Selecting and justifying starting and source materials. The draft Q11 guideline defines starting materials (synthetic, semi-synthetic) and source materials (biotechnological/biological),
and provides six science-based principles to consider when selecting the starting or source material. For synthetic drug substances,
these principles include recognition that changes in material attributes or operating conditions that occur early in the manufacturing
process have lower potential to impact the drug-substance quality; regulatory authorities should be provided with an adequate
description to understand how impurities are formed, how the process affects formation, fate, and purge of impurities, and
the suitability of the control strategy; a starting material should be a substance of defined chemical properties and structure
and a starting material is incorporated as a "significant structural fragment" (1, 7).
When justifying the selection of synthetic or semi-synthetic drug substances, CTD applicants need to justify how each proposed
starting material is appropriate in light of the above principles, suggests Q11. Justifications may include the ability of
analytical procedures to detect impurities in the starting material; the fate and purge of those impurities and their derivatives
in subsequent processing steps; or how the proposed specification for each starting material will contribute to the control
strategy (1). Q11 recommends using a flow diagram to outline the synthetic route(s) for the manufacture of the drug substance
and to clearly indicate the proposed starting materials.
ICH Q11 further notes that an applicant generally need not justify the use of a commercially available chemical as a staring
material and goes on to define a commercially available chemical as one that is sold as a commodity in a pre-existing, nonpharmaceutical
market in addition to its proposed use as a starting material. Chemicals produced by custom syntheses are not considered to
be commercially available and therefore should be justified when used as starting materials (1). Selection and qualification
of biological source materials (e.g., cell banks) are not described in the new guideline, but rather, the industry is referred
to ICH Q5 for such steps (8).
It's important to note that the CTD submission strategy does not change as a result of the starting material proposal, say
the PhRMA Q11 expert working group members. "Overall impurity knowledge and control (fate and purge), including starting materials,
intermediates, raw materials, etc., are still important whether using a traditional or enhanced development approach."
Control strategy and process validation. Control strategy and process validation are also large components of the Q11 guideline. A control strategy is a planned set
of controls, derived from current product and process understanding, that assures process performance and product quality
(5). Every drug-substance manufacturing process, whether developed through a traditional or an enhanced approach (or some
combination thereof) has an associated control strategy (1).
The process validation section of Q11 includes General Principles as well as highlighting specific principles for biotechnological/biological
products, including the consideration of scale up, impurity removal, and the use of platform technology. The guideline's recommendations
in this area, note the industry Q11 expert working group members, reflect current practice and expectations for biologic products.
Life-cycle management. The ICH Q10 guideline on the pharmaceutical quality system includes quality system elements and management responsibilities
intended to encourage the use of science-based and risk-based approaches at each life-cycle stage (5). Q11 reinforces Q10's
life-cycle management approach while also providing more detail for drug-substance process control. "Manufacturing process
performance, including the effectiveness of the control strategy and suitability of any design spaces, should be periodically
evaluated," states the draft guideline (1).
"ICH Q11 promotes awareness of the sources of and potential for variation in the CQAs of the drug substance," explain the
FDA members of the Q11 working group. "This knowledge supports well-informed selection of suppliers capable of consistently
controlling the drug substance manufacturing process." Risk management and quality systems, which are defined in ICH Q9 and
Q10, apply throughout the lifecycle of the drug substance when it comes to identifying, qualifying, and overseeing suppliers,
and in the management of contractual agreements, adds FDA.
Furthermore, say the agency's representatives, it is important that senior management play a critical role in establishing
a qualification program that assesses the supplier's ability to provide the drug substance using a defined supply chain. "These
critical relationships should be managed through use of strong communication processes, written quality agreements, ongoing
review of the performance of the supplier, and the identification and implementation of any needed improvements."
Applying enhanced approaches. The Q11 document includes several illustrative examples for application of Q11 principles to the drug-substance manufacturing
process, including how to: link material attributes and process parameters to drug-substance CQAs, select appropriate starting
materials, use quality risk management to support life-cycle management of process parameters, and present a design space
for a biotechnological product unit operation.
The PhRMA Q11 expert working group members point out that the examples contained in Q11 are not to be used as templates or
best approaches. "The intent of the examples is important for the illustration of a high-level concept not clarified in the
text .... (and) are an oversimplification of science to streamline the document."