophthalmic products (including contact lens care solutions), the TGA requests either results of tests involving repeated microbial challenges, testing of products after exposure to a simulated in-use regimen that mimics the likely use of the product or results of microbial limit tests conducted on partially used containers.

With regard to open shelf life testing involving repeated microbial challenge tests, there are currently no specific international, pharmacopoeial or regulatory agency test methods available. Guidance may be obtained from the international standard ISO 14730.2 Optics and optical instruments - Contact lens care products - Preservative efficacy of multidose preserved contact lens care products. The normative part of the standard gives a test procedure and performance criteria for preservative efficacy over an open shelf life period of 28 days. It should be noted that this test may be extended to justify periods in excess of 28 days. The informative annex gives four examples of preservative efficacy test procedures to show preservative efficacy for products with discard dates longer than 28 days. Test methods that involve repeated microbial challenges over the open shelf life period are preferred as they most closely mimic the in-use situation.

This ISO reference is not being supplied as a standard that must be applied to demonstrate acceptable preservative efficacy over the open shelf life period. It is referenced solely to demonstrate the elements of the type of tests that would be required to support an open shelf life period.

TGA sterility testing guidelines

Now on the TGA internet site is the TGA Guidelines for Sterility Testing of Therapeutic Goods 2002 <http://www.tga.gov.au/docs/html/sterilit.htm> which replaces the TGA Guidelines for Sterility Testing of Therapeutic Goods 1998. This revised document reflects changes to the Test for Sterility that were included in Appendix XVI of the British Pharmacopoeia 2001 that was adopted by the TGA on 1 December 2001. Of most significance are the changes to Table 5 (Table 16A-1, BP), which include more specific requirements for growth promotion, validation and stasis tests.

The purpose of the TGA Guidelines for Sterility Testing of Therapeutic Goods 2002 is to provide guidance to manufacturers and contract testing laboratories on the British Pharmacopoeia 2001, Test for Sterility. These guidelines are not mandatory.

Pharmaceutical water testing

The requirements for microbiological testing of process waters in the BP 2002 are different to those of previous editions of the BP. The BP 2002 monographs for Highly Purified Water, Purified Water and Water For Injection, state that the total viable aerobic count should be determined by membrane filtration, using Agar Medium "S" with incubation conditions of 30°-35°C for 5 days. Agar Medium "S" is R₂A agar and details of this agar are located in Appendix XVI B (Test for Microbial Contamination) of the BP 2002. The changes to the test method are a result of discussions at the international level with regard to microbiological testing of process waters and in which TGA Laboratories was actively involved. The selection of quality control cultures for quality control of R₂A agar is still under active discussion by the EP Group of Experts No. 1 (Microbiology).

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Recent amendments to advertising regulations

Amendments relating to the regulation of advertising were gazetted on 19 December 2002. The main changes include but are not limited to:

• The provision for the pairs of bodies
  1. Federation of Australia Commercial Television Stations and the Federation of Australian Radio Broadcasters and
  2. the Australian Publishers Bureau and the Outdoor Advertising Association of Australia
  to jointly nominate a person to attend the Therapeutic Goods Advertising Code Council meetings as observers.
• The provision for the Complaints Resolution Panel to publish, including on the Internet, a register of complaints and related information.

The Therapeutic Goods Amendment Regulations 2002 (No.5) can be accessed on the Attorney-General's Scaleplus website <http://www.comlaw.gov.au>.

SIME update

The TGA is moving to enhance its electronic online environment. The facility is being developed under the SIME project and allows for the viewing of information and for making applications for entry onto the Australian Register of Therapeutic Goods. This latter service is currently available for medical devices and should be extended to listed medicines by mid-2003.

Using the Internet, sponsors of therapeutic goods available for sale in Australia or agents of sponsors can now:

• view all ARTG records to which they are legally entitled
• view client contact details
• access the TGA approved terminology, now referred to as the TGA code tables
• submit a medical device application for entry onto the ARTG.

