Galenic production may represent the only chance some patients have of receiving the drugs they need; it also solves production, storage and preparation problems. Pharmacists can guarantee quality of service, availability and confidence in the final product
V Monaldi Hospital
Maria Grazia Rossetti
University Hospital of Siena
Any pathology that affects fewer than five people per 10,000 in the European Union is defined as a rare disease. There are an estimated 5,000 such diseases around the world.(1)
These pathologies present many difficulties in terms of diagnosis, therapy and treatment:
- Genetic aetiology: diagnostic approaches to biotechnologies and genetic and cellular therapy are not immediately available.
- Chronic and disabling prognosis: these diseases require high-cost therapies and create social problems in terms of patient care.
- Treatment deficiency (the status of “orphan”): the population affected by a rare disease represents a very small market and the pharmaceutical industry lacks sufficient economic incentive to produce specific drugs and/or other substances aimed at modifying the pathogenetic mechanism.
In the USA an Orphan Drugs Act has been in force since 1983 and the FDA has granted orphan status to 450 drugs.(2)
The US experience has provided a useful reference point for other countries – including Japan and Australia, where this issue was addressed in 1993 and 1999, respectively. Only in 1999 did the EU introduce regulations on orphan medicinal products, setting out rules for pharmacological therapies for rare diseases. These regulations established a range of economic and regulatory incentives aimed at improving the production and distribution of orphan products (see Table 1).
For example, a sponsor – intended to mean any legal or natural person seeking to obtain the designation of a medicinal product as an orphan – can preserve the exclusivity of market authorisation for 10 years, and the EU recognises economic incentives, such as funds allocated to the EMEA for examination fees related to orphan medicinal products.(3)
Additionally, a Committee for Orphan Medicinal Products (COMP) was created.
The EU regulation became operative in Italy with the enactment of law 279/2001; this was followed by the approval of the National Register of Orphan Medicines by the Istituto Superiore di Sanità (Higher Institute of Health), a section of the Italian Ministry of Health. The register holds the identification schedules for rare diseases and their treatment and assembles, verifies and analyses all data sent by regional centres authorised to prescribe and distribute the drugs.
The register lists 47 groups of pathologies involving 284 diseases, along with therapeutic protocols and guidelines.
At present only 98 drugs are indicated, covering only a few of the 5,000 rare diseases recognised by the World Health Organization.
Galenic production in Italy
In Italy, all trade products regularly authorised for distribution on home territory are provided free of charge (under law 279/2001) and come under the Italian A-H-B-C classes of medicines. Based on these distribution classes, drugs are supplied as follows:
- To hospital pharmacies (ambulatory administration).
- To local health units throughout the national territory, for patients included in home assistance programmes, for drugs requiring special authorisation due to availability only outside Italy or for a list of medicinal specialities with off-label indications (with the list governed by law 648/96) for home treatment.
- To community pharmacies, for those few products not included in home assistance programmes.
Other rare conditions are characterised by the lack of immediate availability of appropriate dosages or of the market production of pharmaceutical formulations. In such cases galenic products can represent a very effective alternative to industrially produced products.
Hospital pharmacists are able to solve clinical problems regarding drugs and guarantee patient care by preparing specialised products that cannot be obtained commercially, as established by the Italian 11th Official Pharmacopoeia.
Pharmacists working in hospital pharmacies with production laboratories provided with all necessary equipment in line with good manufacturing rules – the Italian equivalent to GMP for industries – have been authorised to undertake the production, packaging and control of orphan products.
In particular, over the last few years, galenic production of “unmarketable” drugs has increased in Italy.
The Santa Maria alle Scotte University Hospital of Siena, home of the Italian Centre for the Treatment of Cerebrotendinous Xanthomatosis, has been producing the orphan drug chenodeoxycholic acid in 250 mg capsules to treat cerebrotendinous xanthomatosis (CTX), a rare autosomal recessive lipid storage disease.
