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Light at the End of the Tunnel for PAC Complexity

by Melissa Seymour, Biogen, Emma Ramnarine, Genentech/Roche, Denyse Baker, PDA, and Anders Vinther, Sanofi Pasteur | Nov 10, 2015

The state of regulatory postapproval change (PAC) processes worldwide can be characterized as complex and inconsistent for many reasons, such as varying classifications, different submission requirements, and implementation timelines, all of which creates unintended disincentives for manufacturers to continually improve and technically innovate or forces companies to maintain parallel inventories.

Many companies find it easier to postpone improvements to facilities, processes, and analytics or simply refrain from planning for advancements at all in order to avoid the intricate nature of implementing such changes, especially for product registered in multiple countries.

Other companies that do implement even simple changes might choose to segment their inventories over many months in order to meet regional requirements and avoid filing changes in all regions served. Attendees at the recent 2015 PDA/FDA Manufacturing Science Workshop shared several examples of this problem. In the most extreme case, a company maintained more than 30 versions of the same product in parallel due to differences in timing of country-specific regulatory approval processes.

Both strategies—upgrade/improvement avoidance or parallel inventories—are fraught with serious consequences that can contribute to the problem of drug shortages. Technology avoidance can lead to drug shortages that could have been mitigated effectively through process or technology improvements. Segmentation of inventories, on the other hand, makes it more difficult for a manufacturer to accommodate sudden increases in product demand in one of these segments. Both strategies can result in an increasing risk of errors in releasing nonconforming product to a country, and possibly even resulting in cGMP noncompliance.

Industry and Regulators Responsibilities

At the workshop there was a general agreement by regulators and industry alike to see the fulfilment of the three objectives found in International Conference on Harmonisation (ICH) quality guideline Q10: Pharmaceutical Quality System:

  • Achieve product realization
  • Establish and maintain a state of control
  • Facilitate continual improvement.

So how can the industry move in this direction and not let the complexity of PAC regulatory processes serve as a roadblock?

First, workshop attendees agreed that the burden of ensuring safe and compliant PACs falls on the companies themselves. As such, manufacturers must ensure that effective change management processes are in place as part of the pharmaceutical quality system (PQS) within their companies. The process of evaluating PACs must include all relevant functions/organizations in the company, leverage country-specific competences in affiliates, and bundle relevant changes as much as possible. Workshop attendees also agreed that all companies must develop lifecycle management plans and global change protocols as elements of an effective PQS.

Nevertheless, attendees believed that regulatory authorities around the world are responsible for creating a less complicated global system that allows companies to make necessary process improvements. The World Health Organization (WHO) resolution 67.20, which describes the balance between regulatory oversight and availability/access to drug products, was cited as an important guiding principal.

Attendees discussed how the regulatory burden can be reduced for both regulators and industry while encouraging PACs that aim to achieve ICH Q10 objectives. In addition, attendees cited the importance of regulatory authorities relying more on each other for science- and risk-based quality, safety and efficacy assessments of PACs rather than demanding redundant local assessments.

Workshop attendees also mentioned certain worthwhile regulatory tools, such as “expanded comparability protocols” (eCPs), as ways to facilitate postapproval changes.

Attendees pointed out that solving the quagmire of global PAC regulations is difficult at a time of a rapidly growing globalization within the industry, but increasing parochial demands of health authorities.

ICH Q12 a PAC Solution?

A unified platform for addressing the challenges and complexity of managing PACs is forthcoming from the working group for quality guideline Q12: Technical and Regulatory Considerations for Pharmaceutical Lifecycle Management.

ICH Q12 will facilitate alignment of different regions and countries on a common definition and set of established conditions. The document should define a lifecycle management strategy and harmonizing on a foundational framework for postapproval change management, including how an effective PQS can be leveraged to reduce the regulatory burden of implementing changes globally.

Moheb Nasr, Vice President, CMC Strategy, GlaxoSmithKline, who is rapporteur for the document, delivered a presentation covering ICH Q12 at the workshop. One desired objective for ICH Q12 is for it to also be adopted and used in non-ICH regions. This is important as many companies market their products globally, thus solutions to PAC complexity must take a global approach to be efficient.

PDA’s PAC Solutions

PDA is taking an active role in providing input to the ICH Q12 working group to facilitate global harmonization through a science and risk-based approach, building on our 10,000+ strong membership.

In addition to discussions through workshops, surveys and discussion forums, PDA’s activities are currently focused on the following key topics:

  • PAC challenges awareness through promulgation of practical examples
  • Lifecycle management (LCM) plans to enable effective PAC planning and implementation
  • Common technical improvements and innovation facilitated by “global change protocols” (gCPs)
  • Leveraging a robust PQS to effectively manage PACs

PDA will develop reports and working papers on each of these topics and tools.

The LCM Plan will provide an opportunity for the marketing authorization holder (MAH) to prospectively provide information to the regulator regarding their plans for managing the product during its commercial life. It can serve either as a regulatory agreement between the MAH and the regulatory body, or as a mechanism for early communication and prospective planning of post approval changes.

The gCP is a detailed protocol that describes one or multiple PAC(s), including rationale for the change, risk assessment, proposed studies needed for validation and comparability, as well as acceptance criteria. The gCP will provide the possibility to standardize certain types of PACs globally based on solid scientific data and agreed upon requirements. The goal is to expedite the change through the regulatory systems of different countries.

In order for LCM Plans, gCPs and leveraged PQS to be successful, it will be important to achieve proactive planning and transparency with health authorities as early as possible. It will also be important for health authorities to further drive reliance on each other’s approval processes.

A successful outcome will result in more postapproval changes implemented via a standard gCP without prior approval reporting and increased reliance on companies’ robust PQS. This ability will result in faster approval or downgrading of reporting for changes that will enable or incentivize companies to incorporate new technologies, improve capability, process control, and enhance product availability.

Additionally, standard implementation and similar reporting requirements and timelines to approval globally will decrease the current complexity of varying PAC processes, ultimately reducing drug shortages and promoting ICH Q10 objectives.

The authors invite those interested in helping PDA’s PAC activities to contact PDA if interested in volunteering in this space.

[Editor's Note: On Oct. 9, EMA held a drug shortage workshop with attendance by National Competent Authorities, U.S. FDA and JPMA observers, industry associations and patient and healthcare organizations. At this workshop, PDA presented its plans and highlighted the importance of addressing lifecycle management as being key to ensure supply continuity. Additionally, PDA is in the process of developing a survey to solicit input on best practices and how companies achieved successes with PACs.]

About the Authors

Melissa SeymourMelissa Seymour is currently the Vice President of Corporate Quality for Biogen Idec. She is currently serving as Past-President of PDA’s Southeast Chapter.

Emma RamnarineEmma Ramnarine is Senior Director, Head of Biologics QC Network at Roche Pharma and is accountable for the biologics QC network strategy.

Denyse Baker is Senior Advisor of Scientific and Regulatory Affairs at PDA.

Anders VintherAnders Vinther is Chief Quality Officer, Sanofi Pasteur. His experience includes QC, QA, executive and strategic management in a variety of cultures and a number of companies ranging from start-ups to large biologics companies.