Quality management is codified into tangible knowledge through a variety of documents, such as quality manuals and quality plans. These have been described in the Quality System Regulations (QSRs: 21 CFR 820)/ISO 9001 Quality Managment Systems—Requirements. The application of these documents in conjunction with quality risk management defines the site and the corporate quality culture. This concept will be applicable to both development and commercial manufacturing.

Product realization is the part of the life cycle described as the transition from the twinkle in the eye to product launch. It is an exciting time marked by success and failure and trial and error; along the way, a product is readied for market. A transfer of knowledge accompanies the technology transfer. The knowledge in developing, manufacturing, and testing a product is translated from the codified knowledge in laboratory notebooks, experimental reports, and other documents as well as intrinsic knowledge. This knowledge must be translated to a receiving site in a manner that assures successful commercialization, as opposed to a perfectly developed product impossible to manufacture.

Continual improvement describes the ability to enact incremental change in a rational and timely manner. It applies to both quality systems and manufacturing processes. Recent discussions about the "desired state" conclude that knowledge about the product and process increases exponentially during early commercial manufacturing. A corollary of in-creased knowledge is continual improvement. Sites that institute a way to measure and monitor, with the capacity to analyze data from production and quality systems, also have the ability to identify opportunities for improving the product and processes. This is an example of how the three guidances (Q8, Q9, and Q10) can supplement each other, when Q10 is completed. For companies demonstrating enhanced process and product understanding, working within the design space (as defined in Q8) can lead to implementing improvements without seeking prior regulatory approval.

Impact on Biotech Industry

Many of the basic concepts outlined in the three guidances are not new to the biotech industry. The opportunity for innovation they provide is demonstrated through how aggressively the industry pursues their combined synergies.

The Q8 concept of design space provides a common framework for the science of process development for biologics. Because of the challenges in characterizing complex proteins for routine Quality Control, the Q8 lesson to build in quality by design is already practiced to "consistently deliver the intended performance of the product." The fundamentals of demonstrating process control and capability, already in place in our industry, includes scientifically sound studies for:

• Cell bank characterization
• Characterization and control of critical raw materials
• Safety assessment of animal-sourced materials
• Variability assessment of plant-sourced materials
• Predictive scaled-down process models
• Process clearance of impurities, microbes, and endotoxin
• Column lifetime studies
• Critical process parameter determination
• Process control and monitoring

Additionally, ICH Q6B, Specifications: Test Procedures and Acceptance Criteria for Biotechnological and Biological Products, includes guidance for product characterization through the design of product specs specifically aimed at controlling product heterogeneity. It allows for not testing certain impurities if supported by adequate process understanding and demonstrated impurity clearance.

The production of biologic products is inherently risky. Many controls are encoded into our processes and systems to avoid poor outcomes. Risk management analysis and control are typically centered around:

• Engineering controls: Biotech products are extremely susceptible to processing conditions. Exposure to shear forces, extremes in temperature, and abnormal cell culture conditions are minimized by tight controls to assure the consistency and quality of the protein produced.
• Microbial controls: Prevention of microbial contamination is achieved through a variety of methods, including controls for equipment and facility design, and personnel flow and gowning.
• Viral safety: ICH Guidance Q5A, Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin, is devoted to this topic. It includes requirements to control both severity and probability of occurrence of risk via studies of specific "relevant" and "model" viruses combined with orthogonal viral clearance and removal methods.