Valeria Grigoriev- Senior Regulatory Affairs Specialist, Arriello.
The COVID-19 pandemic highlighted the scale of the risk of breaks in medicines supply, causing regulators to issue new manufacturer/MAH recommendations. One change in the EU is the transition to the more streamlined ICH Q12 PACMP protocol, designed to support greater agility and innovation in medicines supply by making it easier to manage production site changes. Arriello’s Valeria Grigoriev looks more closely at the benefits of the new protocol, and what’s involved in using the new framework for post-approval change management linked to finished product manufacturing sites.
High-profile events ranging from Brexit in the UK, the global COVID-19 pandemic, blockages in the Suez Canal, and the war in Ukraine, to the turbulent worldwide economy currently, 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 the death of patients due to medicine 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.
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 the 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 upfront 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-approval change management linked to finished product manufacturing sites?
Current Challenges with Traditional CMC Variations Management Protocols
The established approach to site-related changes can become mired in complexity, especially if there is a cluster of interrelated changes that, 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.
That the likelihood of and timeframes for approvals are difficult to predict can prevent MAHs from moving as nimbly as they might like with finished product manufacturing site transfer. This, in turn, can present a risk to sustainable product supply – and indeed the rollout of important and innovative new therapies and treatments. Because 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 MAHs to be overly thorough in their submissions, to maximize their chances of a good outcome.
ICH Q12 PACMP: Streamlining Site Transfer Approvals
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 lifecycle. It introduces regulatory mechanisms such as established conditions (ECs), product lifecycle 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 for an increased science- and risk-based approach for assessing 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 the agreed supportive data evaluated. In practice, this can cut approval timescales by around six months, because Applicants can confidently collate the information needed, knowing that their site change submission strategy is on the right track.
The Evolution of PACMP
As a concept, the PACMP is more than a decade old, used for post-approval filings in the US and EU, having been first introduced as a means for MAHs to keep a running record describing all changes planned during the lifecycle 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 lifecycle 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.
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.
- A clear, two-step approach to the regulator’s assessment of any changes:
» Early step 1: evaluation of the strategy for the change(s).
» Step 2: separate evaluation of the data produced, based on the agreed strategy.
Geographical Applicability
Although relatively new in its current format, the PACMP tool presented in the ICH Q12 guideline is aligned with FDA Comparability Protocols, as used in the US since 2003. The European Medicines Agency (EMA) was the first global Health Authority to employ ICH Q12 in January 2020, with implementation guidance authorized in March 2020. Yet, as the Regulatory framework invariably supersedes scientific and technical regulations, full integration in the EU legislative system is restricted at this point.
Post Brexit, the UK has not provided any specific advice on the implementation of Q12 guidance. Swissmedic applies the ICH Q12 guideline, with restrictions concerning ECs and the PLCM document to all applications submitted from 1 April 2020 onwards.
Japan’s PACMP pilot program started in April 2018, while China and Taiwan are in the process of implementing the ICH Q12 guideline. Singapore, South Korea, and Brazil have not yet implemented the guidelines. Canada’s ICH Q12 Pilot Program - the ICH Q12 Established Conditions and Post Approval Change Management Protocol Pilot Program - started in December 2021.
Traditional Variations Process or PACMP?
Ultimately, if toxicological and/or clinical data are not required as a result of the site changes being proposed, PACMP could well be the way to go.
The best advice for MAHs looking to streamline their own processes, improve efficiency, mitigate supply risk, and shorten the time to market via new facilities, is to embrace this simplified new process sooner rather than later.
Author Biography
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 MAA and Variations (National, DCP, and MRP).
Arriello is at the forefront of ICH Q12/PACMP-based finished product manufacturer site transfer variations management. Over the two years to March 2023, the company catered for up to 50 finished product manufacturing site transfer variations, both national and MRP applications, with submissions successfully performed across the EU and Eastern Europe.
[email protected], https://arriello.com/
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