Patients with rare diseases are often confronted with the fact that effective pharmacotherapeutic treatments are unavailable. For some (ultra) rare diseases, medicines are simply not developed because the number of eligible patients is too small for a financially beneficial product (Joint evaluation of Regulation (EC), 2020). This problem jeopardizes the health of patients with rare diseases. Pharmacy compounded formulations can provide an alternative route for effective and safe pharmacotherapy when authorized orphan medicines are unavailable or unsuitable (Dooms and Cavalho, 2018).

Pharmacists are healthcare professionals with knowledge on medicine compounding and by European law they are certified to compound medicines for patients with a medical need. Although pharmacy compounded formulations are often perceived as cheaper “copies” of, or of lesser quality than authorized medicines, they do have to comply with strict laws and regulations to ensure product quality and patient safety. Unfortunately, practical guidelines on how to implement pharmacy compounded formulations for patients with rare diseases are limited.

In this article we share our experiences and perspectives to provide practical guidance on the critical steps for the development and implementation of pharmacy compounded formulations for patients with rare diseases. The critical steps are illustrated by two cases we worked on in the past years: pharmacy compounding of chenodeoxycholic acid (CDCA) capsules for patients with cerebrotendinous xanthomatosis (CTX) and cholic acid (CA) capsules for patients with rare bile acid synthesis defects (BASD). For both products the assessments and conclusions for each critical steps are summarized in Table 1. Based on our experiences, we developed a flowchart to provide practical guidance for the development and implementation of pharmacy compounded medicines using starting materials (Figure 1).

There is worldwide no uniform legislation for compounding by pharmacists. For clarification, in the EU each member state formulates its own legislation for pharmacy compounding. To ensure safe and effective treatment of patients, pharmacy compounded medicines have to comply with high quality standards that are in line with national guidelines based on EU Directive 2001/83 (Directive 2001/83/EG). Therefore, pharmacists have to verify whether active ingredients and excipients comply with the European Pharmacopoeia (Ph. Eur.) and that the production facilities, qualification of personnel and documentation are in compliance with EU Directive 2001/83 (Directive 2001/83/EG). Besides the compliance of the quality control (QC) of starting materials, also the quality of the medicinal product has to comply with the specifications of the Ph. Eur. As the CA and CDCA were developed and made in the Netherlands, we worked according to the Dutch law (Dutch Medicines Act Decree).

In case a patient is likely to benefit from a pharmacotherapeutic intervention, but authorized medicines are unavailable, there is a so-called “unmet medical need”. In this situation the physician can explore other routes, e.g., off-label prescribing of an authorized medicine. When off-label use is not feasible, the physician can request a pharmacist to compound the specific medicine.

The decision to develop a pharmacy compounded formulation is preceded by a risk-benefit assessment (Resolution CM/Res, (2016), KNMP, 2016). First, the pharmacist assesses whether the requested pharmacotherapy has an added value for the patient based on expected treatment efficacy and safety, as well as the technical quality of the compounded formulation (Figure 1A). Eventually, the possibilities and uncertainties should be discussed with the prescribing physician and the patient.

The pharmacist is responsible for the quality of the compounded formulation and is therefore inherently responsible for the quality of the active pharmaceutical ingredient (API). This responsibility starts with the selection and auditing of suppliers and all involved parties (Figure 1B). In other words, the pharmacist needs to verify that each step in the supply chain meets the valid requirements for that specific part of the chain. . It must be ensured that the API is produced according to Good Manufacturing Practices (GMP) and that transport is according to Good Distribution Practices (GDP). For common APIs, the wholesaler has already performed the supplier selection and audit, and can often share required documentation with the pharmacist.

However, for the treatment of rare diseases, APIs are usually not readily available at wholesalers. Consequently, selection and qualification of an API supplier has to be performed by the pharmacist himself or it can be outsourced to a qualified third party.

APIs must comply with the general Ph. Eur. Monograph for “Substances for Pharmaceutical Use” (Ph.Eur., 2018b) (Figure 1C). Knowledge on the API synthesis route is required to determine how QC of the API should be performed. For setting up adequate QC analysis, information on the use of heavy metals, solvents and/or reagents during the API production process is required. Knowledge on the stability and decomposition profile of the API is also required as storage conditions can affect the quality of the API. The Drug Master File (DMF) of the manufacturer is the main source for information on API production, specifications, QC and stability. Eventually, the content and purity of the API should be guaranteed and possible harmful substances must be within the permitted limits or absent. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has drawn up specific guidelines for related substances, metal impurities, residual solvents and microbiological quality (ICH, 2006; ICH, 2017; ICH, 2019; ICH, 2021)

When, for whatever reason, the synthesis route of the API is unknown, a broad pharmaceutical QC analysis should be set up according the general substance monographs of the Ph. Eur. and ICH guidelines, and must be in line with appropriate quality risk management principles (Ph.Eur., 2018b; ICH, 2015) If appropriate QC of the API cannot be guaranteed, then the assessment must be made that one should refrain from using the API (Figure 1B).

In some situations it is possible to adapt an authorized medicine for a pharmacy compounded formulation. For patients with rare diseases however, an authorized medicine is often unavailable and the pharmacy has to use starting materials. Either way, the chosen formulation determines the quality specifications and QC analysis of the medicinal product. The Dutch Pharmacists’ Association (KNMP) published a formulary handbook (also available in English) (Bouwman-Boer et al., 2015a) for the formulation, compounding and QC analysis of some of the most common dosage forms (i.e. orals, rectals, parentals, dermatics, oculars and nasals).

