For example, at the Parenteral Drug Association (PDA) meeting in Paris in December 2004, Dr. Emer Cooke, head of the EMEA Inspectorate, remarked, "Risk concept is mentioned 90 times and in 20 documents in EU GMP legislation and guidance."1 Cooke cited the phrase "unless otherwise justified" as direct linkage to Quality Risk Management. In other words, current regulations support good science. In addition, greater emphasis is being placed on guidances based on international harmonization. This article focuses on the most recent quality guidances developed by the International Conference on Harmonization (ICH), both finalized: ICH Q8, Pharmaceutical Development; and ICH Q9, Quality Risk Management. A third document, ICH Q10, Pharmaceutical Quality Systems, is under development. These documents realize the consensus vision statement developed and adopted by all parties and observers involved at the ICH meeting in Brussels in July 2003:
Develop a harmonized pharmaceutical quality system applicable across the life cycle of the product, emphasizing an integrated approach to quality risk management and science.2
The work to date on the above-mentioned trio of documents has been extraordinary. The scope of the work was first envisioned as a harmonized quality system describing a life cycle approach. Now we are at the stage when we are beginning to realize the benefits of two of the three documents. With the anticipated addition of Q10, the entire suite of documents will provide the basis for the full benefits to be realized.
ICH Q8: Pharmaceutical Development
The ICH Q8 guidance document, Pharmaceutical Development, was originally intended to provide details of the expected content for the subsections of section 3.2.P.2 (Pharmaceutical Development) for drug products as defined in the scope of module 3 of the Common Technical Document (ICH guideline M4). This part of ICH Q8, Pharmaceutical Development, is logical, educational, and didactic. Embedded within the document is a gem of a concept: design space. These two words and their associated definition have started a minor revolution in our industry. Here is the definition excerpted from the document:
Design Space: the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters demonstrated to provide assurance of quality. Working within the design space is not considered a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval."3
The definition of design space takes into account raw materials, components used in processes, operating parameters of equipment, and the interactions among them. It also implies the need to carry out a rigorous, science- and risk-based approach (based on ICH Q9) to development studies. Carefully chosen words such as "working within the design space" start to lay the groundwork for firms who invest in understanding their processes to manage continual improvements within their own quality systems. The overall principle, the extent of knowledge obtained by the firm and shared with the regulator, defines the extent of a flexible regulatory approach applied to affecting changes without prior regulatory approval.