ICH Q12 Guidelines Spark Controversies

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology-04-02-2018, Volume 42, Issue 4

The flexibility and incompatibility of ICH Q12 guidelines with current EU legislations raise complications.

As the world’s economy is increasingly threatened by new barriers to trade, the pharmaceutical sector through the Geneva-based International Council for Harmonization (ICH) has been stepping up its efforts to dismantle obstacles to global trade in medicines. At a time when ICH has been restructuring itself to give regulators more clout in the organization, it issued in December 2017 a draft guideline (1) aimed at more uniformity in rules on the quality of medicines throughout their lifecycles, particularly in the period after marketing authorization. It adopted, in December 2017, a guideline (2) on the planning and design of multi-regional clinical trials (MRCTs) to facilitate their acceptance across the world.

ICH Q12 guidelines

The Q12 guideline of lifecycle management, although still in draft form, is already turning out to be controversial because it has been issued without the support of industry, which claims its degree of harmonization does not go far enough. The ICH Q12 proposals, now undergoing a year-long public consultation that started in December 2017, makes up the last of a series of five quality guidelines covering product and process development (ICH Q8 and Q11), application of risk management principles (Q9), and an effective pharmaceutical quality system (Q10). It aims to fill the gaps in the way the four Q8–11 guidelines cover issues relating to lifecycle management, particularly in relation to chemistry, manufacturing, and controls (CMC).

The new guideline underlines the continued progress by a reinvigorated ICH in helping to integrate the management of medicines at the international level through the harmonization of regulations. But the restructuring of the ICH is largely an initiative of the regulators to put themselves in a stronger position to obtain the changes they want, if necessary, without the backing of industry.

ICH was founded in 1990 by the regulators and research-based industry associations in Europe, the United States, and Japan with the objective of issuing jointly agreed harmonized standards on the quality, safety, and efficacy of medicines. In recent years, it has been in danger of losing its legitimacy as the world’s leading body for drawing up medicines standards because its partnership consisted of only six regulatory and industry organizations in Europe, the United States, and Japan. It has, therefore, been creating a governance structure that enables new members, particularly from the developing world, to join the ICH. But the strategy behind this expansion has been to put the regulators in charge.

The ICH Assembly, at a meeting in Geneva in November 2017, approved as a new member Singapore’s regulator, Health Sciences Authority (HSA). This approval gave it a total of 15 members-nine regulatory agencies, including the medicines authorities of Brazil, China, and South Korea and six industry associations including the US-based Biotechnology Innovation Association (BIO), the World Self-Medication Industry association (WSMI), and the International Generic and Biosimilar Medicines Association (IGBA).

Under the terms of the reorganization of the ICH, which although initiated three years ago is still not complete, the technical content of guidelines is drawn up by a working group of regulatory and industry scientific experts. Their adoption, however, is the responsibility of the regulators, who can finalize guidelines without the agreement of industry representatives.

Incompatibility with established framework

During the final stages of the drafting of the Q12 guideline, the European Commission, the European Union executive, discovered after a review of EU rules that parts of the guideline could not be implemented in the EU without changes in legislation. This is despite large sections of the guidelines already being implemented in the Union. At the Commission’s insistence but with the backing of regulatory representatives on the experts working group (EWG) drawing up the guidelines, additions were made to the guideline’s introduction about the incompatibility of the guideline with the “established legal framework” in certain ICH regions.

These differences are mainly centred on the guideline’s concepts of established conditions for manufacturing and control for categorizing quality elements requiring regulatory submission if changed and for product lifecycle management (PLCM), which will provide a central repository on details of established conditions.



The draft guideline (1) allows a degree of incomplete harmonization under which its proposals for established conditions and PLCM could be implemented under existing but possibly incompatible regional or national regulations until the regulations themselves are amended. “These concepts will be considered when the legal frameworks will be reviewed and, in the interim, to the extent possible under the existing regulation in these ICH regions,” the guideline says.

Both the established conditions and PLCM concepts are at the core of the Q12 guideline. The established conditions provide a basis for a key objective behind the guideline of enabling marketing authorization holders (MAHs) to commit themselves, with the agreement of their regulatory agencies, to their own lifecycle management protocols for manufacturing and other changes. It aims to facilitate greater predictability and efficiency in the management of post-approval CMC changes, particularly through the use of increased product and process knowledge. The established condition concept is “the single most important element of the Q12 guideline,” says Beata Stepniewska, deputy director general and head of regulatory affairs at Medicines for Europe, representing generics and biosimilars producers.

