The global biopharmaceutical industry is undergoing a transformative shift as advanced therapy medicinal products (ATMPs) including gene therapies, somatic cell therapies, and tissue-engineered products and complex biologics become central to innovation pipelines. According to a Report by ARM, as of Q2 2025, there are over 1,900 active CGT clinical trials, 2,070 developers, and $5.0 billion in investment committed across North America, Europe, and Asia-Pacific. Biologics continue to account for more than 40% of new FDA approvals annually.
These therapies offer unprecedented clinical benefits. However, their development, manufacturing, and distribution demand a fundamentally different approach to Good Manufacturing Practice (GMP) compliance. Conventional GMP frameworks designed for small molecule drugs are not always directly applicable to living therapies that are variable, time-sensitive, and sometimes patient-specific.
This article outlines the current regulatory expectations, technical challenges, and compliance strategies that manufacturers and developers must adopt to align GMP practices with the evolving realities of biologics and advanced therapies.
GMP Paradigm - What Makes ATMPs and Biologics Unique
Living Products with Inherent Variability
Biologics and ATMPs are derived from living organisms and exhibit natural variability. Even minor changes in process conditions can impact identity, purity, and potency.
- Implications: ICH Q5E comparability protocols are essential for demonstrating product consistency after manufacturing changes.
- GMP Focus: Robust in-process controls, enhanced analytical characterization, and critical quality attribute (CQA) monitoring.
Example: In Q2 2025, multiple first-in-human trials were initiated using novel modalities like epigenetic editing and in-vivo gene insertion for X-CGD , underscoring the complexity of biologic process characterization and validation.
Autologous Manufacturing (One Batch per Patient)
Autologous therapies (e.g., CAR-Ts) require individualized manufacturing with extreme precision in chain-of-identity (CoI) and chain-of-custody (CoC). A single labeling error could compromise patient safety.
GMP Focus: Digitized labeling systems, barcoded batch tracking, and real-time CoI/CoC platforms are mandated by both EMA and FDA.
Real-world context: Autologous cell therapies like ALS product and Parkinson’s therapy continued to show promising data in H1 2025, reinforcing the need for precision batch control at scale.
Aseptic Manufacturing Without Terminal Sterilization
Most ATMPs are not sterilized post-manufacturing due to product instability. Aseptic process validation becomes critical.
GMP Focus: Strict environmental monitoring, personnel qualification, and Contamination Control Strategy (CCS) in line with EU GMP Annex 1 (revised 2022).
Exploring the Evolving Regulatory Landscape for Gene Therapy Trials in the EU
Regulatory Frameworks - Evolving Expectations Across Markets
FDA (U.S.)
- 21 CFR Part 210/211 and Part 1271 apply to biologicals and human cells, tissues, and cellular/tissue-based products (HCT/Ps).
- US FDA requires Phase I ATMPs to demonstrate “CGMP-like controls,” including batch records, QA oversight, and material traceability.
Recent Updates:
- REMS requirements removed from all FDA-approved CAR-T therapies (June 2025), reducing burdensome post-treatment conditions and improving access.
- Platform Technology Designations granted to companies like Sarepta (for viral vectors) and Cellares (for closed-system cell therapy manufacturing), enabling accelerated review and validation strategies.
EMA (Europe)
- EudraLex Volume 4, Annex 2B (2022): Dedicated ATMP GMP guidance, covering:
- Raw material qualification
- CoI/CoC documentation
- GMP for decentralized or hospital-based manufacturing
- Update: The European Commission released a new Life Sciences Consulting Strategy to strengthen ATMP competitiveness by funding multi-country clinical trials and establishing Centres of Excellence.
WHO & ICH
- WHO TRS 1019 (2020) outlines GMP requirements for biological products, with specific annexes for vaccines and cell-based therapies.
- ICH guidelines like Q8–Q11 provide foundational principles for quality-by-design (QbD), control strategy, and process validation.
Facility & Process Requirements - GMP in a Multi-Modal Era
Modular & Flexible Manufacturing Design
Given the rapid evolution of manufacturing platforms (viral vectors, mRNA, iPSCs), GMP facilities must support process agility.
Best Practices:
- Closed-system processing to reduce contamination risk
- Single-use bioreactors to minimize cleaning validation
- Segregation of autologous vs. allogeneic workflows
Example: The FDA granted Advanced Manufacturing Technology designation to Cellares’ Cell Shuttle system in Q2 2025, enabling modular automation for personalized therapy manufacturing.
Short Shelf-Life
Many ATMPs (e.g., fresh CAR-T) have shelf lives of less than 72 hours.
GMP Implication: Real-time release testing (RTRT), validated rapid assays, and seamless handoffs between QA, logistics, and clinical sites.
Raw Material Controls
ATMPs and biologics often rely on human- or animal-derived raw materials (e.g., fetal bovine serum, recombinant enzymes).
Compliance Requirements:
- Viral safety validation
- TSE/BSE certifications
- Audit trails for material origin, testing, and supplier qualification
Digitalization: The Backbone of GMP for Advanced Modalities
With increasing process complexity and traceability demands, GxP-compliant digital systems are now central to maintaining GMP compliance services.
Function | Digital Solution | Compliance Advantage |
Batch records | MES/eBR | Real-time error checks, deviation flagging |
CoI/CoC | Blockchain-based platforms | Audit-ready, tamper-proof chain tracking |
Environmental Monitoring | IoT-enabled sensors | Real-time data + 21 CFR Part 11 audit trail |
Quality Events | Digital QMS | Integrated CAPAs, change control, trending |
Data Integrity | ALCOA+ compliant systems | Secure metadata, time-stamped entries |
A 2023 Deloitte survey found that 83% of CGT manufacturers plan to digitize batch record management within 12 months of commercial launch. Several CGT companies that raised major funding in Q2 2025 are prioritizing digital-first, GMP-compliant platforms for scale-up.
Preparing for Regulatory Inspections
Inspection readiness in the biologics/ATMP space requires proactive preparation. Authorities now expect:
- Demonstrable CCS implementation (per EU Annex 1)
- Product-specific risk assessments for contamination, cross-reactivity, and vector integration
- Data integrity compliance across digital systems (FDA Data Integrity Guidance, 2018)
- Vendor qualification evidence for critical raw materials and outsourced steps
With at least nine CGT BLA/MAA submissions expected in the U.S. and EU in H2 2025, and several therapies nearing launch (e.g., RPL102, Orca-T, OCU400), audit preparedness is non-negotiable.
Companies must treat inspections as continuous readiness exercises, not isolated events.
Conclusion
The rapid evolution of biologics and ATMPs is reshaping the pharmaceutical manufacturing landscape. GMP compliance in this new era is not about rigidly applying legacy systems, but about designing quality systems that are agile, science-based, and digitally enabled.
The regulatory landscape will continue to evolve, but the foundational principles remain unchanged: patient safety, product consistency, and data integrity. Companies that build compliance into their innovation strategy from day one will not only reduce regulatory friction, but they’ll also accelerate patient access and scale with confidence.
How DDReg Can Help
DDReg supports biopharma companies in building GMP-ready systems tailored for ATMPs and biologics. From process validation and facility audits to regulatory submissions and digital QMS integration, we help ensure compliance is scalable, inspection-ready, and aligned with evolving global standards.
Read more from DDReg Experts here: Evolving Safety Reporting in the EU: Beyond EudraVigilance to EVDAS & SPOR