ICH Quality Guidelines: Present Initiatives & ISPE Involvement

At its inception, ICH—formerly the International Conference on Harmonisation—developed a series of indispensable technical quality guidelines, then expanded to issue some multidisciplinary guidelines (e.g., common technical document [CTD]). It further progressed to issue a groundbreaking series of guidelines on the application of science- and risk-based approaches to drug product development and manufacturing, and associated regulatory applications. In parallel, ICH expanded its membership and influence beyond the original “six pack” of regulators and industry associations from the US, Japan, and EU to 17 country regulators and global industry associations, plus 32 observers, as of 2021 (see Figure 1).1

ICH was formed at a meeting in April 1990 when the regulatory agencies and industry associations of Europe, Japan, and the United States met.2 Prior to the formation of ICH, applications for new drug products in Europe, Japan, and the US were very different, often requiring separate studies and data, with results presented in different formats and styles. These differences resulted in significant duplication of effort and many misunderstandings.

The goal of ICH was, and still is, promotion of public health through international harmonization that contributes to:3

• Prevention of unnecessary duplication of clinical trials and postmarket clinical evaluations
• Development and manufacturing of new medicines
• Registration and supervision of new medicines
• Reduction of unnecessary animal testing without compromising safety and effectiveness

ICH accomplishes these goals through technical guidelines that are implemented by regulatory authorities.

ICH is a unique organization: one of the factors for its success is the strong cooperation between industry organizations and regulators using a consensus-driven approach. In its first decade, ICH concentrated on a prioritized series of core regulatory studies in the areas of efficacy, quality, and safety. As ICH activity continued into the new millennium, the need to expand communication and dissemination of information on ICH guidelines with additional regions became a key focus. A significant step was taken in 2015 when ICH underwent a series of organizational changes and a name change to support extending the benefits of harmonization beyond the founding regions.

ICH members and observers, as of 2021, are listed on the ICH website (with explanations of abbreviations) and summarized in Figure 1.

Figure 1: ICH Current Members and Observers.

There are some differences in roles and responsibilities between the various types of members and observers, but at a high level, members have voting rights, whereas observers can comment but not vote. ICH guidelines are approved by regulatory members in step 4 of the ICH process (Figure 2).

In short, ICH has expanded its global reach and influence to encompass well over half of the world’s population. Its work products are required to be implemented by regulatory members; however, the concepts and ideas are often considered by nonICH members as well within their regulatory frameworks.

ICH Guideline Process

The process for producing an ICH guideline4 is summarized in Figure 2. The main steps for members of industry not involved in the ICH process are in step 3, when a draft consensus guideline is agreed upon. Each ICH regulatory agency circulates this draft guideline for comment using its local procedures and comments can be made according to the local regulatory process, usually, but not inclusively, via an industry association. Comments can also be made by interested individuals outside the ICH-affiliated regions, usually via an industry association.

ISPE Activity

For quality topics considered of interest to ISPE members, an ISPE formal commenting process5 is used, which is managed by ISPE’s Regulatory Quality Harmonization Committee (RQHC). ISPE comments are linked to one of the regional regulatory consultation processes at ICH step 3 (see Figure 2).

In short, ICH has expanded its global reach and influence to encompass over half of the world’s population. Its work products are required to be implemented by regulatory members; however, the concepts and ideas are often also considered by nonICH members within their regulatory frameworks.

Approved Quality Guidelines

In the first decade, ICH teams worked on quality topics described in ICH Q1–Q6, working from a prioritized list (as given on the ICH website6 and summarized in Table 1) and focusing on applications for new drug products and substances. Quality guidelines Q1–Q6 are very technical and they impact the design of development studies and the interpretation of results for summarizing in regulatory applications. These studies generate data that are accepted in most regions of the world, with the need for few additional region-specific requirements. The most significant studies not covered by ICH guidelines are stability studies to support hot and dry (Zone III) and hot and humid (Zone IV) regions of the world —regions that were not included under the ICH founding regulatory members. (ICH Q1F was withdrawn: ICH leaves the definition of storage conditions in Climatic Zones III and IV to the respective regions and the World Health Organization (WHO).)6

Following these initial guidelines, the Q7 guideline on Good Manufacturing Practice (GMP) for APIs was required because, at that time, there was increasing regulatory attention being given to GMP for APIs but no region had an API GMP guideline yet.

Due to advances in science and improved understanding, many of these guidelines have been updated; revised and continued modernization of these decades-old guidelines is expected to continue.