All sponsors and agents who currently have a product on the ARTG will have received a letter explaining how to gain access to the online systems. The letters where sent out in mid-2002 and our client details have been progressively amended accordingly. If you are uncertain whether your organisation has received a letter, please email the TGA SIME Help Desk <ebs@tga.gov.au>.

If you have any questions, would like to gain access to the online systems or would like further information, please email the TGA SIME Help Desk.

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Surveillance news

Investigations

The TGA Surveillance Unit began 2002 with 179 outstanding matters carried over from the previous year.

During 2002:

• 496 new referrals were received
• 675 matters required investigation
• 581 investigations were finalised.

Ninety four matters were carried over into 2003.

Investigations carried out during 2002 included counterfeiting, diversion, product tampering, and the smuggling into and out of Australia of goods not included in the Australian Register of Therapeutic Goods.

Of the crime reported to the Surveillance Unit in 2002:

• 62% involved non-prescription medicines
• 32% involved prescription medicines
• 6% involved medical devices.

Administrative remedies imposed by the Surveillance Unit included:

• seizure and destruction of illicit goods
• prohibition of illegal imports
• licence cancellation
• product recalls.

Formal written warnings were issued to 149 sponsors and 234 criminal charges were laid against 13 persons or companies. Many more sponsors and manufacturers were assisted in bringing their activities into compliance without recourse to regulatory action.

Prosecutions

Prosecutions of interest, finalised during 2002, included the following.

International
In June 2002 in Alabama, USA, a Melbourne lawyer was sentenced to 15 years and 8 months imprisonment, and his US co-offender to 6 years and 6 months imprisonment, on charges related to illegally offering prescription drugs over the Internet. This trial resulted from lengthy investigations by the Office of Criminal Investigations of the US Food and Drug Administration (FDA), assisted by the TGA Surveillance Unit, into the activities of an Internet clinic. TGA investigators collected evidence in several States and one external territory of Australia.

The defendants were convicted on 23 counts of conspiracy to commit violations of the US Federal Food, Drug and Cosmetics Act; conspiracy to commit money laundering; mail fraud; dispensing mis-branded drugs; and operating a drug repackaging facility that was not registered with the FDA.

Brisbane
A Brisbane company was fined $60,000 in the Brisbane Magistrates Court in July 2002 for supplying medicines not included in the Australian Register of Therapeutic Goods. The company director was also placed on a $10,000 - 3-year good behaviour bond on the same charges. This company had been supplying bovine tracheal cartilage in oral liquid and capsule form as a treatment for cancer.

Adelaide
In October 2002, an Adelaide pharmacist was convicted in the Adelaide Magistrates Court on 26 counts of illegally exporting prescription medicines and was fined $10,266. The charges related to the export, within a 12-month period, of drugs to a total value of $954,358. The Court forfeited drugs to the value of $60,147, seized by the TGA Surveillance Unit, to the Crown.

International activity

ICDRA - Hong Kong

In June 2002, the World Health Organization (WHO) sponsored the attendance of the Head of the TGA Surveillance Unit, Steve Howells, at the 10th International Conference of Drug Regulatory Authorities (ICDRA) hosted by the Hong Kong Department of Health.

Under the chairmanship of Dr Lam, Deputy Director of Health (Hong Kong), Steve Howells and Dr Toporkov, Deputy Chief of Department, Russian Department of State Control of Drugs and Medical Devices, conducted a workshop on international measures to combat the trade in counterfeit pharmaceuticals.

This was of particular importance to the WHO as it was the first time the ICDRA had been addressed by a "law enforcement officer". The WHO wished to use the ICDRA as a forum to raise the awareness of drug regulatory authorities in the use of enforcement as a means of combating the health crisis associated with the trade in counterfeit medicines. The resultant ICDRA recommendations were supportive of a strong enforcement approach and the workshop highlighted the effective regulatory controls established in Australia.

