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  1. Pharmaceutical Quality - Chemistry, Manufacturing & Controls | PQ/CMC

PQ/CMC and HL7 FHIR

PQ/CMC and HL7 FHIR

In order to assist in understanding the development of the PQ/CMC implementation Guide using Fast Health Interoperable Resources (FHIR) which is a product of the standards development organization Health Level 7 (HL7) this page will walk through some key points of the general process of HL7 project development, an overview of the planned staging to add progressively new content to the FHIR IG, and finally an aid to navigating the various FHIR IG releases over time.

PQ/CMC at HL7.org

The PQ/CMC Data exchange standard is intended to be developed using the data standard called “Fast Health Interoperable Resources” (FHIR) which is a product of HL7. The result of this work will be an Implementation Guide published at HL7.org. For any Implementation Guide to publish at HL7, the first step is the establishment of a project at HL7, approved by consensus vote, and sponsored by an HL7 working group. Every HL7 working group has its specific areas of focus, so different projects are sponsored by the relevant interested workgroup.

The project “Pharmaceutical Quality - Chemistry, Manufacturing and Controls (PQ-CMC) Submissions to FDA" has been established with the HL7 Biomedical Research & Regulation (BR&R) work group which has a focus on use cases for clinical research and regulatory affairs, such as submissions to pharmaceutical regulators like FDA. Discussions regarding representing the PQ/CMC structured elements in FHIR, when they occur from time to time, take place on one of the weekly working group calls of either BR&R or other relevant HL7 WGs. These HL7 BR&R WG calls are open to the public. To see the agenda for the meetings and learn more, go to https://confluence.hl7.org/display/BRR

The goal of this project is the development of the HL7 FHIR Implementation Guide “Pharmaceutical Quality - Chemistry, Manufacturing and Controls (PQ-CMC) Submissions to FDA” to ultimately support submission of ICH CTD Module 3 information in structured format using HL7 FHIR. Every version of an IG which is to be published at HL7 goes through a basic cycle:

  1. Testing of the draft IG at an HL7 Connectathon
  2. Balloting of the IG for vote and comment by HL7 members
  3. Publication of the IG release, reflecting any changes made as a result of Ballot comments

Please note that HL7 Connectathon testing, balloting, and publication of versions of a FHIR Implementation Guide (IG) do not represent the IG in its final form nor do these activities in any way constitute a statement of policy or guidance from FDA. There are formal processes and timelines by which FDA announces support for accepting data in a particular format, so until such time, the growing PQ/CMC HL7 FHIR Implementation Guide is available to review at HL7.org. As new updates are added to the IG at HL7, there will be opportunities to participate in testing new IG content at HL7 Connectathons and to comment during balloting of the new content.

PQ/CMC IG Development Stages

Since the total set of information in PQ/CMC is very large, it was decided to iterate development of the Implementation Guide in “stages”, where a subset of PQ/CMC data domains is addressed in the first stage, then additional domains are added in the next stage, and so on until all of PQ/CMC is covered.

Also, since there are many types of drug products – solid oral (such as tablets, capsules, including different time-release profiles), liquids, biologics, and so on – it was chosen to first focus on the data needs for solid oral dose forms (SODF). In this way, there will soon be an IG that supports all of PQ/CMC submissions for all solid oral dose forms. In parallel, work continues at the FDA to develop additional data standards for liquids, biologics, etc., which will be reflected in subsequent updates of the Implementation Guide.

This table presents the current planning for Stages of IG development. Note that the later stages presented are subject to change as best practices from prior rounds of development are applied.

IG StageAdded support for:Notes:
1Product Description and Composition of the Drug Product 
Substance General Information; Specification (Substance, Excipients, Product); Substance Control of Materials		Optimized for Solid Oral Dose Forms
2Product Impurities;Substance Characterization; Substance Impurities; Product Batch Formula;Optimized for Solid Oral Dose Forms
3Batch Information; Batch Analysis; Stability Summary; Stability Data; Product Container ClosureOptimized for Solid Oral Dose Forms
4Product ManufacturingOptimized for Solid Oral Dose Forms
5Substance ManufacturingOptimized for Solid Oral Dose Forms
6Liquid Dose FormsUpdates all previous domains with additional support for liquid dose forms
7BiologicsUpdates all previous domains with additional support for biologics

For further understanding of what information is part of each of these domains, refer to FDA’s “Guidance for Industry M4Q: CTD-Quality”

