Excipients Attributes Crucial for Parenteral Preparation
Published in PDA Letter, June 18, 2019
The quality attributes of excipients are critical since they impact the quality attributes of the final formulations. With this in mind, I want to describe the quality attributes required for parenteral preparations and focus on the main quality attributes required for each functional excipient used in these types of preparations.
Parenteral preparations are required, like any pharmaceutical dosage forms, to meet the pharmaceutical quality standards as described in pharmacopeias, and to be safe for the intended purpose of use (1-4).
First, let us look at the quality attributes for parenteral preparations. These preparations must be:
• Sterile and pyrogen-free
• Isotonic (e.g., ensure the tolerability at site of injection)
• Close to physiological pH
• Clear or practically exempt of visible particles and free of sub-visible particles as required by pharmacopeias
• No evidence of phase separation for the emulsions or aggregates formation for aqueous dispersion such injectable mAb (monoclonal antibody) preparations
• Appropriate particle size for suspensions and any sediment readily dispersed upon shaking to give stable formulations, ensuring the correct dose is administered
• Stable through the entire shelf life (1-4)
Regulatory views on excipients
When it comes to excipients, quality attributes are just as critical. Just ask the global regulators and pharmacopeias.
Excipients may be defined as the constituents of the pharmaceutical form administered to the patient, other than the active substance (5). In the European Pharmacopeia, they are also defined as substances for pharmaceutical use, organic or inorganic substances, for the production of medicinal products for human or veterinary use.
During pharmaceutical development ICHQ8 (R2) (3), the quality target product profile (QTPP) is defined and the critical quality attributes (CQAs) of the drug product (characteristics having an impact on product quality) are identified. Consequently, the critical quality attributes of the drug substance and excipients are determined by selecting the type and amount of excipients to deliver a drug product of the desired quality.
In addition, the ability of excipients to provide their intended function, and to perform throughout the intended drug product shelf life, should be demonstrated during pharmaceutical development (3).
The European Pharmacopeia also developed a general text on the functionality-related characteristics (FRCs) of excipients (Eur.Ph; 5.15). The intended function of each excipient is to guarantee the required physicochemical and biopharmaceutical properties of the pharmaceutical preparation, and the functionality of each excipient is determined by its physical and chemical attributes that need to be evaluated only in the context of a particular formulation and manufacturing process.
The excipient quality attributes related to functionality are called functionality-related characteristics (FRCs); the monograph section contains FRCs that are known to have an impact on the functionality of the excipient for the stated uses.
USP has described the functionality of excipient in chapter <1059> Excipient Performance (1). The key functional categories of the excipients are described along with the recommended tests or procedures to monitor and control their critical material attributes (CMAs being a physical, chemical, biological, or microbiological property of a material). The functional categories are organized by their most typical use and can apply to multiple dosage forms, including possible association of a functional category with a particular dosage form.
Excipient attributes
The excipients used for parenteral preparations typically fall in the following main functional categories: vehicles/solvents, tonicity agents, buffers, solubilizing agents (such solvent and co-solvents, surfactants, complexing agents), bulking agents, antimicrobials/preservatives, antioxidants, chelating agents and suspending agents (1).
The attributes of these excipients can be separated in two categories: the “universal” ones applicable to all these excipients and the “specific” ones as per the intended functionality of each excipient.
Universal Attributes (2,3)
• Safe (i.e., biocompatible, viral safety for animal origin)
• Endotoxin-free and/or pyrogen-free
• Acceptable microbiological quality (e.g., low bioburden)
• Sterile if there are no further appropriate sterilization procedures in the manufacture of sterile dosage forms (or if offered as sterile grade)
• Free from residual solvents when applicable
• Impurities levels as described in compendia monographs or based on toxicological data (can be more stringent than those in compendia monographs)
• Additional properties (e.g., functionality-related characteristics) defined as the critical material attributes (CMAs) (3)
• Able to withstand terminal sterilization or aseptic processing
Table 1 displays each functional excipient with examples of attributes related to their functionality (1-3).