In the draft guideline (1), established conditions are divided into two categories-“implicit,” derived from existing regional regulation or guidance without being proposed by the MAH and “explicit,” which are specifically identified and proposed voluntarily by the MAH itself. The explicit approach gives the MAH, with the agreement of the regulator, the freedom to focus on process performance by using automation tools such as in-line continuous monitoring. The PLCM system in the guideline provides for documentary back-up for a product-specific approach covering key elements of an MAH’s quality control strategy and any post-approval CMC commitments that have been put forward by the authorization holder and then approved by the regulator. Under the ICH guideline, however, the two concepts may not be brought into effect fully-at least for a while-because regulators would be able to stick to their own existing non-compatible regulations.

“Flexibility to deviate from a harmonized and agreed guideline and to allow some exceptions to not implementing the guideline fully at the regional level would undermine the whole principle of harmonization,” says Stepniewska. “Non-acceptance of the established conditions would have a big impact on companies trying to get a harmonized dossier across several regions.”

Opposition from EFPIA

The European Federation of Pharmaceutical Industries and Associations (EFPIA), representing Europe’s research-based pharmaceutical companies and a founding ICH member, has also been critical of the flexibility allowed in the draft guideline. “[We are] disappointed that stakeholders within the European Union will not be able to benefit fully from the efficiency gains that were hoped to be achieved through full implementation of ICH Q12,” says an EFPIA spokesperson. It sees the main benefit of the Q12 guideline as bringing greater efficiency in the lifecycle management of product manufacturing, which should reduce drug shortages and ensure patient access to medicines.

“EFPIA is keen to work with the European Commission and the European Medicines Agency (EMA) to assess more closely which parts [of the ICH Q12 guideline] might be implemented now and at what point it might be appropriate to address the others,” the spokesperson adds. EFPIA echoed the views of Medicines for Europe that the flexibility allowed in the guideline could affect all pharmaceutical companies in Europe and elsewhere with international operations in medicines subject to manufacturing changes during their lifecycles. “Even if the ICH guideline will be implemented by the majority of ICH [regulatory] members, companies would not benefit fully from it [because their] standard practice is to release products first when the changes in the manufacturing process is accepted by all regulatory authorities,” the EFPIA official explains.

The restructured ICH, now called ICH Association, generally aims to reach consensus with industry and other stakeholders by the end of a guideline finalization process. But that may be difficult in the case of Q12 because of a deep divide over the issue of regulatory flexibility. Nor would a more powerful industry presence in the new ICH have made much difference. “The ICH Q12 is a very specific case, as the Commission found out at a late stage that the draft ICH guideline cannot be implemented without a change in EU legislation,” says the EFPIA spokesperson. “A stronger industry voice or representation would, therefore, not have addressed this issue.”

The industry itself could also take some of the blame. “The conclusion is, however, that both the Commission and the European industry need to make a proper legal analysis earlier in the process for topics that risk being in conflict with EU legislation,” admitted the spokesperson. Nonetheless, the issue of representation at the top level of decision-making on global regulations and standards remains a matter of concern for the pharmaceutical industry.

“[The industry’s worries about the guideline] does not mean that we challenge the [regulators’] dominant role in the ICH and the possibility for them to endorse the guideline even if the industry is against it,” says Stepniewska. “If we want to achieve progress in science and in implementing an outcome of scientific discussion, previously established regulatory frameworks shall not be a barrier to achieving progress.”


1. ICH, Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, Draft version (ICH, Geneva, 16 Nov. 2017).
2. ICH, E17 General Principles for Planning and Design of Multi-Regional Clinical Trials-E17, Final version (ICH, Geneva, 16 Nov. 2017). 

Article Details

Pharmaceutical Technology Europe
Vol. 30, No. 4
April 2018
Pages: 6–8

When referring to this article, please cite it as S. Milmo, “ICH Q12 Guidelines Spark Controversies,” Pharmaceutical Technology Europe 30 (4) 6–8 (2018).