Current Status of Implementation Guide Development

StageFDA Federal Register Notice (FRN)Support added for (relevant ICH CTD Module 3 Section)HL7 Connectathon TestingHL7 BallotHL7 Publication Status
Stage 1Data Elements & Terminology Published in FRNGeneral Information (3.2.S.1) 
Control of Materials (3.2.S.2.3) 
Specification (3.2.S.4.1, 3.2.P.4.1, 3.2.P.5.1) 
Description and Composition of Drug Product (3.2.P.1)		January 2024 (Virtual)May 2024 
(Passed)

Published as Standard for Trial Use 1.0.0 - STU1

Stage 2Data Elements & Terminology Published in FRNSubstance Characterisation (3.2.S.3) 
Product Batch Formula (3.2.P.3.2) 
Product Characterisation of Impurities (3.2.P.5.5)		September 2024 (Atlanta, GA)Jan 2025Q2/3 2025 
(tentative)
Stage 3Data Elements & Terminology Published in FRNBatch Analysis (3.2.S.4.4, 3.2.P.5.4) 
Stability Summary (3.2.S.7, 3.2.P.8.1) 
Stability Data (3.2.S.7.3, 3.2.P.8.3) 
Substance Container Closure (3.2.S.6)		September 2025 
(tentative)		January 2026 
(tentative)		Q2 2026 
(tentative)
Stage 4Data Elements & Terminology Published in FRNProduct Manufacturing (SODF) (3.2.P.3.1, 3.2.P.3.3, 3.2.P.3.4)TBDTBDTBD
Stage 5Not yet publishedSubstance Manufacturing (SODF)TBDTBDTBD

FHIR Implementation Guide Development Cycle

FHIR Implementation Guides are not static documents (such as PDF files) but, instead, are dynamic web-based pages that can be navigated as one would on any other web site.As development of an IG matures, and as newer versions of an IG are published, the number of unique web URLs will accumulate. This may cause some confusion to people new to FHIR IGs. To orient people as to what the various artifacts of IG development represent, here is an overview of the FHIR IG development process and associated URLs:

  1. “Build” Content: At the beginning of IG development, typically the only accessible form of the IG is at what is termed the Continuous Integration (CI) build site for the IG. Here content can and does change daily as more work is put into the IG. This can be thought of as a place one can see edits and changes to the IG happen in near real-time. As versions of the IG become officially balloted and published, the build site will continue to be the work-in-progress location as work begins on the next version of the IG.
    • The CI build is located at the base URL for the IG. For the PQ/CMC IG, the build URL ishttps://build.fhir.org/ig/HL7/FHIR-us-pq-cmc-fda/.
    • Note that content at the build site is not official published, stable content. It is literally work-in-progress. It can change at any time.
  2. Balloted Content: After content in an IG is tested at an HL7 Connectathon, it is submitted to vote during a Ballot Cycle. HL7 ballot cycle is three times a year – January, May and September) When this happens, a snapshot of the content in the build environment is copied into a permanent new URL for reference during voting by HL7 members.
    • It is typical for many changes to happen to IG content between a Ballot and publication which are mainly driven by the comments received during the ballot.Once that version of the IG publishes, the Ballot versions of an IG should mainly be viewed as historical reference.
  3. Published Content:Once an IG passes the Ballot Cycle with sufficient votes in support of it, there is a period of ballot reconciliation (i.e. – all the comments that are received are reviewed and often result in changes to the IG content) This process takes a few months during which the ballot comments are often discussed at BR&R WG meetings and voted on.Once the IG is updated it will ultimately be published at HL7.org as an HL7 Standard with a unique release number and a unique, permanent URL. Unlike content at the build site, content of a published version does not change – it is permanent. Every time a new updated version of the IG is published, the new version will be given a new unique release number and URL. For example:
    • The first version of the PQ/CMC IG was published, given the release number of 1.0.0, and can be found at https://hl7.org/fhir/us/pq-cmc-fda/STU1/.
    • The next major update of the IG, when published, will be release number 2.0.0 and will be found at https://hl7.org/fhir/us/pq-cmc-fda/STU2/. (We hope to publish STU2 by Q2 or Q3 2025, so until that time, this URL will have no content).
    • Occasionally there is a need to update published IG content with minor fixes or refinements.This will not happen in the already published URL, but instead will be published as a new version with a new minor release number (such as 1.1.0) and a new URL (such as one ending in /STU1.1).
  4. Reference page for all versions of an IG: For every IG, you can find the listing and links for all these steps of development, every ballot version, every published version, and even the CI build (called “current”) at the Publication (Version) History page for the IG. For PQ/CMC this is located at https://hl7.org/fhir/us/pq-cmc-fda/history.html

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