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CMC Conformance

Tue 14 November 2023Reading time: 5 minutes

Medicine manufacturers may spend billions in research and development to attain the holy grail of the Industry: an authorisation allowing it to place a medicinal product on the market. Only after this may they start to recoup some of this investment. That is not the end of the story of course, since without a robust system of change control, over time this coveted registration can drift away from the actual product that is being manufactured, which can pose a significant risk to patients. This is far from uncommon and ultimately costs the life sciences industry millions through the necessary allocation of its stretched resources to Chemistry, Manufacturing and Control (CMC) initiatives, not to mention the reputational damage caused with regulatory bodies and the public, when products may be temporarily or permanently removed from the supply chain. By using proven methodologies and tools, and encouraging a robust change management ethos, the burden of CMC conformance on the industry can be reduced from having to undertake repetitive rounds of these resource-intensive activities.

What is CMC non-conformance?

The movement of a medicinal product’s manufacture and control away from its source Marketing Authorisation (MA) results in CMC non-conformance, which may lead to serious safety implications for the patient, as well as the risk of product recall, with associated loss of revenue and impact to company reputation.

The life sciences industry experiences ever more regulatory scrutiny through increasing inspections by regulatory bodies, adherence to new and changing guidelines, due diligence through M&A activities, technology and innovation advancements to name a few. It cannot be understated therefore how critical CMC conformance can be in this context.

Though many definitions will exist online, conformance in the framing of this article is thought to be the alignment of MAs to the actual practices of its organisation i.e. what a company has committed itself to through the terms of its registrations, in contrast to compliance, which is the requirement of an organization to meet local and national laws (and guidelines).

Many companies choose, or are compelled, to undertake CMC conformance initiatives that span many years, requiring significant resources (both time and cost), often by partnering with experienced service providers to save its internal resource, which are frequently stretched, and also to enhance the overall effectiveness of the programme.

CMC conformance is a post-approval activity that can easily be de-prioritised, against the backdrop of the increasingly complex and diverse landscape that the life sciences sector exists in, due to its inherent non-revenue generating nature, however, such measures are essential to protect the MAs (and the MA holders) against drift, ultimately safeguarding the patient.

How to manage – a CMC gap analysis and remediation initiative

From experience, deficiencies in a manufacturer’s change control system/processes, whereby manufacturing changes are not accurately identified, documented, impact and risk assessed, often instead being implemented independently can shift away product conformance from the source MA registration over time. Non-conformance with CMC information can also result from early filing inaccuracies, especially with global products marketed in several jurisdictions having slightly divergent specifications according to the local/compendial requirements, or situations where there is a complex network of manufacturers or licensing partners.

Irrespective of the root cause(s), the requirement for CMC conformance initiatives may present itself every 5-10 years, coming at a huge cost to the industry.

It is necessary to use proven methodologies and digital tools and systems, to conduct an effective programme to analyse and remediate conformance gaps in order to reinstate the standard in effect at the time of MA approvals. Without this, the likelihood is high for product supply interruption or even suspension and regulatory agency action. A framework that optimises the success of such CMC conformance objectives would need to consider the following factors:

Strong leadership and cross-organisation engagement

Conformance/compliance initiatives can cause negativity especially when supported by internal resources alongside existing workloads. A sustained focus and consistent approach, promoted by the leadership team will help deliver the activities when they may impact a significant part of an organisation over several years.

Establish the project scope

A vital step requiring input from the relevant stakeholders is to define the number of MAs/markets/manufacturing sites within scope for the project at the outset, in order to mitigate creep. Inevitable change can of course be managed through the change control protocols, which also are imperative to be established and disseminated. Asking the right questions at the outset will improve likelihood of success:

  • Which markets, production sites and products are to be included?
  • Is the whole module 3 dossier to be reviewed?
  • Will there be a need for translation of MA or site documentation?
  • How will gaps be risk classified?
  • What assumptions should be made where information cannot be identified?
  • Is there capacity for this project to be wholly managed internally or will external support be required?
  • Can the scope be split into waves according to priority?
  • Is there time to run a pilot to test methodology and process before embarking on the full programme?
Define the CMC conformance process

Include process flows, metrics, Key Performance Indicators (KPI), Standard Operating Procedures (SOP) as required. Plan as much as possible with cross-functional teams before commencing activities to ensure smooth and efficient running of the project. Measures should also be agreed for tracking outcomes, communication, and escalation routes for any issues. A clear communication pathway should be established to avoid duplication in requests, particularly with the critical stakeholders e.g. at manufacturing sites and in the markets. If it is possible to provide metrics through a real-time dashboard this will aid project oversight and governance, as well as facilitating the regular interactions with the key personnel.

