Risks Associated with  Compounded Sterile Products - Tip of the Iceberg?

General September 2019

Risks Associated with Compounded Sterile Products - Tip of the Iceberg?


In the last 8 years there have been numerous patient deaths associated with largely unregulated sterile compounding across the USA, including the tragic case of NECC where at least 64 people died and over 700 were infected with fungal meningitis after being infused with medical products contaminated with mold. The incident prompted an ongoing ramping up of FDA warnings and inspections and in 2019 alone the FDA have issued 9 Warning Letters to CSPs.

What is the situation in Australia?

While Australia is yet to have scandal of this magnitude, we have seen some contamination issues as large segments of the compounded sterile preparations (CSPs) industry operate outside GMP regulation.

In 2015 a cluster of patients in NSW presented with the same symptoms of bacterial sepsis all related to an unregulated complementary medicines clinic using a CSP not manufactured under GMP licensing*. The subsequent investigation and report concluded that this cluster of adverse reactions was caused by endotoxin contaminated CSPs administered as a parenteral infusion. The report also found that the source of the endotoxin was likely in the unsterile starting material from an unregulated overseas manufacturer.

Is this the tip of the iceberg?

Sterility assurance is highly dependent on the integrity and aseptic practices and controls over production process as endpoint testing is generally not viable. There is a potentially deadly risk to patients of contamination from inadequate productions controls or insufficient testing of starting materials if these controls are not put into place.

The TGA do recognise that sterile compounding has an elevated level of patient risk should something go wrong and are working together with the Pharmacy Board of Australia to provide additional oversight and guidance on Good Manufacturing Practices that are consistent with TGA regulated manufacturers of sterile products.

Manufacturers of commercial medicines, including sterile products, must register product formulations, packaging, manufacturing processes and label claims on the ARTG. These companies must also have:

  • extensive evidence of product stability to support storage conditions and shelf life;
  • sophisticated controls around sterility assurance and quality control to minimise risk of potential bacterial, particulate or endotoxin contamination;
  • submit to regular TGA inspections of their manufacturing practices and make verifiable corrective actions to maintain a GMP license.

This scheme of TGA Regulation and GMP oversight has protected the health of patients who receive sterile injections for almost 50 years with very few incidents. Nevertheless, there is room for more stringent regulation.

What can we learn from the UK?

In the UK the MHRA have introduced “Specials” legislation and GMP standards for equivalent compounding pharmacies. These manufacturers of “specials” undergo MHRA inspection, GMP licensing and government oversight in order to maintain a GMP license. Specifically, the MHRA GMPs require substantial compliance with Annex 1 (with practical compromise) for the manufacturers of sterile products.

In contrast the Australian TGA expect full compliance of Annex 1 for all licensed manufacturers of sterile products. However, the standard is not mandatory for Australian sterile compounding pharmacies and this represents a significant challenge to the stakeholders, including the Pharmacy Board, the TGA, State Pharmacy Authorities and the compounders themselves.

The Australian Government have provided an additional prescription based remuneration incentive for TGA licensed CSPs and State Hospitals give them preference during tender.

CBE works with a range of GMP licensed sterile extemporaneous manufacturers, GMP licensed CSPs and unregulated pharmacies in providing Quality Assurance programs, gap analyses, sterility assurance, risk assessments and GMP compliance programs.

Author: Steve Williams

*It should be noted that one of CBEs clients can, and do, supply this product with full GMP licensing and high levels of sterility assurance but their product was not used in this case, even though it was available.