Prospects for Post-Approval Change Management

As new types of biologic products enter the market, the need for innovative processes continues to grow. This requires improvements in post-approval change management. ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management offers a solution to post-approval change challenges in the form of a post-approval change management protocol (PACMP) (1).

The PACMP is a tool that provides predictability regarding the information required to support a CMC change and the type of regulatory submission based on prior agreement between the marketing authorization holder (MAH) and a regulatory authority. Such a mechanism enables manufacturers to more efficiently plan future changes to established conditions (ECs).

Adopting the principles outlined in ICH Q12 gives industry greater operational flexibility. While ICH Q8–Q11 introduced a risk-based vision of quality (2), the regulators and the biopharma industry have adopted the product lifecycle approach ICH Q12 advocates. The ICH Q12 prerequisites, i.e., “enablers,” were a challenge at one time; however, with the current innovations in applied statistics along with advancements in modeling, risk assessment and monitoring tools, there are new ways for the biopharma industry to effectively manage post-approval changes. A new level of flexibility in regulatory approval can be achieved, enabling continuous improvement in biomanufacturing.

ICH Q12 has arrived at a time when industry is being pushed toward greater innovation. Quality-by-design (QbD) principles now guide the design of products and process characteristics. Coming out of QbD, process analytical technologies (PAT) and process modeling offer opportunities for continuous improvement. Further, each segment of biologics processing is currently undergoing constant innovation, fueled by the need to enhance yield and productivity in a highly cost-conscious industry. The process efficiency push, newer process technology and PAT advancement, combined with the necessary use of multiple integrated processing technologies, calls for a need to develop a robust post-approval change management strategy. ICH Q12 provides the pathway to such strategy development and adoption.

Upstream and downstream biopharma processes typically involve cell banks, fermentation, purification and filling technologies. These are developed to suit the type of biologic product whether it be a vaccine, albumin, immunoglobulin, clotting factors fibrin sealant, proteinase inhibitor, antitoxin, antivenin, enzyme, toxin or gene-and-cell-based product. Here, an integrated process design is required in bioprocesses with multiple elements of the control strategy for assuring product quantity and quality, allowing biologics manufacturers to take a leading role in adoption of ICH Q12.

Anticipating potential processing changes in complex biologic processes is a challenge, yet there are ample opportunities to consider. Take, for example, switching a traditional aseptic vial filling operation for a biologic molecule to an isolator aseptic filling technology. Isolator technology better prevents or eliminates possible contamination opportunities as traditional aseptic filling presents inherent risks to sterility assurance. Adopting an isolator technology aids in raising the sterility assurance levels (SAL) of the product, especially during the filling operations. The proposed change involves extensive changes in processing equipment and parameters for a higher level of sterility assurance.

A PACMP In Action

A PACMP is an effective tool for adopting such a change. Below are some considerations that need to be included in the protocol:

1. Definitions for the characterization and qualification aspects of the isolators.
2. Descriptions of proposed change elements to be confirmed during process performance qualification and continued process verification.
3. Requirements concerning the quality management system (QMS), SOPs and GMPs, such as media fills or aseptic simulation studies, that need to be conducted as part of implementing the change (3).
4. Information for that supports a reduced submission category, including strategies for characterizing engineering studies, meeting predefined quality and sterility attributes, conducting stability studies and performing equipment qualification activities and process performance studies.

Providing sufficient clarity on the proposed change and demonstrating commitment to performing listed activities can enable the submission and preapproval of a PACMP. An organization’s established pharmaceutical quality systems (PQS) and QMS provides the framework to ensuring that changes will be implemented while also meeting the preapproved commitments. Inspectors can use this to then verify the implementation of activities as part of the routine inspection process.

Apart from the complexity and uncertainty regarding individual regulators, a few other challenges need to be addressed to effectively apply ICH Q12 concepts. One critical area is organizational harmonization. ICH Q12 strategies can help a biologics manufacturer to prepare from potential questions from regulators upon product commercialization. At the same time, this may lead some individuals within an organization to avoid including a PACMP as part of the initial submission in an effort to prevent additional questioning from regulators and requests for additional technical documents. This tendency must be addressed for manufacturers to effectively realize ICH Q12.

A holistic impact assessment is beneficial for each BLA. The standardization of the post-approval change management process can be achieved by following a stepwise procedure using a standard acceptable protocol format with required sections (4). The use of a PACMP empowers regulators and biologics manufacturers to make risk-based decisions based on scientific rationale embedded during the early stages of creating therapeutically safe and commercially viable molecules. Submission of additional supportive data from prior knowledge continues to remain relevant due to the lack of such information for a novel process.

ICH Q12 provides an opportunity to save some of the long-term costs associated with regulatory submissions, enabling swift implementation of process-efficiency enhancement plans without supply disruptions. The guidance, currently in draft form for public consultation, would also benefit from offering additional biologics-specific examples or case studies that provide clarity for early adopters.

In addition, the value of including an all-encompassing product lifecycle management (PLCM) document in this guidance is unclear, as there are already specific sections in the eCTD that address ECs while the PACMP includes the proposed change types and submission categories. Such inconsistencies may be addressed through public commenting and feedback from the regulators to the ICH Q12 Expert Working Group. Regulatory convergence, such as the joint U.S. FDA and EMA pilot program on QbD, Canada–United States Regulatory Cooperation Council (RCC) (5), etc., will further advance process harmonization—a critical need for biologic manufacturers with products in multiple markets.

ICH Q12 solutions are the right fit for biologics due to their complexity and the current challenges they face. Novel continuous improvement changes are imminent in the biologics operations sector due to pricing concerns and the emergence of biosimilars. A PACMP paves a pathway for innovation of manufacturing, optimization of investment and maximization of effort, enabling speedier production of novel products. Biologic manufacturers have already embraced new lifecycle tools and solutions, making this field a prime candidate for adopting ICH Q12 concepts. The regulations are in place, the enablers are available, global regulatory harmonization is ongoing, industry organizations have converged and ICH Q12 is in the approval process(6). Standardizing the submission of the PACMP along with every BLA will help organizations reap the benefit of implementing ICH Q8–11 and reduce operational risks (7).

Adoption of ICH Q12 will promote innovation and continual improvement, ultimately, improving the accessibility of product for patients and product safety.

Note: This article was prepared by the authors in their personal capacities, and the opinions expressed in this paper do not reflect the view of their employers, government, or any affiliated agencies.

References

1. ICH Guidance Document. Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle management (Draft)
2. ICH Quality Guidances. Government of Canada. https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/international-conference-harmonisation/quality.html (accessed May 17, 2018)
3. CMC and GMP Guidances. U.S. FDA. https://www.fda.gov/BiologicsBloodVaccines/Guidance-ComplianceRegulatoryInformation/Guidances/General/ucm217665.htm (accessed May 17, 2018)
4. Pazhayattil, A.B., Sayeed-Desta, N., and Iyer, V., “ICH Q12 Post Approval Change Management Protocol: Advantages for Consumers, Regulators and Industry.” Regulatory Focus (16 May 2017
5. Government of Canada. Canada-United States Regulatory Cooperation Council Joint Forward Plan, August 2014. https://www.canada.ca/en/treasury-board-secretariat/corporate/transparency/acts-regulations/canada-us-regulatory-cooperation-council/joint-forward-plan-august-2014.html (accessed May 17, 2018)
6. PDA’s Post Approval Change: Innovation for Availability of Medicines (PAC iAM) program. PDA. https://www.pda.org/conference/pac-iam/home (accessed May 17, 2018)
7. FDA/Xavier PharmaLink Conference 2018, The PACMP Strategy Presentation (13 March 2018)