PFIPC - South Africa

In August 2002, Steve Howells, as Head of the TGA Surveillance Unit, represented Australia at the 2002 meeting of the Permanent Forum on International Pharmaceutical Crime (PFIPC) hosted by the South African Medicines Control Commission. The PFIPC is an international forum aimed at exchanging information and ideas to foster mutual cooperation in combating pharmaceutical crime. Member agencies are drug regulatory authorities, police services and other public bodies active in the enforcement of pharmaceutical crime. The PFIPC also works in cooperation with a separate Forensic Group (that provides scientific expertise), the WHO, the World Customs Organization and the International Criminal Police Organisation (INTERPOL).

At the 2002 meeting of the forum, Australia was admitted as a permanent member of the PFIPC. As reported in the November 2002 issue of TGA News <http://www.tga.gov.au/docs/html/tganews/news39/gen.htm#award>, the TGA was also presented with the Director's Award in appreciation for support and assistance provided to the US FDA Office of Criminal Investigations.

Membership of the PFIPC is of particular importance to the TGA Surveillance Unit, as the relationship with forum member agencies has proved invaluable in the investigation of major trans-national pharmaceutical crime.

Counterfeit drugs in the Mekong region

In June 2002, the WHO received funding from AusAID to implement strategies to combat the trade in counterfeit drugs in the countries bordering the Mekong region. This region experiences severe difficulty with counterfeit anti-malarial and antibiotic drugs as well as medicines used to treat HIV/AIDS and tuberculosis.

In November 2002, the WHO sponsored the attendance of the Head of the TGA Surveillance Unit to provide technical expertise to the planning workshop held in Bangkok to formulate and coordinate country and regional action plans.

Specific country plans and a coordinated action plan for those countries that comprise the Mekong region were developed. Priorities were established and funding allocated for implementation in 2003. Significant funding was allocated to these countries for expenditure on the training of inspectors by the TGA Surveillance Unit (subject to TGA approval and availability).

This project is important to Australia, as the region is a pharmaceutical export market for the Australian industry. The planned activities will protect the integrity of this market and the reputation of Australian-manufactured product.

The region is the source of starting materials imported into Australia for the manufacture of medicines and is the source of traditional and herbal finished products imported into Australia. As such, the activity will serve to protect the public health, both in Australia and in the Mekong region.

The trade in counterfeit drugs is trans-national and international cooperation between Australia and our regional neighbours is essential in combating this criminal activity.

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Reminders for sponsors

• If your product is included in the ARTG for "export only", it cannot be lawfully supplied in Australia to anyone, including duty-free stores.
• If you export therapeutic goods from Australia, you must include those goods in the ARTG in your name, even if the goods are included in the ARTG in someone else's name. You are responsible for the goods you export.
• If you change the formulation or name of a product you have included in the ARTG, it becomes a different good. You must include the "new" product in the ARTG or, if applicable, vary the details of the "old" product.
• The exemption available to homoeopathic medicines from the requirement for inclusion in the ARTG does not apply to goods of human origin.
• This exemption also does not apply to homoeopathic medicines (of any origin) for the treatment of those serious diseases, conditions, ailments and defects included in Appendix 6 of the Therapeutic Goods Advertising Code <http://www.comlaw.gov.au>.

TGA recalls

A number of consumer-level medicine recalls <http://www.tga.gov.au/recalls/index.htm> have occurred since January 2003.

TGA staffing

Advertising and Export Section, Non-Prescription Medicines Branch

The Export Medicines Unit has recently been relocated to the TGA Symonston complex and has been combined with the Advertising Unit to form a new Section in the Non-Prescription Medicines Branch.

The Advertising and Export Section is headed by Mr Craig Davies who can be contacted on phone (02) 6232 8641 or fax (02) 6232 8577.

Specific inquiries relating to:

1. Export Listings (Medicines), Blood and Tissue Product Exports or Certificates of Pharmaceutical Product should be directed to Mr Mohammed Ali on phone (02) 6232 8638 or fax (02) 6232 8399
2. The advertising requirements for therapeutic goods should be directed to Ms Maria Gonzalez on phone (02) 6232 8283 or fax (02) 6232 8659 or email tga.advertising@tga.gov.au.

