Excipients Attributes Crucial for Parenteral Preparation
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Excipients Attributes Crucial for Parenteral Preparation

Published in PDA Letter, June 18, 2019

Author(s)

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
used in parenteral

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. 
  •  Low organic impurities as measured by total organic carbon.
  • Low inorganic impurities as measured by conductivity.
  • Aluminum content when intended for dialysis solutions.
 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:
  • Viscosity
 Non water-miscible solvents Solubilize lipophilic drug substances (most important group are refined grade oils).   e.g., Refined olive oil:
  • Acid value: 0,3 max
  • Peroxides values: 10 max
  • Absorbance at 270 nm: 1,2 max
 Tonicity agents Make parenteral solutions isotonic with respect to blood (to avoid crenation or hemolysis). 
  •  Solute to be impermeant.
  • Osmolality measured by the method of depression of freezing point.
 Buffer agents

Maintain a pH close to physiological one.

Improve drug solubility and stability (e.g., to avoid proteins aggregation and precipitation). 
  • Buffer capacity in solution, influenced by ratio of salt/acid (or base) and total concentration of acid (or base) and salt.
  • Contribution to ionic strength of the solution (e.g., high concentration could result in pain at site of SC injection).
  • Physical characteristic, e.g., particle size that can impact manufacturability (dissolution).
 Buffer agents used in freeze-dried powders As above 
  • High collapse temperature to facilitate a faster primary drying.
  • Be non-volatile in order to prevent pH drift detrimental to the product stability, and product loss during sublimation.
  • High glass transition temperature (Tg) to ensure stability during storage.
  • Crystallization behavior (e.g., crystallization during cooling and in frozen solution could lead to a decrease in pH).
 Surfactants Increase the dissolution by reducing the surface tension of the drug substances. 
  • Chemical structures (e.g., composition of fatty acid of esters of sorbitan).
  • Traces of impurities (e.g., peroxides).
  • Hydrophilic-lipophilic balance (HLB) influence performance of the solubilizers.
  • Critical micelle concentrations (CMCs), unique value for individual solubilizer with hydrophilic, lipophilic, and/or hydrophobic chains.
 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:
  • Degree of substitution
 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:
  • Physical states of the bulking agent crystalline form).
  • High critical temperature, above which the freeze-dried product loses macroscopic structure and collapses during freeze drying.
  • High eutectic melting temperature with ice (allows high primary drying temperatures with rapid drying and subsequent rapid reconstitution with

    diluent).

  • Glass transition temperatures (Tg) of bulking agent impact the glass transition temperature (Tg) of the formulation and the eutectic melting temperature of the crystalline bulking agent with ice.
  • Low hygroscopicity (moisture retention after lyophilization lead to instable formulation and poor reconstitution).

Chemical properties:

  • Chemical structure: e.g., reducing sugars react with amines of drug substance.
  • Impurities: e.g., trace peroxide levels can initiate oxidative degradation.
 Antimicrobial preservatives Added to kill (bactericidal or sporicidal) or prevent microbial proliferation (bacteriostatic). 
  •  Effectiveness of antimicrobial preservative at the lowest concentration.
  • Assay and acceptable limits in the drug product specifications.
  • Vapor pressure (when used in freeze-dried formulation).
  • Partition coefficient (partitioning into an oil phase can decrease preservative's concentration and function in the aqueous phase).
  • Chemical stability (e.g., phenolic preservatives can undergo oxidation and color formation).
  • Compatibility with drug substances and other components or process equipment.
 Antioxidants Improve stability by reducing the rate of complex oxidative reaction or delaying the oxidation of drug substances and other excipients. 
  •  Effectiveness at the lowest concentration.
  • Assay and acceptable limits in the drug product specifications.
  • Solubility (greater in the formulation phase).
  • Temperature of decomposition (impact for terminal heat sterilization).
  • Stability at different pH (oxygen-scavenging potential of the reducing agents may be sensitive to pH).
 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. 
  •  Solubility
  • Affinity for the target metal ion
  • Stability, e.g., at temperature
  • Compatibility with other excipients
  • Particle size if impact on dissolution rate during processing
  • Hygroscopicity (handling and storage)
 Suspending agents

 

Two main categories:

  • Viscosity increasing agents (hydrophilic macromolecules forming gel).
  • Flocculating agents (electrolytes, surfactant hydrophilic colloids forming loosely bound aggregate that settles rapidly but re-disperses easily upon shaking).
 Stabilize dispersed systems (e.g., suspensions or emulsions).
  • Solubility
  • Viscosity
  • Molecular weight distribution and polydispersity of the macromolecular excipients.
  • Stability, e.g., at temperature for terminal heat sterilization.
  • Impact on surface charge of the system (zeta potential).
  • Particle size if impact on dissolution rate during processing.

 

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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