ICH Q11 should go a long way in helping industry to implement QbD concepts across the entire drug-manufacturing process, including
the application of an enhanced approach beginning with starting materials of synthetic and semisynthetic products and source
materials for biological entities. Still, challenges remain. Among them, say the Q11 expert working group PhRMA representatives,
will be "the ability to make continual improvement in a manufacturing process that is described in detail in filings in many
different countries. The problems begin when one country approves the change while other countries are still considering whether
or not to approve the change. Unfortunately Q11 is not able to resolve or even address that problem because regional postapproval
changes were specifically out-of-scope."
In the meantime, says FDA, "ICH Q11 should help continue the dialogue regarding quality and risk-based approaches and expand
the scope of participants in that dialogue to include those focused on drug-substance development and manufacture."
Online Exclusive Sidebar: The relationship between manufacturing and regulatory flexibility
Quality-by-design or “enhanced” approaches to drug manufacturing offer several benefits to industry, including better process
understanding and better understanding of the interrelationship of material attributes and process parameters. This knowledge
can lead to fewer nonconformances and less rejection and rework, according to several International Conference on Harmonization
(ICH) Q11 expert working group members.
Such an approach can also bring flexibility, whether it be regulatory flexibility or manufacturing flexibility. PharmTech
asked the FDA members of the ICH Q11 working group about this issue and what industry should focus on and expect when applying
a QbD approach.
“For the purposes of this discussion, ‘regulatory flexibility’ can be defined as a manufacturer having greater freedom to
make postapproval changes to a drug-substance manufacturing process and controls, without waiting for prior approval from
regulators, than the manufacturer may have had for similar changes approved in the past. ‘Manufacturing flexibility’ can be
defined as a manufacturer being more capable of accurately predicting the consequences of changes to a drug substance manufacturing
process and controls, based on the increased knowledge and understanding of the drug substance and its manufacturing process
obtained from taking an enhanced approach to manufacturing process development.
FDA went on to say that, “manufacturing flexibility is valuable to manufacturers because it provides them with operational
flexibility including the assurance that changes can be made without adversely affecting the quality of the material being
produced. Regulatory flexibility is valuable to manufacturers because it allows changes to be made more quickly, which in
most circumstances will help save money.
“In an ideal world, manufacturing flexibility and regulatory flexibility would go hand in hand. No manufacturer should be
granted regulatory flexibility that exceeds the extent of the manufacturer’s manufacturing flexibility. Likewise, a manufacturer’s
ability to make changes will be constrained unnecessarily if the extent of the manufacturer’s regulatory flexibility is smaller
than the manufacturer’s manufacturing flexibility. Both types of disparities can exist. Manufacturers should not request a
degree of regulatory flexibility that exceeds their manufacturing flexibility, and they should provide sufficient information
in their submissions to justify the degree of regulatory flexibility being requested. Manufacturers should also consider pursuing
the issue of regulatory flexibility internationally: As long as manufacturers receive different degrees of regulatory flexibility
in different regions of the world, the full benefits of achieving manufacturing flexibility will be beyond their reach.”
1. ICH, Q11 Development and Manufacture of Drug Substances (chemical entities and biotechnological/biological entities), Step 2 Draft Consensus Document (2011).
2. FDA, Pharmaceutical CGMPs for the 21st Century (2004).
3. ICH, Q8 Pharmaceutical Development (2005). Note: The revised Q8(R2) version was finalized in 2009.
4. ICH, Q9 Quality Risk Management (2005).
5. ICH, Q10 Pharmaceutical Quality System (2008).
6. ICH, Q11 Development and Manufacture of Drug Substances, Concept Paper (April 2008).
7. ICH, Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (2000).
8. ICH, Q5A–E Quality of Biotechnological Products.