Cold chain compliance for drug substances: Regulatory standards you should know about
Coming from manual and uncontrolled freezing methods, manufacturers risk non-compliance and poor consistency when cryopreserving drug substances. Non-compliant CDMOs also risk falling out of consideration for pharmaceutical companies seeking partners to manufacture and develop their products. Most importantly, non-compliant cold chain management puts patient safety at risk.
However, the transition toward compliant and well‑controlled processes for freezing, cold storage, and cold‑chain shipping can be complex and overwhelming due to the number of applicable regulatory expectations. However, this effort can be significantly supported through appropriately designed equipment, process solutions, and services that enable GMP‑relevant readiness from the outset. By utilizing process data generated across an end‑to‑end cold‑chain setup, manufacturers can establish standardized and reproducible workflows.
Depending on the specific purpose, process step, and characteristics of the drug substance, compliance requirements must always be assessed individually. Nevertheless, the following provides an overview of the most relevant regulatory and industry standards applicable to freezing and ultra‑cold storage of drug substances in biomanufacturing.
Compliance standards for the freezing process of drug substances
Freezing biologics is a GMP-controlled manufacturing step, not simply “placing product in a freezer.” What does it take for a GMP-grade cold chain freezing platform to support a CDMO manufacturing facility in meeting today’s cold chain compliance pressures?
Several regulations provide guidance in answering this question. Above all, the EU GMP Good manufacturing practices (GMP) guidelines and the FDA Code of Federal Regulations (21 CFR for Food & Drugs) form the core quality and manufacturing frameworks for a compliant pharmaceutical cold chain. Through a broad set of regulations, these risk-based approaches are designed to ensure the safe manufacture of pharmaceutical products and, ultimately, patient safety.
Complementary these frameworks are the guidelines issued by the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), adopted by regulatory authorities such as the European Medicines Agency (EMA). The ICH guidelines develops globally harmonized scientific guidelines for human medicines. For example, ICH Q7 defines GMP requirements for the manufacture of active pharmaceutical ingredients (APIs) under an appropriate system with the goal to ensuring adequate quality and purity consistently.
In addition, the USP (United States Pharmacopeia) provides a set of standards for raw materials, finished products, analytical test methods and reference standards. Efforts are ongoing to harmonize USP requirements with these with the Ph. Eur. (European Pharmacopeia), supporting greater global consistency in pharmaceutical quality standards.
GMP production temperature-control requirements for freezing
EU GMP EudraLex Vol. 4 Part I/II requires that all conditions affecting quality, including freezing and frozen hold, are clearly defined, validated, and justified with data across the entire lifecycle. Bulk drug substance stored in a frozen state must remain under full GMP control throughout.
In practice, this translates into a risk-based validation approach for equipment, utilities and processes used for the manufacture of medicinal products according to EU GMP Annex 15. Annex 15 focuses on URS/DQ, IQ/OQ/PQ (= User Requirement Specification, Design Qualification, Installation Qualification, Operational Qualification, Performance Qualification), temperature mapping of empty and loaded units with worst-case probe locations, alarm challenges, and power‑/ door‑open recovery tests. The depth of these activities follows ICHQ9 and its quality-risk-management logic.
In the U.S., the FDA 21 CFR part 210 and CFR part 211 outlines similar expectations to prevent altering the “safety, identity, strength, quality, or purity of the drug product” in:
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Equipment design and suitability (§§211.63/211.65) and
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Scientific justification through stability (§§211.160/211.166)
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Biologics‑specific regulations in 21 CFR 600–680 strengthen the focus on preventing contamination and degradation during freezing and frozen storage. The European equivalent of the biologics-based scope and intent is EU GMP Annex 2.
The result of this effort is tangible: a validated and uniform freezing process that protects potency, reduces batches at risk, and makes audits and tech transfers faster and more predictable.
Single Use Support’s RoSS.pFTU plate freezer and RoSS.BLST blast freezer provides controlled and reproducible freezing profiles for bags and bottles, while RoSS.ULTF ensures robust frozen storage. Together with Single Use Support’s qualification and validation expertise, these systems support Annex 15‑aligned implementation and help reduce compliance deviations. Whilst maintaining protein stability through cold chain processes the freeze and thaw cycles meet CFR and cGMP standards, backed by ICH Q7 on good manufacturing practices for active pharmaceutical ingredients and ATMP (advanced therapy medicinal products)
CCI - Container-closure integrity and single-use system requirements
Because single-use bags and bottles serve as process-contact materials,
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EU GMP Chapter 3 on Premises & Equipment requires that they are fully fit for purpose at low temperatures, including robustness, uniformity, and maintainability.
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EU GMP Chapter 5 on production further requires clearly controlled handling of frozen in‑process materials, including defined hold times and physical protection during transport or storage.
These foundational GMP expectations work together with
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USP 〈1665〉 and 〈665〉, which will be effective in May 2026, which provide a benchmark for risk‑based extractables and leachables assessments and material qualification for polymer‑based single‑use systems.
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Again, ICH Q7 complements these requirements by defining controls for storing and transporting frozen intermediates, with associated QA‑release principles.
Single Use Support offers solutions for container closure integrity for various single-use sterile consumables, including single-use 2D bioprocess containers and bottles. Irrelevant the type, brand and size of single-use bag a manufacturer has validated to have reduced extractables & leachables, all bioprocess containers can be protected by the RoSS® shell. This secondary packaging significantly reduces the risk of breakages of frozen drug substances in single-use bags during cooling, cold storage and cold shipping. The added layer of protection helps manufacturers reduce the risk of contamination and therefore improves overall productivity. Bottle RoSS is the equivalent approach for bottles, where attached single-use assemblies are protected during cold chain management.