Change-control process

Outside of the existing change-control process used by the organisation, a formal process to manage proposed changes to the scope or processes/systems used in the project would be required.

IT systems

Consider the hardware, training, access and permissions needed for the project team, which may be both internal and external to the organisation. Also a framework for IT support will be necessary.

Pre and post project

A trial or pilot phase might identify useful learnings to refine the proposed processes before committing to a full scale endeavour. A detailed project evaluation on closure of the project will certainly help with the establishment of best practices for future projects.

The CMC conformance process – gap analysis & remediation

The below infographic provides a summary view of the activities involved in a CMC conformance process. Although the individual steps appear somewhat evident, it is crucial to nail down and fully document the process with the cross-functional team before commencing, since without comprehensive buy-in from the leadership and all stakeholders, such initiatives, especially when global in scope, will undoubtedly lose focus and momentum, and be at risk of inconsistency and incompletion.

Current MA/Registration – collation of source registered documents

This step comprises the retrieval of data from markets and collating them to firstly assess their completeness, followed by verification of the data and addressing any queries associated with the data with the markets.

The registration documents from the markets for each licence/MA would typically be housed in an industry-standard document repository. The details however may be composed of a mix of MS Word and Adobe pdf documents, depending on the age of the dossier and the specific markets the products are licensed in. Rarely, hard copy paper documents need to be OCR scanned and QCd into accurate word copy. The expectation would now be for the majority of registered details to be available in Common Technical Document (CTD) format (module 3). Where particularly old historical dossiers are included e.g. Notice to Applicants (NtA) format, such programmes of work would aim to bring these dossiers into alignment with the CTD standard.

Manufacturing documentation – collation from site archives and/or repositories

Likewise, the manufacturing documentation from site(s) will be collected, verified and any initial queries posed.

Stability reports, raw data files, excel data exports, Master Batch Records (MBR), internal method and validation files, SOPs, Active Substance Master Files (ASMF) etc., are the usual site documents required to document the manufacture and control of the medicinal product (and drug substance) from the perspective of the production site(s). There may well be a need to translate and/or convert data to a more usable format for the assessment phase. The verification step is particularly advantageous, where time allows, before formal gap analysis begins, to help identify missing information or inconsistencies. Often regular site representation in such programmes can be a challenge, hence to build the most efficient process and reduce the burden on site experts downstream, resolving clear issues and gaps with the site documentation up front can reap great benefits, as well helping to maintain a good relationship with the site(s).

Both MA and site collation checklists will often be used together with a document-product map to ensure source documents are as comprehensive as possible. This will avoid duplication of requests for common documents from affiliates and production site stakeholders, which is of particular importance in larger programmes of work.

Gap analysis – cataloging, assessing and confirmation of gaps

This is the process of manually comparing (until automation becomes viable) the registered dossier against the manufacturing documents, in which differences are catalogued, confirmed as gaps and prioritised in accordance with their severity/risk. Usually a risk scoring system is developed in order to flag any critical quality/safety observations for immediate impact assessment and handling. Traditionally, MS Excel is used to document and track the differences/gaps in a detailed gap analysis report, which has benefits such as:

  • ensuring each difference is clearly documented
  • capturing activities/decisions made during the review
  • recording relevant IDs for the source documents
  • allowing risk classification alongside each observed gap

There can however be a reticence, fatigue and natural de-prioritisation in reviewing Excel spreadsheets within such initiatives, particularly when they become very comprehensive and numerous in number, such as when large global portfolios with multiple variants are in scope and/or when external vendor support is used with varied ability to discern conformance-relevant observations.

