What is quality of medicines?

In this issue of the Journal, Bell and colleagues report a massive overdose of cholecalciferol caused by a compounded medicine with 1000-fold greater than intended dose. This was due to confusion of units, with the patient receiving 15 mg rather than the intended 15 μg daily. This is not a unique case, for example an under-dosing error affecting several patients was reported recently in Australian Prescriber. The quality of medicines was regulated 107 years ago in the United States by the Safe Food and Drug Act of 1906. The legislation was primarily driven by the need to control food quality. Misrepresentation was common and illness due to rotten or contaminated food endemic. Medicines of the time were often marketed as dietary supplements and were included in the legislation. ‘Patent medicines’ were widely used and many were ‘contaminated’ by alcohol, opioids, acetanilide and a range of other compounds. During the 20th century, manufacturing processes improved with increasing sophistication of manufacturing and of regulatory processes. The quality of medicines came under increasing scrutiny: from regulators of medicines, such as the Australian Therapeutics Goods Administration and the New Zealand Medicines and Medical Devices Safety Authority; from regulators of manufacturing, industry and labour; and from standards organisations, such as the International Organization for Standardization. Responsibility for administering such regulations is sometimes regional (state or city) and sometimes national. In most countries, well-established national bodies regulate medicines. With production being global, aspects of this are increasingly regulated by international agreements administered by trade and customs bodies. However, not all medicines are produced by large-scale manufacturing, and not all are governed by the same regulations. There are several reasons for this. For example, some products are less stable than others and need to be administered within a short time of preparation, while other products are produced in very small quantities or have ‘individualised’ preparations or doses. Most major hospitals prepare a range of medicines on site, for example many cytotoxic preparations. In the community, compounding pharmacists prepare a range of products to meet local ‘need’, for example a different dosage form may be required, such as a liquid form for a child, or a tablet free of added excipients or preservatives in a patient with a specific allergy. In Australia, pharmacists not specialising in compounding services still compound on average three products per week and the 10% of pharmacists specialising in compounding average 25 products per week, just under 1% of all prescriptions. In Australia, prescription medicines are registered in the Australian Register of Therapeutic Goods under the Therapeutic Goods Act 1989 (‘the Act’). Regulations under the Act (Therapeutic Goods (Manufacturing Principles) Determination no. 1 of 2013 MP1/2013) require adherence to ‘good manufacturing practice’ (GMP) according to the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme. This details principles and procedures to ensure that manufactured medicines are of high quality. However, medicines that are extemporaneously compounded for a particular need of a particular patient are exempt from the Act. The risks of the lightly regulated production of medicines by compounding pharmacies were highlighted last year by 37 deaths and 590 reported cases of fungal meningitis from ‘contaminated’ medicines. Preservative-free methylprednisolone acetate produced by the New England Compounding Center was contaminated by Exserohilum rostratum. Similar cases of fungal meningitis due to contaminated methylprednisolone acetate from a compounding pharmacist had been reported 10 years earlier in New Carolina. Assuring quality of compounded medicines is difficult. A community pharmacy cannot meet all GMP requirements when compounding a single drug for a single patient’s therapeutic needs. However, the manufacturing risks are the same regardless of scale, including cross contamination, misidentification of starting materials and weighing errors. This risk to patients increases with the complexity of compounding and the number of patients exposed. In Australia, both complexity and scale of compounding are increasing. A physician usually focuses on prescription medicines, but there are other products relevant to our patients. Complementary and alternative medicines are products used with therapeutic intent and are a multimillion dollar industry in Australasia. They are regulated more lightly than medicines, and their make-up and quality are often uncertain. That pharmacists’ incomes depend on products with unknown effects sold as therapies (complementary and alternative medicines and ‘health supplements’) bs_bs_banner