Quality by Design for Biotechnology Products—Part 3 - Guidance from the Quality by Design Working Group of the PhRMA Biologics and Biotechnology Leadership Committee on how to apply ICH Q8,
Quality by Design for Biotechnology Products—Part 3
Guidance from the Quality by Design Working Group of the PhRMA Biologics and Biotechnology Leadership Committee on how to apply ICH Q8, Q8R1, Q9, and Q10 to biopharmaceuticals.
Products that have been on the market for a considerable amount of time have extensive manufacturing data but may not have
a formally developed design space. Following the current regulatory guidance, incorporating new technology or process changes
requires regulatory agency review and approval. Manufacturing changes are initiated and controlled through internal change
control processes. Comparability studies and protocols are an integral component in the evaluation of manufacturing changes,
and include acceptance criteria and a side-by-side comparison. These processes ensure that the products comply with registered
details and that critical quality attributes have not been affected.
Because there is significant process and product knowledge about these well-understood marketed pharmaceuticals, and a large
number of patient years of pharmaceutical usage associated with them, there is an opportunity to use a risk management system
for assessing changes that may be managed internally and without direct regulatory agency oversight. This opportunity is built
on the process knowledge gained through process changes, and the subsequent safety and efficacy information that has been
generated from long-term manufacturing experience. These data could be used to define a design space retrospectively for single
or multiple unit operations.
When a design space is intended to be established after a medicinal product is on the market, the same principles apply as
for design space evaluation during development, including the use of qualified small-scale models and experimental approaches
such as DOE. For a postapproval design space, the QTPP would include the approved drug substance or drug product specifications.
The risk assessment has the advantage of building on the established criticality of process parameters as well as experience
with a number of full-scale batches.
CMC Postapproval Management Plan
Definitions
With the advent of the QbD approach providing additional knowledge-rich information in the initial marketing application,
the concept of a CMC postapproval management plan (PMP) has been suggested in the US. The PMP is a proposed mechanism to capture
the commitments and reporting requirements in the marketing application that are submitted to and approved by the agency for
these well-understood products. The PMP would address the distinction between information provided to demonstrate knowledge
of the process and product, and the lifecycle regulatory commitments. With the inclusion of increased data that supports items
such as critical quality attributes, process parameters, and the design space, it will be imperative to clearly delineate
between information that is provided for review and approval of the initial application and commitments that will continue
throughout the lifecycle of the product.
The PMP commitment section of a marketing application would contain a summary of the overall control strategy commitments:
raw material controls, CPPs, in-process controls, the design space, final specifications, excipient controls, primary packaging,
the container closure system, in-use stability, and storage conditions. The PMP also would clarify the sponsor's commitment
with respect to reporting postapproval changes, with the understanding that a robust demonstration of knowledge would result
in more flexible regulatory approaches to change management. The PMP would outline in clear terms how future process changes
will be reported —i.e., whether the company must submit a supplement or may rely on internal site change control. One approach
to providing these regulatory reporting commitments would be using a change control matrix, an example of which was described
earlier in Table 1. For example, a CMC postapproval management plan would consider typical changes expected to occur during
the lifecycle of the product and establish reporting requirements that permit innovation and improvements to be implemented
while using inspections and regular annual updates to health authorities as the means for demonstrating that regulatory expectations
have been met. The implementation of PMP for a well-understood product should require less regulatory agency oversight than
for products that lack such an understanding.
The PMP would be subject to FDA approval before taking effect and could be submitted in section 3.2.R.3 or module 1 of the
common technical document (CTD). Although the CPs and ECPs could reside separately in section 3.2.R.3, these protocols also
could be contained within the PMP.
Anurag S. Rathore, PhD, is a consultant, Biotech CMC Issues, and a member of the faculty in the department of chemical engineering at the Indian Institute of Technology. Rathore is also a member of BioPharm International's Editorial Advisory Board.
Articles by Anurag S. Rathore, PhD