An alternate method using tracked changes and comments/notes instead within the impacted CTD sections themselves, facilitates reviewers with a quick and visual understanding of the differences for comment and approval, without the need to document them in detail in Excel spreadsheets. This method is found to be significantly more efficient, with benefits including:

  • avoiding the need to copy registered and site details into such a report, where there can be a risk of transposition error
  • allowing an easy review/approval within the eDMS with all the relevant stakeholders
  • facilitating subsequent CMC authoring to support the remediation packages (variations)
  • should the project work be paused or handed over, it is much simpler for the business to understand the proposed gaps from CTD sections rather than an Excel summary alone
Remediation/Submission plan – proposal to close gaps and submission planning of MA variations

Following the assessment of the gap analysis report and/or marked-up CTD sections by stakeholders, usually including site representatives, Quality Assurance, Subject Matter Experts (SME), CMC and the author of the report (where different), a submission plan is developed. This submission (or corrective action) plan might be an extension to the existing gap analysis report, in whatever guise that takes. It will categorise the observed differences that are indeed conformance gaps, with an appropriate variation type and classification.

At this stage competent authorities may also need to be consulted, particularly in larger programmes involving sizeable product portfolios. The submission plan is to be executed over a suitable time period with a risk-based approach, resulting in the closure of all identified conformance gaps. It is worth noting that remedial actions may also be with the manufacturing site(s) not requiring variations to an MA.

Remediation plans might include the following:

  • list of supporting documentation/data required for the change (closure of the gap)
  • list of impacted CTD sections
  • typical variation timelines can be included to help with planning and prioritisation, if required
  • potential regulatory strategies for grouping changes, submission waves (products/markets)
  • comments or queries raised from discussions and reviews
  • colour coding or another feature to facilitate quick visibility discerning between observations/gaps that are variations, editorial updates or ‘no change’/formatting only updates

The engagement of stakeholders from the markets and production sites continues to be required, as this phase calls for delivery of the supporting data/documents from sites, provision of local module 1 documents (as required), as well as the reviews and approval of the variation packages, with local RA submissions closing the phase.

QMS improvements, where necessary

The end goal is fully updated and compliant registration dossiers in accordance with manufacturing site practice and documentation. After a programme of gap analysis and remediation, it is important that the quality control system is suitably robust to be able to maintain this conformance and manage all ongoing changes. Without such a system and process, there will inevitably be a need to repeat the exercise again every few years as new products, sites, systems are integrated into the business.

How to mitigate future CMC non-conformity

In order for the pharmaceutical industry to maintain CMC conformance of its marketing authorisations with the products being received by patients, it is key to fully understand where the discrepancies originated from. There may be several factors that have contributed and over many years, which have gradually eroded the alignment, particularly in businesses with complex supply chains, marketing/licensing partners and a diversity of products and geographical reach, which is certainly not atypical for the modern-day pharmaceutical sector.

From experience, some areas to focus attention, would include:

  • Adopting a robust, single quality control system, used by all relevant stakeholders across the business. Recognise and encourage quality management as being a continual process of compliance through maintenance and management involving amongst other aspects the change control process, dealing with deviations and investigations and regular internal and external audits. This will avoid revisiting the same problems years down the line.
  • Use industry-standard document repositories and information management. By rolling these systems out company-wide, similar standards will be applied for all registration documentation. Document management systems provide editable pdf renditions, thereby limiting or discontinuing the use of historical paper versions.
  • Ideally manufacturing documentation will not be siloed. Data will be comprehensively documented, readable, using standard formatting/templates, using MS office applications or capable of being exported, and where possible written in a common language. Breaking down any historical separation that exists between the business functions and working to introduce alignment with systems and processes between regulatory, quality, R&D, tech ops will be invaluable downstream.

Article authored by Sunil Singh, Director, Regulink Limited.

Regulink Limited is a CMC & regulatory consultancy and service provider to the UK and wider life sciences sector.

Regulink has extensive experience in the provision of CMC support, including CMC conformance initiatives with multinational pharmaceutical industry clients. Most recent case studies include Drug Master File gap analysis & remediation for Abbreviated New Drug Application submissions and a large global radiopharmaceutical portfolio conformance review.

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Sunil Singh

Co-Founder

Regulatory Affairs & CMC
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