Artikel
Manufacturing site transfers in a volatile world: Pain points, regulatory challenges, and strategic imperatives
As the pharmaceutical industry tries to navigate geopolitical instability, pressure to relocate manufacturing sites has intensified. US tariffs, supply insecurity stemming from the Ukraine war and more recently the Iran conflict, and pandemic preparedness sparked by COVID-19 have all led manufacturers to consider the supply chain and site transfers. For companies with large portfolios, integrating these site transfers into their manufacturing network is hugely complex and adds efficiency risks that can ultimately lead to medicine shortages and delayed patient access to critical therapies.
Balancing urgency and reality with site transfers
Transferring manufacturing sites from one region to another is both time-consuming and costly. Even small, less complex transfers can take two to five years depending on product requirements, how many countries and sites are affected, and which regions are involved.1 More complex products such as an injectable where the drug substance is produced in one region and the final release in another further extend the timeline.
As part of the site transfer, companies must ensure they provide sufficient stability data within relevant variation application to the marketing authorization.2
This process can take years, depending on the region and the data involved. In our experience, some regions – such as some Central America and the Caribbean (CAMCAR) countries – may request real-time stability data covering the approved shelf-life of the product.
As part of the site transfer, companies must ensure they provide sufficient stability data within relevant variation application to the marketing authorization.2
This process can take years, depending on the region and the data involved. In our experience, some regions – such as some Central America and the Caribbean (CAMCAR) countries – may request real-time stability data covering the approved shelf-life of the product.
If the product has five years of stability data, the time involved for a site transfer could be five years plus the time to create the documentation and prepare the submission. If a company plans to close a site and build a new facility elsewhere, the time involved not only in building the new site but applying for and showing compliance with good manufacturing practice (GMP) requirements can be extensive.3
While some authorities have short post-inspection issuance timelines — for example, EU guidance requires GMP certificates to be issued 90 days after inspection where compliance is confirmed4 — the overall lead time from planning to a valid certificate may be considerably longer depending on inspection scheduling, authority capacity, inspection outcome, and any required corrective actions. Publicly available data from Brazil’s health authority ANVISA illustrates this variability: drug-product GMP inspections were reported to occur on average five months after application in 2019, whereas historical ANVISA certification data for medical devices showed inspection waiting lists exceeding two years.5
While some authorities have short post-inspection issuance timelines — for example, EU guidance requires GMP certificates to be issued 90 days after inspection where compliance is confirmed4 — the overall lead time from planning to a valid certificate may be considerably longer depending on inspection scheduling, authority capacity, inspection outcome, and any required corrective actions. Publicly available data from Brazil’s health authority ANVISA illustrates this variability: drug-product GMP inspections were reported to occur on average five months after application in 2019, whereas historical ANVISA certification data for medical devices showed inspection waiting lists exceeding two years.5
Managing the regulatory complexities of site transfers
Regulatory expectations can differ significantly between countries, with some authorities requiring additional data, local testing, GMP certification, or specific supporting documentation beyond standard variation package.
Typically, companies file in reference regions, such as the US and the European Union, first and then submit to other countries once they receive approval in the largest markets. For example, the United Kingdom introduced the International Reference Procedure in 2024, allowing the Medicines & Healthcare products Regulatory Agency (MHRA)6 to consider decisions made by trusted regulatory partners, such as the European Medicines Agency (EMA). Companies must also ensure they are familiar with guideline updates and how these impact a site transfer. In Europe, any new variations must adhere to the revised variations framework,7 which provides greater clarity around the documentation, procedures, and assessments required.
In the US, the Food and Drug Administration (FDA) assigns the reporting category for a manufacturing site transfer according to the change’s potential to adversely affect product quality and the nature of the operation.8 Depending on the risk, the transfer may be reported in an annual report, a changes-being-effected supplement, or a Prior Approval Supplement, with FDA approval required before distribution for a major change. The submission should justify the reporting category and provide appropriate CMC evidence; including the new site’s cGMP status and, as applicable, process validation, comparative batch analyses and stability data in order to demonstrate that the transfer does not adversely affect the product’s identity, strength, quality, purity or potency as these relate to safety or effectiveness.
A comparability assessment is also highly relevant to site transfers because regulators want to know whether moving manufacture to a new site could affect the product's quality, safety, or efficacy. Demonstrating product comparability as part of a site transfer helps to confirm that the change in manufacturing location does not impact the product's established quality profile.
In parallel with evolving variation requirements, companies must also prepare for upcoming dossier and submission framework changes, including ICH M4(R2), which defines the new structure of Module 2.3 and Module 3 and restructures how quality information is presented, and eCTD 4.0. While these initiatives do not alter the scientific evidence required to support a manufacturing site transfer, they are expected to reshape how quality data are structured, presented, and maintained throughout the product lifecycle. Organizations planning multi-year site transfer projects should therefore consider the future impact of these changes on authoring, publishing, dossier maintenance, and lifecycle management processes.
