Counterfeit drug detection

Placement with the US FDA

TGA has been developing relationships with other regulatory agencies to share information on counterfeit and sub-standard medicines and laboratory methods for their detection. In Issue 26 of the TGA News it was reported that arrangements were being made for an extended placement of a senior officer from the Chemistry section with the US FDA National Centre for Forensic Chemistry (FCC) in Cincinnati. This laboratory is at the forefront of pharmaceutical and food forensic analysis and is equipped with state of the art instrumentation.

Robert Prestridge, a senior scientist in the section, spent six weeks at the FCC working on the development of analytical methods for the detection of counterfeit active raw materials. The focus of the work was on the detection of subtle differences between materials, which are not addressed by the usual pharmacopoeial test methods. Determination of trace levels of contaminants can be used to characterise a substance and provide a source-specific 'fingerprint'. Examples include solvent residues detected by gas chromatography-mass spectrometry and synthesis-related impurities detected by liquid chromatography-mass spectrometry.

The knowledge gained and networks formed during Mr Prestridge's placement will enhance TGA's technical capabilities to detect counterfeit pharmaceuticals. Following his return to TGA, Robert has spent some time working jointly with FCC scientists to further refine the test methodology. This type of work is of international importance. TGA will continue to be a part of the international collaborative efforts to address the problems associated with counterfeit and sub-standard pharmaceutical products.

TGA Presentation in China

In August 1998, the Peoples Republic of China established the State Drug Administration (SDA) to act as the national regulatory agency for medicines. Steve Howells (TGA surveillance unit) and Larry Kelly (Chemistry section) were recently invited to give presentations to the newly established authority on the subject of counterfeit and sub-standard medicinal products. The two officers spoke of TGA's role and experiences in this area and gave examples of how such products are detected and regulated in Australia. The trade in pharmaceuticals is an international one and as such so is the trade in counterfeit drugs. Liaison between national drug regulatory authorities, such as this visit, greatly assists the TGA in combating the trade in counterfeit products and serves to protect the integrity of Australia's pharmaceutical export markets.

Discussions with World Health Organization, Geneva

Dr Elaine Walker, Director of the TGA Laboratories, represented the TGA at the Annual Meeting of the WHO Global Training Network (GTN) in Geneva 23-25 February. WHO Head Office, the six WHO regional offices and 14 training institutes meet annually to coordinate the deliver of training designed to achieve worldwide vaccine quality and supply.

As part of its contribution to the GTN, the TGA has developed a curriculum for training staff of other National Control Authorities (NCAs) that are responsible for regulating vaccines. The course, which is accredited by the WHO, is designed to strengthen the capacity of NCAs to ensure that vaccines marketed in the respective countries are of acceptable quality, and are safe and efficacious. It will be offered for the first time later this year to trainees selected by WHO. This work was made possible by financial support from WHO and AusAID.

In addition, Dr Walker had useful discussions with WHO staff involved in regulation and standard setting for essential drugs, vaccines, blood products and biologicals. A recent reorganisation of WHO has brought together most WHO staff involved in these activities in a single group called the Health Technology and Pharmaceuticals Cluster. This group will provide TGA with more direct access to an important means of harmonisation of international standards.

Preservative efficacy in multidose pharmaceutical preparations

Sterile products presented for use in multi-dose containers and non-sterile dosage forms, particularly those intended for multiple use, unless inherently antimicrobial, should contain antimicrobial preservatives. Adequate preservation should prevent or inhibit the growth of microorganisms which may pose a risk of infection to the user or result in product degradation. International regulatory authorities agree that preserved products should be subjected to suitable tests to determine the adequacy of the preservative system. There have been differences, however, in the nature of the recommended test procedures and the assessment of results.

Harmonisation of international preservative efficacy requirements is currently being addressed by the International Committee on Harmonisation (ICH). At present there are minor differences between the European Pharmacopoeia (EP) / British Pharmacopoeia (BP) and the United States Pharmacopoeia (USP) in relation to the challenge organisms used. However there are major differences in sampling times and in criteria for acceptance, though the USP test now includes different criteria for separate categories of products. The USP sampling schedule for all product types has an initial sampling timepoint at 7 days which is considered by the EP/BP and the TGA to be inadequate for some products, eg. multidose injections with open shelf-life of 24 hours.

Historically the TGA has required compliance with the USP Antimicrobial Effectiveness Test as a minimum but has encouraged compliance with the more stringent requirements of the EP/BP (Resolution No. 12 of the 18th Therapeutic Goods Committee (TGC) Meeting, 22nd March 1985). In 1993 the BP/EP introduced two levels of compliance for preservative efficacy recognising that it is not always possible for all products to achieve the more stringent requirements. Given these improvements in relevance and flexibility, the TGA will propose to the Therapeutic Goods Committee (TGC) that the EP/BP approach be adopted. During product development, the stability of the preservative throughout the product closed shelf-life and antimicrobial efficacy throughout the open shelf-life should both be established. Demonstration of chemical stability of the preservative is insufficient since "...other chemical and physical changes in the finished product may influence the efficacy of the antimicrobial preservative..." (CPMP/CVMP/QWP/115/95 Note for Guidance on Inclusion of Antioxidants and Antimicrobial Preservatives in Medicinal Products, Jan 1998).

For many years, the TGA has evaluated the adequacy of the preservatives in multidose injectable and ophthalmic products over the open shelf-life period. Evaluation criteria have been reviewed and found to be consistent with CPMP/QWP/159/96 Note for Guidance on maximum shelf-life for sterile products for human use after first opening or following reconstitution, July 1998.

To support an open shelf-life period for multidose injectable and ophthalmic products (including contact lens care solutions), TGA requests results of either repeated microbial challenges to the product or microbial limit tests conducted on containers that have been partially used by patients over the full open shelf-life period. It should be noted that chemical analysis of preservative alone is not acceptable, as it does not provide an accurate indication of antimicrobial activity.

There are currently no specific international or pharmacopoeial test methods specified for repeated microbial challenge tests during open shelf-life. However, the draft International Standard ISO/DIS 14730 Ophthalmic Optics - Contact Lens Care Products - Antimicrobial Preservative Efficacy Testing and Guidance on Determining Discard Dating describes a test procedure and performance criteria for preservative efficacy over an open shelf-life period of 28 days or longer. In addition the informative annexes B (Discard date procedure I) and E (Discard date procedure IV) to the standard outline acceptable procedures for establishing preservative efficacy for discard dates for contact lens care products that are over 28 days.

These test methods most closely mimic the in-use situation as they involve repeated microbial challenges over the open shelf-life period. The test protocols in this draft ISO standard and the methodology in the EP/BP may be modified and applied to pharmaceuticals to justify the labelled open shelf-life period (discard date).