Table 1. Attributes as per the intended functionality of each type of excipient
|
FUNCTIONAL EXCIPIENTS |
FUNCTIONS |
EXAMPLE(s) of ATTRIBUTES |
| Water for Injection (WFI) | Preferred vehicle/solvent as it is safe, well tolerated by the body and easy to handle and administer. |
|
| Water-miscible solvents | Solubilize certain drugs in an aqueous vehicle with limited amount used due to toxicity concerns (e.g., hemolysis). | e.g.: Macrogols as per FRC in Eur.Ph.(1444) when used as solvents:
|
| Non water-miscible solvents | Solubilize lipophilic drug substances (most important group are refined grade oils). | e.g., Refined olive oil:
|
| Tonicity agents | Make parenteral solutions isotonic with respect to blood (to avoid crenation or hemolysis). |
|
| Buffer agents |
Maintain a pH close to physiological one. Improve drug solubility and stability (e.g., to avoid proteins aggregation and precipitation). |
|
| Buffer agents used in freeze-dried powders | As above |
|
| Surfactants | Increase the dissolution by reducing the surface tension of the drug substances. |
|
| Complexing agents | Increase aqueous solubility and stability of drug substances, by formation of soluble inclusion complex. | e.g., Hydroxypropylbetadex, as per FRC in Eur.Ph (1804) when used as solubility-increasing agent:
|
| Bulking agents in freeze-dried powders: cryoprotectants and/or lyoprotectants |
Provide an elegant/adequate freeze-dried cake by crystallization with noncollapsible structural integrity (no macroscopic collapse) and that will reconstitute rapidly before administration.
Prevent product loss caused by blow-out during freeze drying.
Facilitate efficient drying. Provide a physically and chemically stable formulation matrix.
Lyoprotectants protect drug substances by stabilizing and preventing the degradation through stable amorphous phase. |
Physical properties:
Chemical properties:
|
| Antimicrobial preservatives | Added to kill (bactericidal or sporicidal) or prevent microbial proliferation (bacteriostatic). |
|
| Antioxidants | Improve stability by reducing the rate of complex oxidative reaction or delaying the oxidation of drug substances and other excipients. |
|
| Chelating agents |
Remove certain metal ions from solution (Cu, Fe, Mn, Pb, Ca...) by forming soluble complex molecules to minimize or eliminate their ability to react with other elements and/or to precipitate. Eliminate as well the capacity of the metal catalysts to participate in oxidative reactions. |
|
| Suspending agents
Two main categories:
|
Stabilize dispersed systems (e.g., suspensions or emulsions). |
|
Conclusion
Excipients must meet the pharmaceutical quality standards as described in pharmacopeias and relevant ICH quality guidelines, and also to ensure the clinical tolerance as well as to be safe for the intended purpose of use. This is a challenge that I see, and I hope that the material herein can help parenteral manufacturers identify the correct quality attributes for their excipients.
Only biocompatible excipients should be used in parenteral preparations. The excipient attributes, either physical, chemical or biological properties, should be evaluated in the context of a specific formulation in order to determine the critical material attributes (CMAs) and to ensure the critical quality attributes (CQAs) of the final parenteral preparation.
References
1. European, US and Japanese Pharmacopeias
2. ICH Q6, Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products
3. ICH Q8 (R2), Pharmaceutical development
4. Blouet, E. "Parenteral Preparations, Challenges in Formulations." Pharmaceutical Outsourcing (Nov. 20, 2016). https://www.pharmoutsourcing.com/Featured-Articles/331618-Parenteral-Preparations-Challenges-in-Formulations/
5. DIRECTIVE 2001183/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 6 November 2001 on the Community code relating to medicinal products for human use
Reproduced with permission of PDA (https://www.pda.org/pda-letter-portal/home).
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