Even when regulatory processes are followed, production processes are rarely identical between sites due to differences in equipment, scale, and local expertise. Consequently, processes must often be adapted rather than simply replicated. Ensuring that product quality remains unchanged requires extensive comparability studies, process validation activities, and stability testing. These efforts demand significant time and resources and carry an inherent risk of unexpected variability. A successful transfer requires a robust comparability strategy supported by appropriate validation, analytical, and stability data to demonstrate that product quality, safety, and efficacy remain unaffected following the transfer.
Typically, companies file in reference regions, such as the US and the European Union, first and then submit to other countries once they receive approval in the largest markets. For example, the United Kingdom introduced the International Reference Procedure in 2024, allowing the Medicines & Healthcare products Regulatory Agency (MHRA)6 to consider decisions made by trusted regulatory partners, such as the European Medicines Agency (EMA). Companies must also ensure they are familiar with guideline updates and how these impact a site transfer. In Europe, any new variations must adhere to the revised variations framework,7 which provides greater clarity around the documentation, procedures, and assessments required.
In the US, the Food and Drug Administration (FDA) assigns the reporting category for a manufacturing site transfer according to the change’s potential to adversely affect product quality and the nature of the operation.8 Depending on the risk, the transfer may be reported in an annual report, a changes-being-effected supplement, or a Prior Approval Supplement, with FDA approval required before distribution for a major change. The submission should justify the reporting category and provide appropriate CMC evidence; including the new site’s cGMP status and, as applicable, process validation, comparative batch analyses and stability data in order to demonstrate that the transfer does not adversely affect the product’s identity, strength, quality, purity or potency as these relate to safety or effectiveness.
A comparability assessment is also highly relevant to site transfers because regulators want to know whether moving manufacture to a new site could affect the product's quality, safety, or efficacy. Demonstrating product comparability as part of a site transfer helps to confirm that the change in manufacturing location does not impact the product's established quality profile.
In parallel with evolving variation requirements, companies must also prepare for upcoming dossier and submission framework changes, including ICH M4(R2), which defines the new structure of Module 2.3 and Module 3 and restructures how quality information is presented, and eCTD 4.0. While these initiatives do not alter the scientific evidence required to support a manufacturing site transfer, they are expected to reshape how quality data are structured, presented, and maintained throughout the product lifecycle. Organizations planning multi-year site transfer projects should therefore consider the future impact of these changes on authoring, publishing, dossier maintenance, and lifecycle management processes.
Even when regulatory processes are followed, production processes are rarely identical between sites due to differences in equipment, scale, and local expertise. Consequently, processes must often be adapted rather than simply replicated. Ensuring that product quality remains unchanged requires extensive comparability studies, process validation activities, and stability testing. These efforts demand significant time and resources and carry an inherent risk of unexpected variability. A successful transfer requires a robust comparability strategy supported by appropriate validation, analytical, and stability data to demonstrate that product quality, safety, and efficacy remain unaffected following the transfer.
Lessons learned from manufacturing site transfers
In our experience, companies looking to transfer manufacturing sites tend to overlook the time, money and global submission complexity. Manufacturing site transfers are rarely standalone changes. Rather, they commonly comprise multiple regulatory variations of varying complexity that are reviewed differently by health authorities around the world.
Sometimes companies do not have sufficient or clear comparability data available to demonstrate that the new site’s processes are comparable to the previous site, without risk to safety or efficacy.9,10
From a technical perspective, there may be misalignment between the technical transfer and regulatory dossier, which is usually a result of lack of collaboration between different functions.
Sometimes companies do not have sufficient or clear comparability data available to demonstrate that the new site’s processes are comparable to the previous site, without risk to safety or efficacy.9,10
From a technical perspective, there may be misalignment between the technical transfer and regulatory dossier, which is usually a result of lack of collaboration between different functions.
Our advice is to analyze the critical aspects of the variation dossier – such as comparability data, process validation, and regional regulatory requirements – conduct an early gap analysis and regulatory strategy (involving regional intelligence, submission strategy, CMC positioning, timelines and requirements), and foster strong cross-functional team processes led by an experienced project manager to ensure efficient execution collaboration and regulatory compliance. Successful manufacturing transfers rely on transparent communication, comprehensive knowledge sharing, and complete documentation throughout the process. Additionally, technical and operational risks can be addressed through structured technology transfer and early GMP readiness.
Another major regulatory risk relates to GMP compliance and inspection readiness. New manufacturing sites must demonstrate full GMP compliance, often through pre-approval inspections. However, geopolitical barriers, travel restrictions, or resource constraints may delay or hinder inspections. In such cases, regulatory approvals can be significantly delayed, regardless of the quality of the submitted data. This creates a critical bottleneck that is often beyond the direct control of the company.
Internally, it’s important to have an integrated planning strategy to align quality assurance and quality control operations, and to define the submission pathway based on regional requirements. For complex situations, companies should engage with the health authorities early in the process to determine whether their proposed strategy approach and supporting data package are sufficient and reduce regulatory uncertainty and the risk of delays or rejection.