The QC of a medicinal product consist of three aspects: product validation, process validation and QC analysis (Figure 1D). To set the quality parameters of the medicinal product, any interaction between API, excipients, and production steps has to be assessed during the product development (Bouwman-Boer et al., 2015b). Limits need to be specified for critical production parameters (e.g., blending, apparatus, weighing, filtration, filling, volume control) and quality parameters (e.g., appearance, content, pH, (microbiological) impurities, uniformity) to ensure the quality of the medicinal product (Bouwman-Boer et al., 2015b). During the product validation the impact of critical parameters on product quality has to be studied and it should be assessed whether the specified limits are set accordingly (Bouwman-Boer et al., 2015c).

A validated process is required to ensure that the production process is robust enough to manage critical production steps and to ensure that the medicinal product is consistently produced with the intended quality (Bouwman-Boer et al., 2015d). Whereas product validation is location independent, process validation is facility-based and so the following parameters should be taken into account: facility properties, equipment, utilities, automated systems, cleaning methods, analytical methods, and training of personnel (Bouwman-Boer et al., 2015c; Bouwman-Boer et al., 2015d).

Once all critical production- and quality parameters have been determined, a QC analysis protocol for the medicinal product can be drafted. For the most common dosage forms, the primary quality parameters and specifications are described in the Ph. Eur. There is a general monograph “Pharmaceutical Preparations” (Ph.Eur., 2013) and for the most common dosage forms a specific monograph exists. In principle, the medicinal product should comply with both monographs. There is a practical guideline for pharmacists on how to perform QC analysis on medicinal products (Bouwman-Boer et al., 2015a).

Pharmacy compounded medicines can provide an essential and safe option for the treatment of patients with rare diseases when authorized orphan medicines are unavailable or unsuitable for the intended use. The flowchart we developed (Figure 1) provides practical guidance for the development of pharmacy compounded formulation.

Recent evaluation of the “Orphan Regulation” (Regulation 141/2000) and the “Paediatric Regulation” (Regulation, 2006)—both adopted by the European Commission in 2000 and 2006 respectively to stimulate the development of orphan medicines and paediatric formulations—showed that the accessibility of orphan medicines varies considerably across EU member states (European Commission, 2020). Differences in national prices, reimbursement systems, prescribing behaviour, and pharmaceutical companies’ strategies, are indicated as the main causes for unequal accessibility within the EU. This is also the case for CDCA and CA treatment in the Netherlands. Reimbursement for CDCA treatment was stopped when the price increased 500 fold (Dutch National Health Care Institute, 2018). For CA, the authorization holder has not applied CA for reimbursement in the Netherlands. Pharmacy compounded CDCA and CA capsules provide a suitable and financially feasible alternative for patients. Next to this, pharmacy compounded formulations allow for more personalized treatment. In particular in the case of CA treatment, the pharmacy compounded formulations provided more flexibility in dosages, facilitating easy dose adjustments based on serum biochemical profile, liver transaminases levels and side effects (Table 1).

Pharmacy compounding especially provides improved treatment accessibility for children with rare diseases. Neither the “Orphan Regulation” nor the “Paediatric Regulation” has led to a boost in the development of innovative medicines for children with rare diseases (European Commision, 2020). Moreover, authorized medicines often have to be adjusted for children as most dosage strengths have been standardized for adults. CDCA Leadiant^® for example, is authorized for the treatment of CTX patients from 1 month old, with a starting dose of 5 mg/kg/day divided over three doses (Leadiant, 2017). However, CDCA Leadiant^® is only available in 250 mg capsules (Leadiant, 2017) and is therefore unsuitable for younger patients. As clinical studies show, early start of CDCA treatment is critical as it can improve disease prognosis and can reverse—or prevent—the development of neurological symptoms (Salen and Steiner, 2017; Stelten et al., 2019; Verrips et al., 2020). As rare diseases are often diagnosed in childhood, it is extremely important that peaditric formulations are made available.

There are several challenges in pharmacy compounding for rare diseases. It is increasingly difficult to source APIs that comply with EU laws and regulations as manufacturing of QPI; s has shifted to Asia, the number of API suppliers is limited and supply chains are often protected by market authorisation holders. In our opinion, pharmaceutical companies should recognize pharmacy compounded medicine as an addition to their products and not as a thread. Especially when dosage forms are needed that are not commercially available. We therefore encourage sharing of information between pharmacists, health care providers, pharmaceutical companies, health insurers and governments. Furthermore, pharmacists involved in compounding for patients with a rare disease should share information and knowledge on their developed formulations. Especially because there is no harmonized regulation worldwide for pharmacy preparations. Moreover, the costs of pharmacy compounded products will increase as sourcing of API, development of products and quality control, maintaining facilities takes more and more time and effort. Sharing this information across borders can help improve the inequality in accessibility of orphan medicines between countries.

All involved parties in the health care sector have the responsibility to keep healthcare accessible and affordable, and should support initiatives that contribute to that cause. In the Netherlands we see positive developments in the recognition of pharmacy compounded formulations in pharmacotherapeutic treatments for patients. This is important, because less pharmacists are interested in compounding as the revenues don’t compensate the necessary investments. It should be acknowledged that pharmacy compounded medication is an essential part of the treatment of patients with a rare disease.