Addressing supply chain challenges: Expert insights on GMP media, xeno-free solutions and raw material management

Lucía Cespón
GMP Business Unit Lead
PromoCell

Lucía Cespón is the GMP Business Unit Lead for Excipient GMP-grade products and services at PromoCell, a leading provider of human primary cells and cell culture systems for biomedical research and clinical applications.

She holds a PhD in Molecular and Cellular Biology from the Biochemistry Center at Heidelberg University (Germany), where she studied unconventional protein secretion using FGF2, a mitogen involved in tumor-induced angiogenesis. Her academic background also includes research in intracellular protein transport and early-stage drug discovery.

Before transitioning to project management in 2023, Lucía spent 5 years in business development roles at PromoCell, supporting clients in France, the UK and Germany. She has previously spent over 7 years in scientific support roles at Thermo Fisher Scientific (MA, USA) and Life Technologies (Darmstadt, Germany), specializing in cell analysis and cell culture applications across the Europe, Middle East and Africa region.

In her current role, Lucía leads a cross-functional initiative to establish a new business line at PromoCell focused on excipient GMP-grade services and products, delivering tailored solutions for research institutions, biotech companies and red biotech innovators.

Maximilian Gert-Kleint
Regulatory Affairs Manager / Material Compliance
PromoCell

Maximilian Gert-Kleint is Regulatory Affairs Manager / Material Compliance at PromoCell GmbH in Heidelberg, Germany. In this role, he is responsible for regulatory and material compliance aspects related to manufacturing processes, raw materials and GMP-relevant quality requirements. In this function, he contributes to the GMP Business Unit by supporting the translation of regulatory, quality and customer requirements into practical internal processes and controlled documentation.

Following his master’s degree in Toxicology from Charité – Universitätsmedizin Berlin in 2016, Maximilian started his scientific career at the University of Lübeck (both Germany), as a researcher in gene therapy, working with adeno-associated viral vectors and proof-of-principle studies in mice.

He later combined his experience in in vivo research and toxicology at a contract laboratory for preclinical studies in Hamburg, where he worked in data analysis and scientific reporting. Shortly afterwards, he took the opportunity to lead a GMP-regulated department responsible for in vivo batch release assays for the pharmaceutical industry.

Maximilian joined PromoCell in 2022, bringing together scientific, preclinical, GMP and regulatory experience at the interface between cell culture media manufacturing and pharmaceutical use.

Lucía (LC): An RUO analogue is produced under RUO conditions but aligned with the intended GMP formulation and manufacturing concept. This ensures biological performance and handling characteristics are comparable to the future GMP version, while regulatory requirements are implemented later. A GMP‑grade medium designed based on such an RUO analogue reduces risk and shortens timelines because it keeps the biology and process performance as constant as possible, while upgrading only the “compliance layer” needed for regulated manufacturing: quality system, documentation and supply reliability. This allows data generated during RUO to remain relevant in GMP, reduces the need for re-optimization or bridging studies, and minimizes redevelopment. In practice, it avoids changing both the medium and regulatory status at the same time, which is a common source of delays during transition. 

 From a comparability perspective, an RUO analogue supports a like-for-like performance bridge. The customer can apply the same protocol and generate meaningful baseline data in RUO, then transition to the GMP version with minimal (or no) process re-optimization — because the medium’s functional intent and performance targets remain aligned. 

 To facilitate performance transfer, we often use a pilot evaluation batch concept: a RUO variant that is designed to simulate the later Excipient GMP-grade manufacturing approach, enabling customers to confirm functionality early and de-risk the GMP step. This helps minimize redevelopment because key elements (handling, performance expectations, and—critically—manufacturing intent) are already anchored.The GMP phase primarily adds the expanded release testing and the formal documentation package (e.g., defined documentation sets and agreements) required for regulated use. 

 Finally, from a business point of view, RUO-analogue design enables earlier alignment on scale-up, tech transfer, and consistency/reproducibility goals This improves planning across procurement, QA, and manufacturing, so the transition is not only technically smoother, but also operationally predictable. 

