The FDA has been attempting to nudge pharmaceutical companies away from batch processing toward continuous manufacturing for approximately 20 years, and much of the agency’s emphasis in the first few years was on the introduction of in-process analytical equipment. This is highlighted by the 2004 guidance for process analytical technology (PAT), in which the FDA also made clear that it sees batch processing as archaic and inefficient, and an impediment to drug product quality.
However, the cost of switching over to continuous manufacturing isn’t necessarily limited to the introduction of chromatographs and other analytical equipment into the manufacturing workflow. In many instances, the manufacturer must replace the manufacturing equipment itself, and the long timelines required to recover these investments essentially guaranteed that this would be a transition of much longer than a decade.
Enhanced Analytical Procedure Development Requires Risk Assessment
The scope of the Q14 guidance captures new and revised analytical procedures used for stability testing and product release for chemical and biological/biotech drug substances. The draft characterizes two approaches to analytical procedure development, the minimal and the enhanced approaches. The minimal approach is described as generally acceptable, but ICH states that the enhanced approach may be more suited to lifecycle management for analytical procedures.
The minimal approach to analytical procedure development consists of four elements, such as conducting the appropriate development studies used to evaluate the performance of that analytical procedure. An analytical procedure control strategy is also part of this minimal approach, describing details such as parameter settings and system suitability.
The enhanced approach is additive to the minimal approach, requiring that the manufacturer define the analytical target profile (ATP). Given that this enhanced approach is designed to provide a systematic method for developing and refining knowledge of the selected analytical procedure(s), the manufacturer may also:
- Conduct a risk assessment and an evaluation of prior knowledge so as to identify the analytical procedure parameters that may affect procedure performance;
- Conduct univariate or multivariate experiments that characterize the interactions between the parameters selected for the procedure; and
- Define an analytical procedure control strategy along with a life cycle change management plan, which provides definitions and reporting categories for established conditions, proven acceptable ranges, and method operational design regions.
Among the other features of the Q14 guidance is a section for lifecycle management and post-approval changes to the analytical procedures. This section deals with one of the potentially more burdensome aspects of life cycle management, depending on any drift in state-of-the-art analytical technology and any changes to a regulator’s expectations regarding the appropriateness of those technologies.
The draft states that a post-approval change management protocol (PACMP) may be necessary to keep the marketing authorization holder (MAH) apprised of how the manufacturer might manage any future changes to analytical methods, as well as providing that MAH with some degree of comfort about the ability of the manufacturer to manage any such changes. The PACMP is one of several methods of life cycle change management characterized in ICH Q12, but the demands of this management task hinge to a large extent on whether the analytical changes are limited to a modification of technologies already in use at that manufacturing site.
The introduction of a new analytical technology to a production line may require more work on the part of the manufacturing site’s staff than would apply to a modest change in the use of an existing analytical technology. When the change consists of the addition of new analytical equipment, the workflow chart in section 2.3 of the guidance may apply, which depicts a process consisting of:
- Risk assessment;
- Identification of parameter set points and/or ranges;
- Definition of analytical procedure control strategy; and
- Validation of the new analytical procedure.
Section 4.2 of the Q14 draft takes up risk management, the text of which recommends ongoing monitoring as part of the manufacturing site’s risk review process for analytical procedures. However, the draft also states that quality risk assessment can consist of both formal and informal activities, seeming to suggest that not all such activities need be memorialized in a standard operating procedure (SOP).
Circumstances May Prompt a Change in Analytical Methods
Risk assessment is ordinarily performed early in the development of analytical procedures and should be conducted anew as new information about the production process emerges, but of special note in this context is knowledge management, which is described in Section 4.1. While Section 4.1 points to the role of prior knowledge of the product and the associated analytical processes as a key asset in determining the selection of an appropriate analytical technique, manufacturers must also be aware of both current regulatory expectations and state-of-the-art analytical technologies. What is not clear from the draft is what sort of circumstances would lead a regulatory authority to conclude that the analytical technology in use at a manufacturing site is either out of step with the state of the art or is otherwise deficient for the task at hand.
Conversely, Section 4.1 also acknowledges that existing technologies may still suffice for evaluating product characteristics, thus alleviating any need to replace or add an analytical procedure for that production line. The example given here is the use of UV spectroscopy for protein determination.
Section 4.2 states that the risk assessment tools described in Annex 1 of ICH Q9 can be used to:
- Identify the analytical procedure parameters that may have an impact on the performance of that procedure;
- Assess the specific potential impact of these parameters on the performance of the analytical procedure; and
- Identify and prioritize parameters that should be investigated experimentally.
The outcome of this risk management process should be documented in the site’s pharmaceutical quality system, but the draft also states that risk communication should be part of the activities that support continual improvement of an analytical procedure’s performance throughout the life cycle of that procedure. We might point out that ICH Q9 describes risk communication as any information obtained from any one of a number of stakeholders, including patients, and may address considerations such as the acceptability of a known or emergent risk to product quality.
The Q14 guidance provides details on a number of other considerations, far too many to exhaustively describe here. We will provide a description of the new ICH draft guidance for analytical procedures validation (the Q2 guidance) in a future blog, but while the Q2 validation draft revisits an existing ICH guidance, the Q14 is an entirely novel document. While Q14 offers a level of harmonization that is perhaps unmatched in the world of medical device regulation, the degree of specificity is such that drug manufacturers should at least examine this draft so as to avoid being caught by surprise by the demands of this policy when the document is finalized. The FDA is taking feedback through Sept. 28.
