Stability Studies: A Scientific Mission of the Hospital Pharmacist

The preparation of medications is a fundamental part of the pharmacist’s profession. Today, hospital pharmacists prepare mainly sterile products i. e. anticancer drugs, antibiotics, medications for intensive care units in Centralized Intravenous Additive Services (CIVAS), eye-drops or parenteral nutrition especially for pediatrics. Oral solutions are prepared for patients who have difficulties to swallow such as pediatric or elderly patients. The more traditional preparations (such as capsules or unguents) are still carried out but today represent a small part of the activity of pharmacotechnics.

Nevertheless, for all these preparations, hospital pharmacists need stability data to assign a shelf life to their compounded products.

The need for stability studies is huge and this field of activity is a part of our mission defined in the official Good Manufacturing Practices (GMP) for compounding pharmacies. These GMP guidelines are similar in many countries. For example, in the French guidelines, the text makes it clear in chapter 1 that “The shelf life of the preparations can be determined by using bibliographic references or by performing stability studies.” and in chapter 2 “Control”: The hospital pharmacist has various missions including … “the control of stability” [1].

Here is a non-exhaustive list of examples of stability studies which can be performed by hospital or university teams:

1. intravenous (IV) mixtures used in intensive care units or oncology,

2. parenteral (IV or subcutaneous) new monoclonal antibodies that are often prepared in advance or can be conserved if the prescription is cancelled after the preparation,

3. oral solutions for pediatrics or geriatrics,

4. very expensive drugs in the case of limited stability data provided by the manufacturers, to save money,

5. dilutions of antibiotics in unusual solvents such as peritoneal dialysis solutions,

6. anticancer drugs at elevated temperatures for intraperitoneal hyperthermic chemotherapy,

7. leaching of plasticizers into the solutions from containers. Diethylhexylphtalate (DEHP) is a well-known example of potentially toxic additive used in polyvinyl chloride containers but other less known products can leach into the solution and be potentially harmful to the patient,

8. etc.

However, stability studies performed by hospital pharmacy teams or university teams should be of high quality. This is why specific guidelines have to be followed and a good training is needed. Thus, the international Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) give recommendations for validation of analytical methods and stability studies. There are 6 specific ICH guidelines (Q1A, Q1B, Q1C, Q1D, Q1E and Q1F) dedicated to stability. These guidelines have been proposed to assure the quality of the prepared products besides 11 other groups of guidelines in this area. However, these guidelines are written for industry and not for hospitals [2]. This is why specific recommendations for stability studies in hospital pharmacies have been written by various expert societies [3, 4]. In addition, a new university degree devoted to stability entitled “Stability of pharmaceuticals: fundamentals and practices” will open in 2018 in university of Paris, France.

The following areas will be covered during the courses (in the forms of lectures and seminars)

1. Chemical and physical stability of active pharmaceutical ingredients: degradation routes, physical changes in the solid state, reaction kinetics, stabilization strategies…

2. Stability of antibody-targeted therapies: chemical, physical and in vivo pathways of their degradation, kinetics, in-use stability…

3. Stability of conventional and specific dosage forms.

4. Analytical and experimental methodologies.

5. Stability regulation and practices.

A website named stabilis^® (http://www.stabilis.org/) is dedicated to presenting and sharing stability data extracted from a worldwide publication database. A new function of this database called “Research teams” opened in 2017 and presents the list of all research teams who perform stability studies and have articles selected in the database. 594 teams are registered in Stabilis and 140 are still active (publications during the past 5 years). The e-mail address of the team allows the users to contact the person responsible for the team. Stabilis^® users also have the possibility to propose ideas of stability studies on the Stabilis website.

All these initiatives should undoubtedly stimulate this part of our scientific activity.

In this special issue on stability, five articles show the diversity of stability studies, which can be performed in our laboratories. The readers will find the first stability study on decitabine solutions where the authors have demonstrated the interest to freeze the solution for this temperature-sensitive drug, a stability study of epinephrine allowing in advance preparation, an example of a stability study for a morphine and baclofen mixture, another one on a sorption study between ophthalmic drugs and multi dose eyedroppers in simulated use conditions and the last one for an oral solution of dexamethasone syrup.

I would like to finish this editorial with a sentence of the great Dr. Lawrence Trissel, who dedicated his research work to obtain stability data on dozens of compounds.

“Science is a part of our mission and the stability and compatibility applied to the clinical setting contribute to patient safety and is clearly a part of ‘clinical pharmaceutics research’” [5].