LC: I see a clear regulatory and market trend: Global agencies such as the FDA, EMA, WHO, and Japan’s PMDA are leaning toward the use of animal component free (ACF) and more chemically defined or recombinant materials in cell therapy manufacturing to improve safety, consistency and ethical alignment.

From a customer and business development perspective, the driver is not only “regulatory preference,” but the practical reality of global market access. When programs plan for multi‑site manufacturing and global commercialization, they need a consistently defensible raw‑material risk and documentation package across audits and submissions. ACF approaches simplify that complexity and help teams build a manufacturing narrative that is easier to defend across markets.

Operationally, this shift is driven by recurring challenges associated with animal‑derived materials — most notably the risk of adventitious agents (e.g., viruses, mycoplasma) including transmissible spongiform encephalopathy (TSE)-related concerns, as well as lot‑to‑lot variability and traceability gaps. Biologically undefined inputs, such as serum, increase uncertainty and testing demands. At the same time, regulatory guidance increasingly supports replacing them with recombinant and chemically defined alternatives to enable more reproducible processes and reduce deviation investigations.

Mitigation needs to be risk‑based and hierarchical: First, avoid or substitute animal‑derived inputs wherever feasible (ACF/XF, recombinant or chemically defined). Where animal‑origin materials remain necessary, robust supplier qualification and traceability, appropriate processing/viral risk‑reduction steps, and confirmatory testing and documentation are essential to ensure safety and compliance.

Taken together, these pressures mean that early adoption of ACF strategies allows developers to de‑risk scale‑up, strengthen comparability, and improve regulatory readiness. This approach directly addresses the contamination and variability risks inherent to materials of animal origin, which are a primary regulatory concern.

Maximilan (MGK): Building on Lucía’s overview, when we consider technical risk, the most prominent hazard is the presence of adventitious agents such as viruses, bacteria, mycoplasma and TSE agents. The main sources of these contaminants are bovine serum, bovine serum albumin, porcine trypsin and hydrolysates derived from animals. Viral contamination in porcine trypsin with circovirus and parvovirus is a known issue. Secondary risks include inconsistency in different batches (especially bovine serum, which is biologically undefined), immunogenicity of residual xenogeneic proteins carried through to the final cell product, and regulatory issues from undocumented or poorly traceable sourcing.

The regulatory standard is given in Ph. Eur. 5.2.12: avoidance, raw materials of human or animal origin should be substituted by materials of non-animal origin whenever possible. In cases where such substitution is not feasible and avoidance is not practical, TSE compliance according to EMA/410/01 must be achieved, implying controlled geographical origin, tracing of herds and tissue categorization. Mitigation through processing involves the use of interventions such as irradiation of sera, along with viral inactivation or removal measures aimed at reducing viral levels. Testing then sits on top of sourcing and processing: In vitro and in vivo adventitious virus testing, species-specific PCR panels, and mycoplasma and sterility testing per Ph. Eur. 2.6.7 and 2.6.1. Additional relevant documentation, e.g. TSE Certificate of Suitability where available, country-of-origin statements, full traceability to the animal or herd, closes the loop.

MGK: A provision needs to be issued here: While significant progress has been achieved in the field, there hasn’t been one breakthrough; instead, it has evolved significantly as a whole. Recombinant replacement of animal proteins has moved from niche to mainstream. Over the past five to seven years, this well-known phenomenon has become widespread and achieved much better quality levels. Advancements like recombinant human albumin, transferrin, insulin and growth factors — expressed in yeast, rice or microbes — can now replace all functions of serum constituents. Fully chemically defined media, where every component is a known chemical entity at a known concentration, are commercially available for several major cell therapy products.

It is worth keeping in mind that chemically defined is a stricter category than XF or ACF; many ACF media still contain undefined plant hydrolysates. These, hydrolysates based on both plants and syntheses have been developed as alternatives to animal peptones, although they too present issues of their own.

Beyond formulation, there has been a shift in how media are developed and used. The industry is moving away from standardized XF media toward formulations tailored to specific cell lines, often through close collaboration between media and process developers. At the same time, closed-system and ready-to-use formats have become more common, helping to reduce contamination risk and simplify the transition from research to GMP manufacturing.

