Applying quality by design principles to excipients supplier selection during formulation development

Many biological therapeutics are administered parenterally through intradermal, subcutaneous, intramuscular, and intravenous injection. Biological therapeutics such as monoclonal antibodies (mAbs) are inherently unstable requiring additional components or excipients which are inactive substances that serve as the vehicle or medium for a drug.

Formulation development is a pivotal stage in the life cycle of a therapeutic drug product, it can be the make or break of it. The goal of formulation development is to convert an active substance (drug molecule or other) into suitable dosage forms or product, which remains stable and is acceptable at the point of use. A drug is any molecule or structure intended for therapeutic use, but it cannot be taken in its pure form, so it is formulated into suitable dosage forms for safe and compatible administration into the body.

Once a drug molecule has been identified for a clinical need, the Quality Target Product Profile (QTPP) and Critical Quality Attributes (CQAs) of the drug can be established. Through applying Quality by Design (QbD) principles, the formulation and manufacturing process can be developed efficiently, with risk management and mitigation strategies, while ensuring high product quality and patient safety. 

Quality by Design

QbD is a concept that quality should be designed into a product, and that most quality issues relate to the way in which a product was first designed. The US Food and Drug Administration (FDA) encourages risk-based approaches and the adoption of QbD principles in drug product development, manufacturing, and regulation. 

FDA’s emphasis on QbD began with the recognition that increased testing does not necessarily improve product quality, quality must be built into the product. QbD is also described in ICH Q8 (R2) 2009, ICH Q9 (R1) 2923 and ICH Q10 (2008) guidance documents, these documents provide high level directions with respect to the scope and definition of QbD as it applies to the pharmaceutical industry.

Target Product Profile and Critical Quality Attributes

Establishing a TPP of a drug product is the first step during drug development and outlines the desired ‘profile’ or characteristics of a target product that is aimed at a particular disease or diseases. TPPs state intended use, target populations and other desired attributes of products, including safety and efficacy-related characteristics. TPP is a summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, considering safety and efficacy of the drug product.

Typical questions answered by the TPP are:

• What is the intended use in clinical setting, route of administration, dosage form, delivery system?
• Who is the patient population?
• What is the container type?
• How will it be administered?
• What are the ideal dosage strengths?
• What is the release, delivery or attributes affecting pharmacokinetic characteristics (e.g., dissolution, aerodynamic performance) appropriate to the drug product dosage form being developed 
• What is the drug product quality criteria (e.g., sterility, purity, stability, and drug release) appropriate for the intended marketed product 

A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. They are derived from the TPP and potentially prior knowledge of similar products. The list of potential CQAs can be modified when the formulation and manufacturing process are selected and as product knowledge and process understanding increase during the development of the product.

Risk management during formulation development and manufacture

Once the CQAs have been identified, variables and parameters which may impact or cause risks to these can be highlighted, and mitigation strategies can be put in place. 

One such risk is the impact of batch-to-batch variation or inconsistent excipient specifications during development and clinical manufacture. During early formulation studies, and in subsequent studies, it is important to use pharmaceutical grades of excipients which have minimal batch-to-batch variation. This safeguards against the excipients causing variable impact on the results of the studies. Another risk is the impact of impurities on the stability of the drug molecule but also more importantly to patient safety. Any potential risk to the product or patient can be reduced by prioritising the use of excipients with batch-to-batch consistency and higher purity. 

It is important to maintain the same grade and source of excipient through development studies and into commercial manufacture of the drug formulation, as this should ensure product quality and consistency across different batches.  Additional due diligence should be conducted so that supply of the material can be maintained through the products lifecycle.

Impact and interaction of impurities with protein-based drug therapies

Several impurities can impact drug stability, these can come from the contact materials such as the tubing or mixing vessels used in the drug manufacture leeching impurities into the drug product, be introduced from the API manufacturing process, or can be introduced from the excipients being used. 

Impurities or contaminates include:

• Heavy metals
  Metals ions, such as Cu2+, can bind to the mAb and undergo hydrolysis or oxidation, which can lead to cleavage of the molecule. Fragmentation in the hinge region of an IgG1 mAb can affect product stability, potentially causing changes in potency and efficacy.
• Endotoxins
  Endotoxins are lipopolysaccharides found in the cell wall of Gram-negative bacteria, which can induce inflammation and fever as an immune response in higher organisms. Reaction to endotoxins can lead to anaphylactic shock and death of patients.
• Side product impurities from manufacturing process
  Peroxides can impact mAb stability by causing oxidation of the amino acids causing the mab to lose activity. 

All impurities should be maintained at their lowest level but also consistent across different batches, to ensure reproduceable batches with similar performance and stability. 

Summary 

• Using the Quality by Design framework can be a valuable tool to help direct the course of product development and develop mitigation strategies.
• The use of pharmaceutical grade excipients from suppliers with consistent specifications during development and into commercial manufacture can ensure consistency between lab scale and commercial manufacture of the drug product.
• Prioritising the use of excipients with batch-to-batch consistency and higher purity can reduce potential risk to the product stability and patient safety, as well as ensuring consistent performance across multiple batches of the same drug.

View the IPEC QbD guide here.