ICH Q12 Post-Approval Change Management Protocol Streamlines Manufacturing Site Transfer Approvals

By Valeria Grigoriev, Arriello

High-profile events ranging from Brexit in the U.K., the global COVID-19 pandemic, blockages in the Suez Canal, and the war in Ukraine to the current turbulent worldwide economy have driven home the importance of shoring up medicinal supplies, as breaks in supply have resulted in visible shortages of critical products ranging from vaccines to antibiotics to hormone replacement therapies (HRT).

The latest statistics from the Pharmaceutical Group of the European Union (PGEU), which tracks drug shortages year on year, found that all 29 responding countries had experienced medicine shortages in 2022, which for more than three-quarters had worsened from the previous year. As just one example, Spain identified 140% more shortages in 2022 compared to 2021. Cardiovascular, respiratory system and nervous system medications, and anti-infectives for systemic use are the most common drug classes in short supply.

Four countries reported deaths of patients due to medicines shortages, and 18 proposed sourcing the same medicine from alternative authorized sources as a legal solution for covering gaps in supply. This required the regulatory submission of finished product manufacturing site transfer variations.

Bringing New Manufacturing Sites Online More Swiftly

Recognizing the need to secure pharma supply chains, and as part of wider drives to streamline the path of drugs to market, regulators are working toward new approaches to bringing new manufacturing sites online more swiftly, without cutting corners and potentially introducing quality or safety concerns.

Specific new measures under International Council for Harmonization (of Technical Requirements for Pharmaceuticals for Human Use) guideline Q12 include the Post-Approval Change Management Protocol (PACMP). This aims to simplify the process of registering site changes under certain criteria, through an emphasis on gaining accelerated up-front feedback from the regulator before detailed submissions are compiled. Already, to date, this has been seen to reduce the approval cycle by up to six months.

So, what’s involved under this protocol and in using the new framework for post-approvals change management linked to finished product manufacturing sites?

The established approach to site-related changes can become mired in complexity, especially if there is a cluster of interrelated changes, which, ideally, would be handled simultaneously with the regulator – e.g., changes that go beyond the addition of a new manufacturing site. This take on CMC variations management sets out various pathways for the different types of change-related submissions, each with its own set of expectations and expected timelines.

Simpler Process Speeds Up Approvals

As the outcome of the approvals process isn’t ultimately known until the end, which could be many months down the line, there is a temptation for marketing authorization holders (MAHs) to be overly thorough in their submissions to maximize their chances of a good outcome.

The ICH Q12 guideline provides a globally harmonized framework to facilitate the management of post-approval CMC changes in a more transparent, predictable, and efficient manner across the product life cycle. It introduces regulatory mechanisms such as established conditions (ECs), product life cycle management (PLCM), and the post-approval change management protocol (PACMP) to simplify and speed up post-approval change implementation and to encourage continuous product improvement.

The main aim is to provide greater opportunities to use a science- and risk-based approach to assess changes, with a view to greater flexibility in managing post-approval changes. This in turn is designed to promote manufacturing innovation and ongoing incremental improvements, while allowing regulatory authorities to better understand companies’ pharmaceutical quality systems (PQSs).

Specifically, PACMP allows MAHs to first have their variation strategy approved, and then have the agreed supportive data evaluated. In practice, this can cut approval times by around six months, because applicants can confidently collate the information needed, knowing that their site change submission strategy is on the right track.

PACMP – Assessing The Effect Of A Proposed Change

As a concept, the PACMP is more than a decade old, used for post-approval filings in the U.S. and EU, having been first introduced as a means for MAHs to keep a running record describing all changes planned during the life cycle of the medicinal product. Under ICH Q12, the harmonized international protocol presents a comprehensive plan for assessing the effect of a proposed change, or multiple (related and consequential) CMC-only post-approval changes, on the quality of a product – e.g., its identity, strength, purity, potency, performance, and/or stability.

The protocol describes specific quality change(s) that the applicant would like to implement during the life cycle of a product and how the impact can be verified. Based on product process understanding and a risk assessment of the potential impact of the change on the quality of the product, a PACMP would include studies, specific tests, and the acceptance criteria that demonstrate the lack of negative impact of the proposed CMC changes on the factors mentioned above. For example:

• Justification of the proposed changes.
• Risk management plan comprising quality target product profile (QTPP) and critical quality attributes (CQAs), risk assessment, and control strategy.
• Confirmation if analytical method transfer was or was not conducted at the proposed site. If it was not, you need to prove that the in-house methods were validated and the pharmacopeial methods were verified by the new proposed site.
• A proof that the capability of the new manufacturing site to repeatedly and reliably produce a finished product that meets the desired specifications is ensured.
• Supportive data from previous experience with the same or similar products related to development, manufacturing, characterization, batch release, and stability.
• An appropriate description of the analytical procedures and proposed acceptance criteria for each test or study.
• Comparative analysis (routine release controls) between the first batches produced on the proposed new site and the last batches manufactured at the currently registered site, demonstrating that the quality, safety, and efficacy of the finished product remains similar independent from the manufacturing process and site.
• Confirmation of the absence of elemental impurities in the finished production scale batches.

The main parameters of PACMP are as follows:

• CMC changes only: PACMP-based submissions are not supported where non-CMC data, including non-clinical, clinical, and/or immunogenicity data, would be required to support the change.
• Type of products: PACMPs can be applied to all product types, i.e., small and large molecules, including vaccines and cell/gene therapies.
• A clear, two-step approach to the regulator’s assessment of any changes:
  • Step 1 (to be completed early in the process): evaluation of the strategy for the change(s)
  • Step 2: separate evaluation of the data produced, based on the agreed strategy.

Embrace The Process

Unpredictable approval timeframes prevent MAHs from moving as agilely as they might like with finished product manufacturing site transfer. This can present a risk to sustainable product supply – and the rollout of important and innovative new therapies and treatments. If toxicological and/or clinical data are not required as a result of the site changes being proposed, MAHs would do well to embrace this simplified new process to streamline time to market while mitigating risk.

About The Author:

Valeria Grigoriev is a senior regulatory affairs specialist at regulatory affairs service provider Arriello. Her experience spans research and development and project management for different types of submissions, from initial due diligence to approval, across Europe, for regulatory activities including new marketing authorization applications (MAAs) and variations (national and decentralized procedures, as well as mutual recognition procedures). Grigoriev can be reached by email at valeria.grigoriev@arriello.com.