It should be recognized that while XF and ACF formulations are a clear regulatory and strategic goal, they do not always automatically result in improved biological performance. For certain primary or sensitive cell types, achieving equivalent efficacy and phenotype retention can remain a development challenge. In such cases, xeno- and animal component-containing formulations may still be used temporarily while optimized XF or ACF alternatives continue to mature.

LC: From an industrial standpoint, customer expectations are also evolving. Requirements are becoming more explicit and procurement-driven: beyond “XF/ACF” labeling, customers increasingly expect end-to-end traceability and a documentation package that supports their risk assessment and regulatory filings (e.g., robust CoA/extended release testing, raw material traceability, and clear change control).

In parallel, they are looking for “one-medium” solutions that can be used across key steps (e.g., isolation and expansion/maintenance) to reduce re-development work and improve comparability when transitioning toward regulated manufacturing.

Finally, practical implementation requirements, such as closed/ready-to-use formats and scalable packaging, are increasingly treated as standard expectations to reduce open handling and streamline the research-to-GMP transition.

MGK: There are four concrete factors, starting from most frequently mentioned one.

1. There is an absence of adventitious agents, since removal of an animal-derived starting material eliminates the major vector of possible contaminations with viruses and BSE/TSEs, which simplifies the viral safety assessment and ATMP manufacturer’s risk assessment according to the EU GMP Part IV.
2. There is a lower risk of immunogenicity of the end-product because xenogeneic proteins (such as BSA or bovine IgG) can be present in the end-product and provoke immune reactions in patients. The clinical significance depends on specific indications and dosages but is increasingly considered an issue by regulatory authorities.
3. There is batch-to-batch consistency, as chemically-defined media are not derived from biological materials like serum and therefore do not inherit the same level of lot variability that affects comparability studies or the final product itself. Many programs lose precious time at that stage of CGT drug development, when they want to switch to a xeno-free medium.
4. Finally, regulatory and logistical simplification: Fewer TSE/BSE documentation, less consideration of country-of-origin issues, less reliance on a limited serum market, and an easier story when engaging with health authorities.

From a practical standpoint, the key consideration is timing. Transitioning to XF/ACF media at later clinical stages can introduce unanticipated comparability studies and associated costs. Conversely, programs that adopt XF/ACF media earlier often reduce long‑term development risk and overall cost by avoiding late‑stage process changes, making this decision not only a regulatory or quality consideration, but also a strategic CMC and business one.

LC: Building on this, the key is that XF/ACF media can be used not only as a compliance measure, but as a development strategy to preserve continuity from RUO to GMP.

1. Earlier adoption reduces late‑stage redevelopment. Teams that wait until Phase I/II+ to switch away from serum often trigger unplanned comparability work. Using an XF/ACF (ideally GMP‑available) system earlier can reduce disruptive process changes later.
2. It also supports better performance transfer. When the RUO process and the GMP process are aligned (or based on an RUO/GMP analogue strategy), developers reduce the risk of shifting critical quality attributes during scale‑up and tech transfer.

XF and ACF media support cell therapy development by de‑risking raw materials (safety and immunogenicity), improving consistency for comparability, and simplifying regulatory and supply chain complexity. It is also shifting the discussion from late‑stage remediation to early‑stage design choices.

MGK: Raw material qualification refers to a systematic procedure for the manufacturer to verify the fitness-for-purpose of a particular raw material from a given source.

1. Qualification starts with clear specifications: For GMP cell culture media, material qualification starts with definition of the specifications, which includes identity, purity and, if applicable, potency; microbial content and endotoxins; host cell for recombinant components; and functional performance in intended cell system.
2. Pharmacopoeial standards : The next step, wherever feasible, is grade selection in accordance with Ph. Eur. or USP monographs. Components that have a Ph. Eur. or USP monograph should be sourced to that monograph. This is not optional for pharmaceutical product manufacture in the EU, the regulations and the associated GMP framework require compliance with pharmacopeial standards where a monograph exists. In case there are no such monographs, which might apply to some cell culture components, the manufacturer sets the specifications and demonstrates justification of those criteria, for example using USP <1043> guidelines for raw materials not covered by compendial requirements.
3. Supplier qualification: This is another qualification task, which includes performing risk-based audits (either site visits or remote) together with signing the quality agreement, evaluating the supplier’s quality system, and confirming change controls. For excipient producers, EXCiPACT/IPEC-PQG certification is commonly accepted as part of this assessment, nevertheless it does not replace the user’s own qualification process.
4. Identity testing: The next step is incoming inspection. The identity test is required according to the EU GMP guidelines, while limited testing is possible only after proper justification and additional testing scaled to risk. Performance qualification consists of proving adequate performance in real manufacturing processes for typically three lots, or even more if necessary for critical materials. Ongoing monitoring through trend review, periodic requalification and change notification handling keeps the qualification live rather than static and historical.