Changing global dynamics require careful site transfer planning
In today’s volatile and fragmented global environment, manufacturing site transfers have evolved into high-stakes strategic undertakings.
As companies navigate pressure to transfer manufacturing sites – whether for geopolitical and local access reasons or for their own commercial objectives – they will need to carefully consider global product supply security to safeguard patient access to medicines. The interplay of geopolitical uncertainty, supply chain fragility, and regulatory complexity creates a challenging landscape in which both risks and expectations are elevated.
From a regulatory affairs and CMC (chemistry, manufacturing and controls) perspective, the central challenge lies in balancing speed, compliance, and flexibility while ensuring uninterrupted supply of high-quality products. Preparing for a site transfer and defining some of the potential issues early on, having a cross-functional team, strong project governance, and proactive regulatory engagement, and creating adaptable manufacturing networks can prevent submission delays or rejections of manufacturing site transfers. Site transfers need to be understood as not simply technical changes, but as critical components of a resilient strategy to navigate an increasingly unpredictable world.
As companies navigate pressure to transfer manufacturing sites – whether for geopolitical and local access reasons or for their own commercial objectives – they will need to carefully consider global product supply security to safeguard patient access to medicines. The interplay of geopolitical uncertainty, supply chain fragility, and regulatory complexity creates a challenging landscape in which both risks and expectations are elevated.
From a regulatory affairs and CMC (chemistry, manufacturing and controls) perspective, the central challenge lies in balancing speed, compliance, and flexibility while ensuring uninterrupted supply of high-quality products. Preparing for a site transfer and defining some of the potential issues early on, having a cross-functional team, strong project governance, and proactive regulatory engagement, and creating adaptable manufacturing networks can prevent submission delays or rejections of manufacturing site transfers. Site transfers need to be understood as not simply technical changes, but as critical components of a resilient strategy to navigate an increasingly unpredictable world.
*Onderstaande bronnen
About the author:
Dr. Nelli Ziegler is Director, Regulatory Affairs CMC, at Cencora, where she draws on more than 15 years of experience in global CMC regulatory affairs, supporting pharmaceutical companies with regulatory strategy, lifecycle management, manufacturing site transfers, and dossier authoring. Her work focuses on developing pragmatic regulatory solutions helping clients coordinate complex global regulatory CMC projects.
Disclaimer:
De informatie in dit artikel vormt geen juridisch advies. Cencora, Inc. raadt lezers ten zeerste aan om de beschikbare informatie met betrekking tot de besproken onderwerpen door te nemen en te vertrouwen op hun eigen ervaring en expertise bij het nemen van beslissingen met betrekking tot deze onderwerpen.
Sources:
1. Harris R., Vanhooren M., Follmann K., et al. An Evaluation of Postapproval CMC Change Timelines, Pharmaceutical Engineering, ISPE, Sept/Oct 2023. https://ispe.org/pharmaceutical-engineering/september-october-2023/evaluation-postapproval-cmc-change-timelines
2. EMA. Guideline on stability testing for applications for variations to a marketing authorization, Dec 2025. Accessed 9 July 2026. https://www.ema.europa.eu/en/stability-testing-applications-variations-marketing-authorisation-scientific-guideline
3. Howan, Lowell, Cadwalader. How Trump’s reshoring EO affects plans to build or expand a domestic drug manufacturing facility, May 2025. Accessed 9 July 2026. https://www.hlc.com/en/publications/how-trumps-reshoring-eo-affects-plans-to-build-or-expand-a-domestic-drug-manufacturing-facility
4. EMA/European Commission. The issue and update of GMP certificates, May 2023. Accessed 9 July 2026. https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/issue-update-good-manufacturing-practice-gmp-certificates_en.pdf
5. ANVISA. GMP Certificate for drug products: companies can request earlier inspection dates, June 2019. Accessed 9 July 2026.
6. MHRA. International Recognition Procedure, Updated 21 Jan 2026. Accessed 9 July 2026. https://www.gov.uk/government/publications/international-recognition-procedure/international-recognition-procedure
7. EMA. Guidance on the application of the revised variations framework. Accessed 9 July 2026. https://www.ema.europa.eu/en/guidance-application-revised-variations-framework
8. FDA. Manufacturing Site Change Supplements: Content and Submission, 2018. Accessed 11 July 2026. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/manufacturing-site-change-supplements-content-and-submission
9. WHO. Annex 7, WHO guidelines on transfer of technology in pharmaceutical manufacturing. Accessed 9 July 2026. https://www.who.int/docs/default-source/medicines/norms-and-standards/guidelines/production/trs961-annex7-transfer-technology-pharmaceutical-manufacturing.pdf
10. FDA. Changes to an Approved NDA or ANDA, 2004. Accessed 9 July 2026. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/changes-approved-nda-or-anda
