Like any pharmaceutical dosage forms, they are required to meet the pharmaceutical quality standards as described in pharmacopeias and to be safe for the intended purpose of use.1,2,3
In addition to being sterile, parenteral preparations must be pyrogen-free. Sterility can be achieved by different processes of sterilization that should be appropriate to the formulations4 while the pyrogen-free aspect will require, if no depyrogenation process is used during the preparation of the sterile drug products, the use of pyrogen-free pharmaceutical ingredients—drug substances or API (Active Pharmaceutical Ingredient) and excipients.
They are usually supplied in single dose glass or plastic containers. PVC is nowadays less recommended. More and more they are being supplied in pre-filled syringes or pens to facilitate ease of use.1 This article will describe the main challenges encountered during the formulation of parenteral preparations, as well as solutions meeting the formulator’s needs.
Properties of parenteral preparations
Parenteral preparations are intended to be administrated through the human or animal body, either by direct injections, for example, bolus intravenous (IV), intramuscular (IM) or subcutaneous (SC), or by infusion with a controlled infusion rate or by direct implantation through IM or SC.
They must meet the following minimum compendia criteria1,2,3:
- To be sterile and pyrogen-free;
- To be clear or practically exempt of visible particle and to be free from sub-visible particles as required by pharmacopeias EP, USP and JP;
- No evidence of phase separation for the emulsions, or aggregates formation for aqueous dispersion such injectable Mab (monoclonal antibody) preparations; and
- In the case of suspensions, the use of appropriate particle size and any sediment should be readily dispersed upon shaking to give stable formulations and ensure the correct dose to be withdrawn and injected.
- To make the preparations isotonic with respect to blood (glucose/dextrose, mannitol, sodium chloride);
- To adjust the pH to the physiological one (mineral or organic acids or salts);
- To prevent the degradation of the drug substances (stabilizer);
- To ensure or increase the drug substance’s solubility; and
- To provide adequate antimicrobial preservative property (only applicable to multidose preparations).
Challenges in formulations
The main challenge of all the different parenteral dosage forms is to achieve a good compatibility of the drug substances with the excipients—no formation of new impurities either by degradation of the drug substance or formation of new chemical entity between the drug substance and the excipients—as well as the compatibility of the preparations with the primary container—no leachable or adsorption to container.3
With regards to solutions and emulsions, the drug substances should be soluble and remain soluble during the entire shelf life of the drug products. When drug substances are not soluble, dissolution can be achieved with the use for instance of either co-solvents, surfactants, a soluble pro-drug, or eventually the use of solubility enhancers such the cyclodextrins due to the formation of inclusion complex.
The pH is one of the critical aspects of parenteral preparations, which should have a pH close to the physiological one. However, in certain cases, a compromise should be found between the pH ensuring stability of the drug substance, such as for peptides requiring alkaline pH or proteins at pH close to the isoelectric point, and the physiological one. In all cases, large volumes preparations—LVP, i.e. more than 100 ml as defined in pharmacopeia—should not contain a pH buffer as the blood already has a buffer effect property that could enter into competition with the injected drug product.
The stability of the drug substance is another critical point that a formulator can face during the development of the formulation. Unstable drug substances will lead to the formation of new impurities jeopardizing the safety of use of the preparations. When the use of a stabilizer is justified, such as the use of mannitol as a free-radical scavenger or cysteine in paracetamol solution for injection, it should be included at the minimum concentration demonstrated to be efficient at release and during the entire shelf life.3
In the cases of powders for injection or infusion obtained through a freeze-drying process, the use of bulking agent, such as mannitol, and/or a cryoprotector will be needed when the dose of drug substance(s) cannot ensure solely the formation of acceptable “cake.”
Finally the process of the sterilization should be selected according to the characteristics of the parenteral preparations. For instance, heat steam sterilization for aqueous solutions and dry heat for non-aqueous solutions, but in any case it can be justified by the nature of the primary containers.4 Figures 1 and 2 display the decision trees for the selection of the sterilization process for aqueous products or non-aqueous solutions including semi-solid and dry powder products.
The efficiency of the selected sterilization process should be demonstrated through validation studies, using the appropriate biological indicators, to ensure an ASL (Assurance Sterility level) of 10-6.1
Roquette has developed a pyrogen-free range of products that are biocompatible for the manufacture of parenteral preparations. Lycadex PF (dextrose/glucose monohydrate pyrogen-free) is used as a source of carbohydrates in large volume and small volume preparations (LVP and SVP) as well as an osmotic agent for dialysis solutions. Pearlitol PF (mannitol pyrogen-free) is used in LVP and SVP as an API and isotonic agent, as well as a bulking agent for freeze-dried injectable powders. Neosorb PF (sorbitol pyrogen-free) is also used as source of carbohydrates in LVP and SVP as well as an osmotic agent in sterile irrigating fluids. Kleptose HPB and HP parenteral grade (hydroxypropyl betacyclodextrin pyrogen-free) are used as solubility and stability enhancers of APIs as well as an enhancer of clinical tolerance.
This pyrogen-free range of products is obtained from natural and renewable raw materials. In addition to their compliance with pharmacopeias and other ICH quality requirements, for instance ICHQ3D for elemental impurities, all these pyrogen-free products, even when used as excipients, are manufactured in compliance to GMP, ICHQ7, and certified by competent authorities—France’s ANSM and U.S. FDA.
- EP, USP and JP Pharmacopeias
- ICH Q6, Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products
- ICH Q8, Pharmaceutical development
- Decision trees for the selection of sterilization methods (CPMP/QWP/054/98)
Dr. Elham Blouet is global market manager of injectables and dialysis in Roquette’s pharma and health global business unit.