Callers may also use the freecall general information line: 1800 020 653.

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Office of Chemical Safety

The Office of Chemical Safety (OCS) comprises:

• the National Industrial Chemicals Notification and Assessment Scheme (NICNAS)
• the public health risk assessment for veterinary chemicals, pesticides and other environmental chemicals
• the drugs and poisons scheduling secretariat
• the treaties and monitoring area, which gives effect to international conventions on narcotics and other controlled substances.

The OCS provides advice on potential public health risks posed by chemicals used in the community. This is achieved by conducting risk assessments and providing toxicological advice to other regulatory authorities on public health issues relating to agriculture, veterinary and industrial chemicals, and by setting health standards to ensure community safety in using domestic chemicals. The OCS also provides a national notification and assessment scheme to protect the health of the public, workers and the environment from the harmful effect of industrial chemicals.

The Director of the Office of Chemical Safety is Dr Margaret Hartley.

The OCS Sydney Office can be contacted on phone (02) 8577 8800, free call 1800 638 528.

The OCS Canberra Office can be contacted on phone (02) 6289 3200.

Office of Devices, Blood and Tissues

The TGA established the Office of Devices, Blood and Tissues on 17 January 2003. The Office brings together the Conformity Assessment Branch programs of premarket evaluation of medical devices, GMP Audit and Licensing and Recalls, with the scientists responsible for policy and evaluation in the haematology group of the TGA Laboratories Branch. As part of the restructure the GMP Audit and Licensing Section has been renamed the Manufacturers Assessment Section.

CAB and TGAL have shared the responsibility for the regulation of fresh blood since July 2000, covering GMP, recalls, technical master file review and policy advice. With the proposed development of new regulatory frameworks for in-vitro diagnostics, human tissues and cellular therapies, it was considered timely that the TGA have a more consolidated approach to the regulation of blood and human tissues.

The Director of the Office is Ms Rita Maclachlan and Dr Albert Farrugia is Acting Head of the Blood and Tissues Unit, established within the Office of Devices, Blood and Tissues.

TGA Team receives an Australia Day Achievement Medallion

Twelve TGA officers, working across three branches were recently awarded a Department of Health and Ageing Australia Day Achievement Medallion. Medallions are presented to officers who have attained a high level of achievement within the Department or who contributed to the wider community through services or adding voluntarily to the departmental role in supporting people in the community.

Australia Day Achievement Medallions were presented to the Internationally Harmonised Medical Devices Regulatory System Team from the Therapeutic Goods Administration: Rita Maclachlan, Janice Larkin, Siepie Larkin, Keith Smith, Shelley Tang, Michael Johnston, Glenn Street, Craig Davies, Michael Flood, Jorge Garcia, Anthony Gould and Andrew Muir.

The team received the award for developing and establishing the policy, legislative and information technology framework for the internationally harmonised system for the regulation of medical devices which came into effect on 4 October 2002.

The new regulatory framework adopts the principles for the regulation of medical devices agreed by the Global Harmonization Task Force. The challenge for the team was to develop the legislation and a set of operating procedures, based on the international principles, without the benefit of an existing template. Along with the new legislation, the team developed a web-based electronic lodgement system to allow industry to lodge applications to the TGA through the Internet.

The team has made an outstanding contribution to Australia's standing in the world as a regulatory leader in the field of medical devices.

TSE update

Following two rounds of consultation with industry during 2002, the final version of the document Supplementary Requirements for Therapeutic Goods for Minimising the Risk of Transmitting TSEs <http://www.tga.gov.au/docs/html/tsesupp.htm> was published on the TGA website in December 2002.

The TGA is now working with industry on the implementation program and held an initial Workshop with the four industry associations on 7 February 2003. It is proposed that further open workshops will be held in Sydney, Melbourne and Adelaide during March 2003 to assist sponsors with collating the information necessary to comply with the new requirements for TSE risk assessment of ingredients such as gelatin, milk derivatives, tallow derivatives, wool derivatives, amino acids and ruminant blood.