This drug is the only therapy for CTX. The disease is characterised by widespread tissue deposition of two neutral sterols, cholestanol and cholesterol, resulting in tendinous xanthomas, juvenile cataracts, progressive neurological defects and premature death from arteriosclerosis.(4,5)
During the 1980s, clinical studies demonstrated that patients affected by CTX had a significant decrease in biosynthesis of chenodeoxycholic acid.6–8 Administration of this substance – initially introduced for the chemical dissolution of gallstones – prevented the progression of the disease and yielded good results compared with other therapeutic approaches.(9,10)
However, the commercialisation of chenodeoxycholic acid was interrupted due to its low economic returns for the industry, and the discovery of new and better molecules for the same therapeutic indication.
At the University Hospital of Siena, the substance is produced in the hospital pharmacy’s galenic area. Raw materials are purchased from an industry that produces chenodeoxycolic acid as an intermediate metabolic product of the synthesis of ursodesoxycholic acid. The galenic area of the pharmacy has six laboratories, two devoted to nonsterile and four to sterile production.
Each product respects the standards prescribed by the national pharmacopoeia, with all processes standardised to guarantee effectiveness and safety. Furthermore, three hospital pharmacists, two nurses and four biomedical laboratory technicians are employed and are regularly involved in continuous education activities so as to maintain staff expertise in the production process.
Therapeutic effects and patient follow-up guaranteed by the reproducibility of the formulation are monitored by an international group of specialists in neurology coordinated by Professor Antonio Federico of the University of Siena − one of the world’s top specialists in this disease.
The production process is very straightforward; to produce 3,000 capsules requires the blending of 750 g of chenodeoxycholic acid, 300 g of excipient and a small amount of colorant. The blending phase is carried out using a mechanical blender, following which the capsules, size T00, are filled.
The finished products undergo accurate analysis to ensure uniformity of the mass in accordance with Italian regulations and have an expiry date of six months from the preparation date.
Secondary packaging must also be carried out (see Figure 1). The ethical committee participated in drawing up an information leaflet summarising the drug’s characteristics (see Figure 2).
The final product is therefore very similar to marketed specialities for patient use and the use of blisters protects the stability of the galenic formulation.
Orphan drugs are currently prepared for 40 Italian patients at the Department of Neurological and Behavioural Studies at the University Hospital of Siena.
Distribution of the drugs is free, with patients receiving capsules at the prescribing centre, on the distribution ward of the hospital pharmacy or at the local health unit’s pharmaceutical department. The local health unit stipulates an agreement with the hospital (the contract is based on chapter 12 of the pharmacopoeia’s good manufacturing rules) and receives the packaged drug, delivered from the hospital pharmacy.
Certain other drugs considered to be orphans due to lack of commercial availability but with no other available therapeutic alternative are prepared in the galenic area. Such drugs include L - citrulline in powder formulation (for two patients with ornitin-transcarbamilase deficit), ubidecarenone, chloral hydrate and eyewash of ciclosporin and voriconazole.(11)
In such cases, galenic production may represent the only chance patients have of receiving the medicinal product they need.
The pharmacist’s involvement should not be undervalued, as it can guarantee quality of service, immediate availability and assured confidence in the final product.
In fact, clinical galenic production provides the solution for production problems, storage, preparation and individually prepared dosages, especially in the wide field of orphan drugs. ■
Santa Maria alle Scotte University Hospital of Siena:
Department of Neurological and Behavioural Studies
T: +39 0577 585763
T: +39 0577 586321
1. Pharmacol Res 2000;42:1.
2. Pharmaeconomics 1997;12:312-26.
3. European Council. Orphan Regulation (141/2000). Brussels: European Council; 1999.
4. J Lipid Res 2007;48(5):1167-74.
5. J Lipid Res 2007;48:185-92.
6. N Engl J Med 1984;311:1649-52.
7. Arch Neurol 1992;49:469-75.
8. Dev Neurosci 1991;13:371-6.
9. Neurol Sci 2004;25:135-91.
10. Neurology 2001;56:695-6.
11. Ragiufarm 2005;90:6-12.