The guidelines are available on the ICH website, and the implemented versions are available on local regional websites. On the ICH website, references are given under each guideline to the implementation status in each regulatory region.

At the start of the new millennium, the ICH Quality Working Group developed a vision for quality:

Develop a harmonized pharmaceutical quality system applicable across the lifecycle of the product emphasizing an integrated approach to quality risk management and science.

This vision drove development of a series of more conceptual guidelines, including Q8 (R2), Q9, Q10, and Q11, which introduced an enhanced science- and risk-based approach to drug development and regulatory applications.

Q8 describes how an applicant can choose to conduct pharmaceutical development studies that can lead to an enhanced knowledge of product performance over a wider range of material attributes, processing options, and process parameters. This enhanced approach should lead to greater understanding of the product and its manufacturing process and this greater understanding “can create a basis for more flexible regulatory approaches.”7

Q9 describes a systematic process for the assessment, control, communication, and review of risks to the quality of the drug (medicinal) product across the product life cycle. Application of quality risk management is fundamental to the enhanced approach discussed in Q8 (R2) and is also a key enabler in operation of a pharmaceutical quality system described in Q10.8

Q10 describes a comprehensive model for an effective pharmaceutical quality system that is based on International Standards Organization (ISO) quality concepts, includes applicable GMP regulations, and complements ICH Q8 and Q9. ICH Q10 is a model for a pharmaceutical quality system that can be implemented throughout the different stages of a product life cycle.9

Annex 1 of ICH Q10, Pharmaceutical Quality System, discusses potential opportunities that could result from an enhanced regulatory approach such as “increase use of risk based approaches for regulatory inspections” and “optimise science and risk based post-approval change processes to maximise benefits from innovation and continual improvement.”

Due to advances in science and improved understanding, many of these guidelines have been updated; revised and continued modernization of these decades-old guidelines is expected to continue

The concepts behind Q8, Q9, and Q10 were, in many ways, paradigm-changing and their implementation was sometimes unclear for both industry and regulators. ICH working groups strove to provide additional clarification and examples through a series of Question and Answer and Points to Consider documents.

The science- and risk-based approaches developed for ICH Q8, Q9, and Q10 were further applied to drug substances in ICH Q11, which, in its core guideline and Q&A document, also discusses some unique aspects of drug substance manufacturing such as designation of regulatory starting materials and impurity clearance.

Additional Life-Cycle Guidance

Nearly a decade after implementation of ICH Q8 (R2), Q9, Q10, and Q11, it was recognized that these guidelines alone were not sufficient to deliver on the ICH vision of a harmonized pharmaceutical quality system applicable across the life cycle of the product. As discussed in the Q12 Concept Paper:10

There is a lack of a harmonised approach on technical and regulatory considerations for lifecycle management. While the concepts in ICH Q8, Q9, Q10 and Q11 provide opportunities for a more science and risk-based approach for assessing changes across the lifecycle, several gaps exist which limit full realisation of intended benefits. The envisioned post-approval ‘operational flexibility’ has not been achieved. The main emphasis at ICH to date has focused on early stages of the product lifecycle (i.e., development through launch).

A similar focus is now needed for the commercial manufacturing phase in order to fill the gaps in the implementation and fully realize the opportunities promised by ICH Q8 to Q11. For example, lack of alignment has led to confusion on the necessary information and level of detail in the dossier and its impact on change management and regulatory reporting. The lack of harmonised approaches for technical and regulatory aspects for lifecycle management can hinder innovation and continual improvement in the pharmaceutical and biotechnology sectors.

Consequently, ICH initiated the development of ICH Q12, “Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management,” which was adopted in November 2019.11

Q12 has introduced new regulatory tools and enablers, some of which already existed in some ICH regions; however, these were not optimally applied by sponsors and accepted or understood in other regions. Examples of such tools and enablers are:

• Established conditions (ECs)
• Postapproval change management protocol (PACMP)
• Product life cycle management (PLCM) document

A summary of these concepts is given in Table 2.

Although finalized in November 2019, as of spring 2021, ICH Q12 is not yet fully implemented in any region, which is not unexpected given that the current regional legislation may not easily allow implementation of all concepts introduced in ICH Q12. An ICH Q12 Implementation Working Group continues to work on developing training material.

CTD and Electronic CTD

In parallel with ICH quality topics Q1–Q6, the multidisciplinary topic (M4) delivered the common technical document (CTD), which is considered a major success for ICH. Also, in parallel, a team of specialists issued standards to support electronic submission of a CTD (eCTD). An overview of the regulatory submission and review process is given in Figure 3.

