Criteria for the clinical use of Intravenous Immunoglobulin in Australia - Second Edition

Production of normal immunoglobulins

Pooled human plasma is the starting point for the manufacture of intravenous immunoglobulin (IVIg). Plasma is obtained either by separation of whole blood or by plasmapheresis. Plasmapheresis is a process whereby only plasma is collected at the time of donation and the cellular components of blood are returned to the donor. The procedure is more time consuming for the donor. However, it does enable larger quantities of plasma to be collected more frequently from each donor.

Plasma fractionation

The plasma component of blood contains a large number of proteins, each of which performs a different role. Work conducted in the late 1930s by Dr Edwin Cohn and associates at Harvard University established a process by which the major proteins within plasma could be selectively precipitated using variations in the concentration of ethanol, salt, temperature and pH. This process, known as the Cohn Process, is a method used for the fractionation of plasma and most manufacturers use the Cohn Process or variations of it.

There have been a number of alternative processes developed for the fractionation of plasma, but only one of these has been implemented on an industrial scale. This is the chromatographic process developed by John Curling and associates in Sweden in the late 1970s. The process relies on the separation of plasma proteins based on their size and charge rather than their solubility. The CSL Biotherapies Australia plant in Australia uses a combined Cohn and chromatographic process to separate plasma fractions.

Of critical importance in the manufacture of plasma products over the past 20 years has been the incorporation of procedures that either eliminate or destroy viral pathogens. All licensed manufacturers have incorporated viral reduction procedures into their manufacturing processes and have completed studies that confirm that the possibility of a viral transmission to a patient using these products is exceptionally small. When combined with donor screening and plasma quarantining procedures now in place in all developed countries, these manufacturing procedures result in a close to zero risk of viral transmission to the recipients of plasma products.

Product safety and regulation

The Therapeutic Goods Administration (TGA) is the Australian Government body responsible for ensuring the quality, safety, and efficacy of therapeutic products manufactured and/or supplied in Australia.

A sponsor company that wishes to supply an immunoglobulin product in Australia must apply to the TGA to have its product included in the Australian Register of Therapeutic Goods (ARTG). The sponsoring company is required to support its application with detailed information relating to:

In terms of the type and extent of data required from companies, the TGA has aligned its data requirements with those of the European regulatory authority, the European Medicines Agency (EMA).

If the sponsoring company’s application is accepted, the supporting information is evaluated to determine whether the quality, safety and efficacy of the product have been demonstrated. On completion of the evaluations the application is considered by the Advisory Committee on Prescription Medicines (ACPM), an independent advisory committee composed mainly of practising specialist clinicians drawn from outside the TGA. The ACPM provides the TGA with expert advice on any issues that have arisen during the evaluation process. Once an IVIg product is registered, the sponsor company has marketing approval to supply the product in Australia. The product’s registration imposes certain restrictions and conditions on supply. For example, each IVIg product is approved for certain indications and dosage regimens based on the clinical data provided to the TGA. Sponsor companies are not permitted to promote their IVIg products for indications and at dosages not approved by the TGA. The registration also sets out specifications for the quality of the product. Any product supplied in Australia must comply with these specifications.

The TGA requires the sponsor company to submit updated post- marketing safety data at regular intervals for the first three years after registration. After this period, the sponsor is required to keep the TGA informed of any significant safety issues that arise with the product. The TGA also collects information from health care professionals on adverse reactions occurring in Australia through the Adverse Drug Reactions Advisory Committee reporting scheme.

Many of the indications for which IVIg products are used in Australia have not been approved by the TGA, as sponsor companies have not provided data to support registration. Use of a product for an unapproved indication is commonly referred to as 'off-label use'. Although ‘off-label’ use is a clinician’s prerogative, the TGA encourages sponsor companies to seek formal approval of their products for such indications. To facilitate approval, the TGA will accept applications based upon published literature. In addition, under its Orphan Drug Program, the TGA is able to waive normal evaluation fees for products intended to treat rare diseases. The registration of IVIg products for currently unapproved indications is an issue to be resolved by sponsors in association with the TGA and is beyond the scope of this document.

Virus and prion removal

In the past, all plasma derivatives have been implicated in the transmission of infectious blood-borne pathogens. The risk has decreased considerably over the past 20 years due to increased regulatory oversight.

The TGA assesses all IVIg products available in Australia for transmissible disease risk. Measures undertaken to reduce risk include ensuring plasma quality by screening and excluding high-risk donors, testing of plasma for viral markers, and viral inactivation and removal steps during the manufacturing process. Viral inactivation and removal steps during the manufacturing process are the most significant in reducing the risk of viral transmission in these products.

Different manufacturers use different viral inactivation and removal processes. The fractionation processes (cold ethanol and chromatography) are themselves efficient at removing viruses from plasma. Additional viral inactivation steps such as pasteurisation (heating in aqueous solution at 60°C for 10 hours), solvent or detergent and low pH incubation, and filtration are used to kill and remove both enveloped viruses, such as HIV and hepatitis B and C viruses, and the non-enveloped virus, hepatitis A. The TGA requires a minimum of two viral reduction steps in the manufacturing process.

The TGA uses international best-practice guidelines and the advice of the Transmissible Spongiform Encephalopathies Advisory Committee (TSEAC) in minimising prion transmission risk in plasma products on the Australian market. Each plasma derivative on the market is carefully assessed for this risk, irrespective of its source. All overseas-derived products approved for the Australian market by the TGA have a prion and viral safety profile that is at least equivalent to that of the Australian product.

To date, no known recipient of a plasma derivative has developed a transmissible spongiform encephalopathy although prion transmission was detected at autopsy in one haemophilia patient who died of unrelated causes. While prions cannot be inactivated by processes used to inactivate viruses, they can be removed through the manufacturing process, although each such purification step has to be validated to ensure prion removal. In general, alcohol precipitation results in the clearance of prions away from therapeutic proteins and into waste fractions. Similarly, chromatographic separation tends to purify therapeutic fractions separately from prions.

Intravenous immunoglobulin products in Australia

Several intravenous immunoglobulin products are currently registered on the ARTG and are available for use in Australia.

While all products are assessed by the TGA against the same criteria, each manufacturer’s IVIg preparation is a unique product carrying its own specific evidence-based indications and safety profile.

Information on individual products should be obtained from the TGA or the manufacturer.