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Drug stability in the clinical environment

Pharmaceutical companies perform stability studies that form an integral part of the information provided to regulatory authorities in support of a drug’s marketing authorisation. However, little attention is paid to the practical situation and how these drugs will be used in clinical practice.

In many cases, the results of these studies are insufficient and do not meet the need for information that hospital pharmacists require. Hospital-compounded drugs require well-documented data on chemical and physical stabilities after reconstitution, after further dilution with different diluents, at different concentrations, and under particular storage conditions. Data provided in the Summary of Product Characteristics (SPC) are frequently limited to 12–24 hours in-use stability. Hence alternative scientific sources that can integrate information into SPCs, and therefore extend stability beyond 24 hours, are necessary. Therefore collecting available evidence on practical stabilities in the clinical environment from shared databases, as well as conducting stability studies as part of the responsibilities of hospital pharmacy teams, should be undertaken. 

When reviewing SPCs, the general assumption is that a drug will be dissolved before use, and presumably administered on a clinical ward. But the situation for hospital compounded drugs is increasingly changing. Making a drug ready for administration to a patient is based on risk assessment of the quality of the preparation processes,1 and on the quality and safety assurance requirements for medicinal products prepared in pharmacies for individual patients’ needs. When the reconstitution is considered to be low risk, it can be carried out on the ward; otherwise it should be prepared in centralised sterile compounding units or, in the case of hazardous drugs, in biological safety cabinets in specific compounding units. 

In addition, the availability of a limited number of dose strengths/vial sizes (and for some drugs, just one size) gives rise to a demand to use the available drug more efficiently and avoid waste when compounding a personalised dose.

There is a strong need to fill any gap between available data in the SPC and practical needs. The industry targets stability research to fulfil licensing requirements. The storage conditions and the lengths of studies chosen are often not sufficient to cover storage, shipment, and subsequent use. However, clinical needs might require more information regarding in-use stability data. Pharmaceuticals start a new life once applied in clinical practice. Nowadays, in most hospitals, reconstitution and preparation takes place in centralised compounding units, under a controlled and validated environment, with expert staff.

When compounding sterile preparations for patients in these units, a number of factors need to be taken into account including: dose accuracy; sterility assurance; contamination safety; and stability under practical clinical conditions.

This leads to quality products from bacteriological, dosage and contamination perspectives, as these patient-ready preparations have been prepared according to good manufacturing practices.

This would allow:

  • Preparation in advance for a whole treatment cycle
  • Optimisation of workload, and reduced stress for pharmacy and nursing/technician staff 
  • Preparation of medicines in advance to cover 7-day/24-hour availability (for example, over weekends and holiday periods)
  • Increase efficient use of existing dose strengths and reduce waste
  • Dispensing in ambulatory devices for continuous infusion over extended periods
  • Batch preparation to allow dose-banding.

In general, a well-organised compounding unit allows for more efficient, flexible and cost-effective use of the drugs, permitting end product testing and quality control.

A relatively new development is the principle of dose-banding, through which the pharmacy produces pre-defined strengths of ready-to-use products that can be administered to a patient at any required time. The dose strengths are selected such that with these products, most dosage needs can be met with acceptable accuracy (for example, ±10%).

To increase the quality of hospital preparations, it has to be taken into consideration that drugs can be prepared in a variety of containers, ambulatory devices and different tubings, etc. Supporting data regarding optimal storage conditions and the sensitivity of a product when a controlled temperature chain is broken are required.

It could be argued that sufficient guidance is available, for example, in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), European Medicines Agency (EMA) guidelines, or EU Pharmacopoeia monographs;2–5 however, these guidelines and monographs have been designed for different purposes. The ICH guidelines have the aim of regulating quality of marketed drugs in an international context. EU Pharmacopoeia monographs often refer to raw materials and offer no solution for marketed products under practical conditions. However, methodologies proposed in these materials might be helpful in developing and supporting methodology of in-use stability in practical situations. 

A different approach has been taken by the USP 27th review, Chapter 7976 and PIC/S Guide PE 010-3,7 setting standards that are specifically applicable in the practice environment, and the recent update of the US Pharmacopeia on hazardous drugs.8 

The limited stability data required for licensing purposes do not always cover the many ways in which medicines are handled in modern clinical environments. As a consequence, there exists an urgent need for additional stability data to support these practices.

It would be ideal if pharmaceutical companies would generate stability data in their drug development programmes to allow for more flexible clinical applications, or would make data that have been generated beyond the official package insert available to the pharmacist community. However, as long as such data are lacking, in the quality required by hospital pharmacists, we should take responsibility to engage in systematic research programmes to support our practical needs. This means that it is necessary to establish validated assays for a wide range of drugs and subsequently test the different ways we are compounding and storing prepared medicines for periods extending beyond the official durations detailed in the package inserts.

  1. Council of Europe. Committee of Ministers on 19 January 2011; Resolution CM/ResAP(2011) on quality and safety assurance requirements for medicinal products prepared in pharmacies for special needs of patients. 
  2. European Medicines Agency. Note for guidance on maximum shelf-life for sterile products for human use after first opening or following reconstitution. 1998; EMEA, CPMP.
  3. European Medicines Agency. Note for guidance in in-use stability testing of human medicinal product. 2001; EMEA, CPMP.
  4. ICH Harmonized Tripartite Guideline for Stability Testing of New Drug Substances and Products. September 23, 1994 [ICH Q1A].
  5. Council of Europe. European Pharmacopoeia.
  6. Pharmaceutical Compounding: Sterile Preparation USP 27th review; Chapter 797. 
  7. PIC/S Guide to good practices for preparation of medicinal product in pharmacies. PIC/S Guide PE 010-3, Pic/S Guide to Good Practices for the Preparation of Medicinal Products in Healthcare Establishments (2014).
  8. US Pharmacopeia 2016. Hazardous drugs: handling in healthcare settings. Chapter 800 (USP 39-NF 34)

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