Data compliance standards
Automated bioprocesses helps to increase process efficiency overall. Temperature data and alarms qualify as GMP records. This means that monitoring software and all electronic records must comply with EU GMP Annex 11 and FDA 21 CFR Part 11. Compliance requires validated monitoring systems, secure audit trails, controlled user access, synchronized timestamps, and reliable temperature history retention and retrieval for quality assurance (QA) assessment.
GAMP 5 is what you hear in this context as well: GAMP 5 serves as a lifecycle-based validation methodology for demonstrating compliance with Annex 11 and 21 CFR Part 11 for electronic temperature records. While it’s not a regulation itself, it provides a risk-based framework for computerized-system validation, covering system classification, scalable testing, and supplier involvement with a focus on patient safety, product quality, and data integrity.
Again, the GMP and 21 CFR expectations are backed by scientific justification for the selected freezing and storage setpoint, maximum frozen hold time, and excursion criteria are grounded in ICH guidelines. And by the USP 〈1079〉, which is about operational discipline around temperature control. This including for example sensor‑placement strategy, documenting and evaluating excursions, and day‑to‑day cold‑chain handling.
Overview of most relevant regulatory standards for freezing drug substances
| Decision | Standards |
| GMP Obligation & Scope |
EU GMP Part I & II + Annex 2; FDA 21 CFR 210/211 + 600-680 (biologics): give guidance in freezing & frozen holds of biologics e.g. equipment suitability, protection from contamination & degradation. |
| Risk & Scientific Justification |
ICH Q7: drives GMP for cold chain handling of drug substance ICH Q9: drives quality risk management (QRM) to identify freezing-specific risks, e.g. cryoconcentration. ICH Q10: drives changes in pharmaceutical quality systems (PQS), e.g. scale-up or freezer technology |
| Qualification & validation of freezing platform | EU GMP Annex 15: proving the freezer works with URS to IQ/OQ/PQ, e.g. empty & loaded mapping, worst-case placements, alarm challenges, door-open recovery. Risk‑based via ICH Q9 |
| Infrastructure & material control |
EU GMP Chapter 3 & Chapter 5: fit for low-temperature use, e.g. uniformity, robustness and prevention of damage. Complemented by USP 〈665〉 / 〈1665〉 with risk-based E&L and material suitability, CCI |
| Monitoring & data integrity | FDA 21 CFR Part 11: includes monitoring, e.g. audit trails, retention for temperature profiles and alarms on freezers |
Cold chain compliance for ultra-cold storage of drug substances
The above mentioned applies for freezing as well as for frozen hold of drug substances. However, there are additional highlights to cold storage of biopharmaceutical products:
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FDA 21 CFR part 211.150 requires pharmaceutical manufacturers to protect product quality in storage and handling conditions during warehousing and distribution, including product traceability and quality protection.
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USP 〈1118〉 provides guidance on the technologies, performance characteristics, and qualification of time/temperature (and humidity) monitoring devices: what accuracy and precision to expect, how to qualify indicators and data loggers, and how to verify performance over time. This allows you to define meaningful specifications and calibration plans so that the data you trend and the excursions you evaluate reliably reflect reality.
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USP 〈1079〉 translates validated storage into day-to-day operation, e.g. placement concepts, mapping logic and alarm responses.
Single Use Support’s RoSS.ULTF is designed to deliver stable, uniform sub-zero environments for single-use formats. Combined with Single Use Support’s qualification and validation expertise, it helps establish a compliant, auditable storage program quickly that aligns with robust device selection on top of the existing GMP/ICH framework.
Standards for ultra-cold shipment of drug substances
The handling from storage to staging or transport of drug substances at sub-zero temperatures must maintain its performance under realistic ambient conditions. ASTM D3103 offers a test method for evaluating the thermal insulation performance of distribution packaging, including guidance to test with the actual payload and to simulate worst‑case ambient profiles. It also recommends temperature mapping inside the package to identify variability. The method references ISTA 7D as a transport‑focused temperature‑test protocol. Together, these approaches support specification, qualification, and documentation of shippers so sub‑zero control is preserved between units, areas, and sites.
The cold chain container RoSS.SHIP is Single Use Support’s solution for transport of drug substances. The insulated shipping containers for passive cooling are based on ISTA / ASTM D4169 qualification and offers optional tracking of temperature, GPS and G-Force during transport.
Solutions for regulatory compliance in cold chain management
Achieving cold chain compliance requires an end-to-end strategy rather than isolated technologies. Single Use Support provides a connected workflow of single-use technologies with sterile and non-sterile consumables around single-use bags and bottles, single-use assemblies:
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RoSS® shell protects single‑use bags during freezing, storage, and transport, ensuring mechanical safety and optimal heat transfer.
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RoSS.pFTU delivers controlled plate‑freezing with homogeneous ice formation.
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RoSS.BLST offers smart, controlled‑rate blast freezing for bottles and bags with high‑performance air distribution.
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RoSS.ULTF provides uniform ultra‑cold storage down to −80° C for bags in RoSS® shells and bottles in Bottle RoSS.
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RoSS.SHIP maintains temperatures below −60° C for multiple days and includes real‑time track‑and‑trace capabilities.
Together, these validated systems help address risk-based qualification, single-use system control, compliant monitoring, protect product integrity and create a regulator-ready data trail during cold chain.
Cold chain compliance is not about ticking boxes. It’s about presenting a defensible, data-driven story. With an integrated end-to-end ecosystem, that story becomes consistent, auditable, and aligned with modern regulatory expectations.
Single Use Support’s qualification, validation & documentation services
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