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.

BioPharm International
Volume 23, Issue 1

Marketed Products

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

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.

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