Lack Of Harmonization In ICH Q12 Draft Guideline Draws Fire In US

Major pharmaceutical industry groups in the US, like their counterparts in the EU, are concerned that the draft ICH Q12 guideline does not align with the established legal framework in certain ICH regions, including the EU, in terms of implementing key concepts such as established conditions and product lifecycle management.

Major pharmaceutical industry groups in the US say that while they support in principle many of the core principles of the draft ICH Q12 guideline on lifecycle management and post-approval changes, they are concerned about its implementation, and about its incompatibility with the established legal framework in certain ICH regions, including the EU.

They complain that not having a global framework for some core concepts of ICH Q12 like established conditions (ECs) and product lifecycle management (PLM) would mean that these concepts are open for regional regulatory interpretations, thus posing a risk of divergence across countries.

The groups also said there is lack of clarity on such terms as key process parameters (KPPs), and that more clarity is needed on explicit versus implicit established conditions.

The draft ICH Q12 guideline was issued on Nov. 16, 2017. (Also see "Global Post-Approval Changes Outlook Murky As Q12 Lurches Into Consultation" - Pink Sheet, 4 Jan, 2018.) In May 2018, FDA posted the ICH Q12 draft guidance for public comment. The agency received 22 comments from major pharmaceutical trade associations and manufacturers by the Dec. 18, 2018, deadline. The document is expected to be signed off as a Step 3 guideline (regulatory consultation and discussion) in June.

Many of the comments supported in principle the overall goals of the ICH Q12 guideline, but commenters envisioned major problems with implementation and its potential to cause more divergence in the process of reporting post-approval changes.

A core concept of the draft guideline is established conditions, which are defined as “legally binding information (or approved matters) considered necessary to assure product quality.” Any changes to ECs “necessitates a submission to the regulatory authority.” It further states that EC can either be implicit or explicit.

Overall Guideline Supported

Two industry groups, the Biotechnology Industry Organization and Pharmaceutical Research and Manufacturers of America, said the guideline is based on sound philosophical concepts offering "useful regulatory tools and enablers" such as established conditions, post-approval change management protocols and post-approval lifecycle management.

PhRMA said that “if well-executed and implemented, the concepts and tools articulated in the guide hold out the promise of reduced regulatory uncertainty and more efficient post-approval chemistry, manufacturing and controls (CMC) changes.”

The International Society for Pharmaceutical Engineering said that “the ICH working group has laid out an impressive document in ICH Q12 covering the lifecycle of a product to provide clear expectations for change management, encourage manufacturers to adopt lifecycle approaches for continual improvement and innovation. The development of this guideline is a welcome progression of the ICH vision and the Q8-Q11 guidelines.”

Problems Seen With Regulatory Divergence

Yet while groups support the underlying principles, the difficulty is applying these principles to practice, as the guideline is not “fully compatible” with the legal framework with regard to the use of ECs and PCM in ICH regions including the EU.

The ICH Q12 guideline says that in certain ICH regions, “the current ICH Q12 guideline is not fully compatible with the established legal framework” with regards to ECs and product lifecycle management.

The guideline adds that concepts will be considered when the legal frameworks of these non-compatible regions are reviewed and, in the interim, to the extent possible under the existing regulation in these ICH regions.

BIO writes that while “pleased” that FDA has confirmed that ICH Q12 is fully compatible with established legal framework, the group is “concerned that this regional incompatibility will impact the broader harmonization efforts and will not reduce the burden on either industry or regulators. Regulatory processes across the ICH regions need to be harmonized and the purpose of ICH is to promulgate this harmonization across its regions.”

In its current form, said BIO, “this stated conflict with established legal framework … leaves a lot of room for regional regulatory interpretations (notably, the term 'region/regional' is mentioned multiple times). In this context, there is a real risk of divergence across countries/regions, both in terms of approved ECs and reporting categories, which are by default regional as well. Divergence in regional implementation might lead to different sets of approved ECs for different scopes and even more divergence in regulatory documentation and approval timelines and requirements.”

PhRMA concurred. “It is unclear how the draft guidance will lead to harmonization and reduction of regulatory burden as a practical matter. … Flexibility in regional implementation might lead to different sets of approved ECs and PACMPs for different scopes and an even further divergence in regulatory documentation and approval time lines/requirements.”

The Parenteral Drug Association chimed in with similar concerns, saying this lack of a legal framework “provides no guarantee of medications and therefore will dampen the harmonization effort and fail to reduce the regulatory burden for both regulators and industry.”

Similar complaints were heard from a number of EU pharmaceutical industry associations responding to the European Medicines Agency’s call for comments on ICH Q12. The EMA published a consolidated response, and the response also voiced concerns about the lack of a legal framework in the EU or ECs and PACMPs. (Also see "EU Pharma Slams ICH Proposal For Selective Adoption Of Quality Guideline" - Pink Sheet, 9 Jan, 2019.)

Confusion About Implicit ECs and Explicit ECs

Industry groups also said that there is confusion about what is meant by explicit and implicit established conditions.

BIO said that “as currently written, the concepts of implicit ECs are not well defined. We find that the current definition enables a wide scope of elements to be categorized as implicit ECs. It does not seem necessary to create this category of ECs, or make the distinctions between the approaches to define ECs. We strongly recommend removing the distinction between implicit and explicit ECs and maintain a single category of ECs within the guideline.”

The group added that if the concept of implicit and explicit ECs are maintained, then specific examples should be shown of each.

KPPs Should Be Removed

A number of comments also said that the term “key process parameter” should be removed. The guideline defines KPPs as parameters of the manufacturing process that may not be linked to critical product quality attributes but need to be tightly controlled to assure process consistency as it relates to product quality.

Gilead Sciences said that “the definition of KPP is problematic and likely to lead to variation in interpretation between regulators and industry.” The company recommended that the term be deleted in the guideline.

ISPE said that the term key process parameter should be “clarified and amplified.”

“There is already difficulty understanding CPPs. At the time of application, process consistency has historically not been required, hence the need for KPPs is hard to understand both from a technical and regulatory viewpoint. We suggest a simpler definition of a KPP, a parameter of the manufacturing process which is not critical to product quality but that needs to be controlled.”

Shire Wants Linkages To Other ICH Documents

Shire is concerned about the lack of linkages between this guideline and other ICH guidelines. The company also notes “significant discrepancies” between this guideline and other related ICH guidelines, specifically ICH Q8 on pharmaceutical development and ICH Q11 on development and manufacturing of drug substances.

Shire writes that “given our substantial concerns regarding potential challenges to proper and timely adoption and implementation due to apparent misalignment, Shire urges the FDA and the ICH Expert Working Group to consider expanding, clarifying and specifying the linkage of this document to existing ICH guidelines. We believe that this will result in ensuring closer convergence with ICH Q8 and Q11, among others.

PhRMA Wants New Annex For Vaccines

In other comments, PhRMA said that it wants a new annex that describes common pre- and post-approval changes for vaccines and that shows how ECs could be managed. Such changes should include considerations of working seeds and reference standards.

PhRMA also suggested that the guidance be voluntary. “Many sponsors will embrace a risk-based approach to post-approval CMC changes, but some companies may find the additional filings and tools outlined in Q12, along with related regulatory engagement, too burdensome. This seems especially likely for sponsors of products that are already approved.”