CTD brings together all quality, safety, and efficacy information in a common, harmonized format, accepted by regulators in all ICH regions. It has revolutionized regulatory review processes for regulators and industry. The structure of a new drug product application and the relationship to the quality, safety, and clinical topics of CTD are shown in Figure 4.

The agreement to assemble all quality, safety, and efficacy information in a common format has led to harmonized electronic submission that, in turn, has facilitated convergence of review practices. For industry, it has reduced the need to reformat the information for submission to the different ICH regulatory authorities. It also enabled some cross-region initiatives: for example, the EMA-FDA Quality by Design (QbD) pilot program.12 The aim of this pilot program was to facilitate the consistent implementation of QbD concepts introduced through ICH Q8, Q9, and Q10 documents and to harmonize regulatory decisions to the greatest extent possible across the two regions.

There remain, however, some region-specific quality requirements in terms of content and presentation for new applications—for example: in Japan, the Quality Overall Summary is of a different level of content because it is the primary review document. Some challenges remain for the quality topics; for example, the content of submissions for postapproval submissions can differ across regions. Some of these challenges are being addressed as part of some ICH current initiatives.

Multidisciplinary Guidelines

Approved relevant multidisciplinary topic guidelines applicable to CMC development and registration of new drug products are summarized in Table 3.

M7 is intended to resolve inconsistencies in the early guidances between the EMA and FDA relating to impurities that are DNA reactive, and the recommendations in the ICH general impurities guidance, Q3A. A science- and risk-based approach is used in establishing levels of mutagenic impurities that are expected to pose negligible carcinogenic risk.

The BCS-based biowaiver described in M9 is only applicable to immediate-release, solid, orally administered dosage forms or suspensions designed to deliver drug to the systemic circulation; drug products with narrow therapeutic index are excluded from eligibility. This guidance is useful to support potential drug product changes during clinical development and through to commercialization.

ICH Quality and Multidisciplinary Initiatives

Current activity is driven by new technology and scientific advancement and has led to revision of some signed off guidelines, as well as new topics. A major milestone for an ICH guideline is the issuance of a draft consensus document at step 2. Current ICH guidelines that are pre-step 2 are summarized in Table 4.

The existing guidelines in Table 5 have reached step 2 and issued the draft consensus guideline; they are undergoing revision based on comments received from regulatory review before final regulatory sign off and subsequent implementation.

ISPE Initiatives Supporting ICH

To assist industry with the understanding and implementation of ICH guidelines Q8, Q9, Q10, and Q11, ISPE established the Product Quality Lifecycle Implementation (PQLI®)initiative focused on providing practical implementation guidance. Key outputs for members are the PQLI Guide series in four parts:

• Part 1, Product Realization Using QbD: Concepts & Principles13
  • Overview
  • Criticality
  • Design Space
  • Control Strategy
• Part 2, Product Realization Using QbD: Illustrative Example14
  • Drug product and API
• Part 3, Change Management System as a Key Element of a Pharmaceutical Quality System15
• Part 4, Process Performance & Product Quality Monitoring System16
• Many emerging topics and other ICH topics have a related active subteam in ISPE, either through PQLI or other regulatory teams. These teams work to help develop the concepts underlying the regulatory guidances and to assist regulators and ISPE industry members with implementation.
• A knowledge management ISPE Good Practice Guide, aligned with the principles of ICH Q9 and Q10, was published in May 2021.17 ISPE teams have also provided training to regulators on ICH concepts to US FDA, UK MHRA, and Brazil ANVISA.

ISPE’s global RQHC has established a team to assist members with implementation of revisions to Q9. The quality risk management topic is important to many ISPE programs, for example, the Drug Shortages Initiative. ISPE has provided the ICH Q9 EWG with relevant ISPE training material and PQLI documents for consideration in their deliberations.

A PQLI Continuous Manufacturing team has been established for several years. It has published multiple articles,18 sponsored biannual ISPE Continuous Manufacturing Workshops since 2016, and frequently provides sessions at ISPE conferences. It continues to track progress of the ICH Q13 guideline in preparation and is expected to comment on the ICH Q13 Step 2 draft document.

A PQLI Q12 team has been established to assist industry and regulators with implementation of ICH Q12. It is very active and published an article19 in Pharmaceutical Engineering® in May-June 2019 on the challenges the ICH EWG faced in reaching consensus for the signed off ICH Q12 document. The team delivered a webinar20 with FDA participation in March 2021 on the challenges and successes of Q12 implementation. It has provided case study examples for consideration by the ICH EWG in their efforts to produce a step 2 draft document.

