Quality by Design for Biotechnology Products—Part 2 - Second in a three-part series that discusses the complexities of QbD implementation in biotech development. - BioPharm International


Quality by Design for Biotechnology Products—Part 2
Second in a three-part series that discusses the complexities of QbD implementation in biotech development.

BioPharm International
Volume 22, Issue 12


Figure 2
The ICH Q10 definition for control strategy indicates that controls for a product consist not only of process controls and final specifications for drug substance and drug product but also controls associated with the raw materials, excipients, container and closure, manufacturing equipment, and facility. It is a state of control in which all of the "planned controls" work together to ensure that the product delivered to the patient meets the patient's needs. Design space boundaries, as described above, are an integral part of a comprehensive control strategy. The control strategy for a product is expected to evolve through the product lifecycle. As product knowledge evolves, there is the likelihood of less reliance on end-product testing.

The purpose of a control strategy for a product is to ensure that sufficient controls are in place to maintain the risks associated with the product at a tolerable level. Thus, the concepts of risk management and control strategy are intimately connected. Product risk is synonymous with potential risk to the patient. The risk from a product is measured in terms of the amount of harm (or losses because of the inability to supply the market) it can potentially cause. This harm is created by hazards that are associated with the product and its manufacture and supply. The control strategy builds in layers of protection that reduce the risk of the hazards creating actual harm. Given that each layer of the control strategy will not be perfect, it will always be possible for hazards to find a way through the controls to create harm. This concept is illustrated by the "Swiss Cheese" model of risk shown in Figure 2.1 Each control strategy layer can have holes, and if the holes line up, a hazard can become a harm (or loss). The following are four considerations that must be addressed when evaluating the ability of a control strategy to manage risks:

1. Are there enough layers of protection in the control strategy?

2. Are there some layers that are not required because they do not protect against any harm?

3. Does each layer of protection function adequately?

4. Does the control strategy itself introduce any new hazards?

This integration of risk management and control strategy can be done in conjunction with the principles described in ICH Q9. Coupled with the principles of QbD defined by ICH Q8 and the appropriate Quality Systems (ICH Q10), the effective use of risk management will dictate a sufficient level of controls to protect the product without introducing new failure modes (for example, from inappropriate product sampling) or without incurring excessive cost that is passed along to patients. A well-designed control strategy that results from appropriate leveraging of Q8/Q9/Q10 principles, then, leads to reliable product quality and patient safety profiles. Although firms may not choose to leverage these principles in exactly the same way, all effective product control strategies use at least some of the elements of risk management.

For biotechnology products, a holistic approach to control strategy is of particular importance because the complexity of biopharmaceutical products makes it unlikely that product quality can be adequately controlled simply by ensuring that end-product specifications are met. Although it has often been said that the quality of a recombinant product is dictated by the process rather than driven by specification testing, with QbD the quality is designed into both the product and process, and a combination of in-process controls and end product specification testing is used to verify that quality. The integral link between process and product defines unique challenges for the development of robust control strategies for biotechnology products. Some of these challenges for biotechnology products are:

  • Many recombinant products are heterogeneous species rather than a single component as in organic synthesis of an active pharmaceutical ingredient (API).
  • The analytical characterization of recombinant products has evolved significantly over the years. However, the state-of-the-art for analytical science for bioproducts is not as mature and capable as it is for synthetic API characterization.
  • Microbiological and viral controls (e.g., host cell proteins, bioburden, mycoplasma, adventitious viruses) are critical aspects of biopharmaceutical manufacturing.
  • Essentially, all recombinant products are parenteral products that 1) require aseptic processing during drug product manufacture, and 2) emphasize container closure delivery systems.
  • Cold chain management is vital in maintaining product quality throughout the distribution channels because of the potential instability of recombinant proteins at room temperature.
  • Proteins have a higher order structure that must be maintained throughout processing and shelf-life, and assessed by complex bioassays.

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