Additional workgroups will continue to be added to ISPE’s regulatory teams as new topics emerge.

ISPE Initiatives Supporting Future ICH Activity

ISPE has ongoing projects and initiatives that could support any future ICH activity:

• PQLI has a team working on Patient Centric Quality Standards, which hosted a session at the 2018 ISPE Quality Manufacturing Conference21 and published an article.22 This team is available to work on any proposed Q6A and Q6B revision.
• PQLI’s Accelerated Development team has published three articles23^, 24^, 25 that can help provide foundation for future related ICH topics.
• ISPE’s RQHC North America Regional Focus Group has established a Modernization of Module 3 team to consider the implications for industry members on the FDA Knowledge-aided Assessment and Structured Application (KASA) and regulatory submission-associated projects. This team could support revisions to ICH M4Q CTD.
• ISPE’s global RQHC has established a team to examine how the learnings from “distant assessments” and mutual reliance could be promoted and implemented in a harmonized manner based on learnings from the COVID-19 pandemic. This activity could be available to any ICH activity resulting from the ICH collaboration with PIC/S.
• ISPE has established a new ATMP Community of Practice with the goal of considering:
  • Manufacturing processes/techniques, including the development of a robust control framework to ensure product quality
  • Robust analytical and stability methodologies
  • Strategies for raw materials, in process, and accelerated product release
  • Regulatory landscape

Future ICH Activity

In May 2020, the ICH Assembly endorsed the proposal “Revision of M4Q(R1) CTD on Quality guidance,” with an M4Q(R2) informal Working Group to be established with a delayed start once the Q13 EWG would reach steps 1 and 2a/b. The Assembly supported work on the following topics:

• Revision of M4Q(R1) CTD
• Structured product quality submissions

Much of this future work for the M4Q revision is driven by the US FDA and their programs on Knowledge-aided Assessment & Structured Application (KASA)26 and Product Quality/CMC (PQ-CMC) structured product data. The vision is for a unified system that will capture and manage knowledge during the life cycle of a drug product, with consistent rules and algorithms for risk assessment, control, and communication. Such a system will facilitate com-puter-aided analyses of applications using structured assessment that minimizes text-based narrative. Of course, activity by the FDA has the potential to impact CTD submissions and review in all ICH regions.

There are ongoing discussions by an ICH team called the Quality Discussion Group to review new quality topics in consideration for future ICH development. A publicly available report with recommendations from this team is expected by the end of 2021. Potential recommendations are likely to include:

• Q6A and B revision
• Stability topics: Q1 series plus Q5C
• Impact of learnings from the COVID-19 pandemic, e.g., accelerated approvals
• Advanced therapy medicinal products such as gene therapy medicines, somatic-cell therapy medicines, and tissue-engineered medicines

There are other ongoing ICH activities that can influence pharmaceutical development and manufacturing. The Pharmaceutical Discussion Group (PDG) is piloting an approach for the engagement of the pharmacopoeias of the countries/regions of non-founding ICH regulatory members. The aim is to review how a selected number of pharmacopoeial monographs considered interchangeable by European Pharmacopoeia, Japanese Pharmacopoeia, and United States Pharmacopeial Convention in Q4B Annexes could also be considered interchangeable in other ICH regulatory regions’ pharmacopoeias.

ICH has agreed to a pilot collaboration with PIC/S on ICH Guideline work with relevance to both regulator assessor and inspector disciplines that may be able to build on the success of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) in mutual recognition of inspections and harmonization of GMP requirements.

The ICH Management Committee has a responsibility in the 2021 Work Plan to continue ICH-driven mechanisms to assess implementation and adherence to the ICH guidelines through surveying and results analysis.

Conclusion

ICH has been a successful organization for over 30 years, delivering on its mission to achieve greater harmonization worldwide to ensure that safe, effective, and high-quality medicines are developed and registered in the most resource-efficient manner. Apart from the many efficacy, quality, safety, and multidisciplinary guidelines that have been issued, its success can be measured by both the increased participation and the growing number of regulatory authorities and other organizations becoming members of ICH or following its activities closely.

ISPE is an affected organization and consequently has increased its involvement: for example, by assisting with implementation and training of some quality guidelines. ISPE has positioned itself to continue assisting ICH and other harmonization processes to facilitate regulatory harmonization and mutual reliance of regulatory review and inspection to assure efficient global availability of quality medicines for patients.