Why does this matters? Material variation is among the most common root causes of batches failing, deviations, and lack of comparability in cell therapy manufacturing. A certificate of analysis tells you what the supplier tested; it doesn’t tell you that the material meets the requirements of your process. This is where qualification comes in. Inspectors, especially in pre-approval audits, will examine the qualification rationale for any material they consider critical, and saying “the supplier said it was GMP grade” isn’t enough of an answer. And here’s where the European Pharmacopeia/United States Pharmacopeia reference is important. This means that when a raw material is covered by a pharmacopoeial monograph, use of a grade that does not meet that monograph must be justified both scientifically and from a regulatory perspective. For advanced therapy medicinal products (ATMP), raw materials this can be more nuanced, but for materials that are clearly monographed — such as sodium chloride, sodium bicarbonate, glucose, water for injection, and many amino acids — pharmacopoeial grade represents the expected baseline.

MGK: 

The risks:

The most common delaying issues, in rough order of frequency of occurrence, begin with critical raw materials sourced exclusively from a single qualified supplier. Growth factors, specialized media, viral vectors, and selection reagents in an ATMP or CGT process might be sourced from one single qualified supplier. So, if the supplier experiences a quality issue, manufacturing capacity issue, or gives a discontinuation notice, it could hold up an entire program for months.

Related to the above is any issue stemming from changes made upstream. Closely related are supplier‑initiated changes, namely a formulation change, site transfer, or raw material substitution by an upstream supplier that is not communicated in time for the manufacturer to assess impact. This is the silent hidden problem, because it often only surfaces during a deviation investigation.

Biologically derived components exhibiting lot‑to‑lot variation represent another category of concern. Even within set specifications during qualification, biological components have the potential to drift from batch to batch. For sourced biologic components, also the climate change might influence the composition of raw material.

Lastly, geographic/logistical risks cannot be ignored. Customs hold‑ups, international disruption due to wars and natural disasters, temperature deviations in shipping, and geographical concentration of the supply chain also must be considered.

Mitigation strategies:

Effective mitigation, that actually works, depends on certain fields. Dual sourcing for critical materials, pre‑qualified in advance, is the most effective step that can be taken in this regard; it is also the most time‑consuming and expensive one, which is frequently deferred and frequently regretted.

Formal quality agreements with change notification clauses that specify timelines and the level of detail required are essential, and a vague “supplier will notify of changes” clause is mostly not enough.

Strategic inventory built up of critical materials, sized against realistic lead times and shelf life and with defined rotation, buys time when disruptions hit. Defining a comparability strategy upfront, so that the analytical and functional tests used to bridge a material change are known before one is needed, shortens the response time when a change occurs. Comparability is where most CGT delays converge, because a material change triggers a comparability exercise, which triggers a regulatory interaction, which triggers a timeline delay, which puts itself the patient at risk not receiving the treatment.

Also, supplier relationship management, not only supplier qualification, matters more than most programs acknowledge. Early visibility into the supplier’s own supply chain and capacity planning is more useful than a clean audit report. You might get information about a discontinuity before the official change notification.

The difficult reality is that supply chain risk management is undervalued for most CGT programs in comparison with clinical risk management and manufacturing risk management, due to supply chain events being less frequent and harder to predict.

MGK: Storage is the place where the material either maintains or fails to maintain the qualities it has been qualified for. The internal supply chain does not end at incoming goods inspection; it ends at the point of use, and many of the problems attributed to raw materials are in fact storage or handling problems inside the user’s own facility.

Risks associated with cell culture materials are known but not always controlled compared to e.g., Active Pharmaceutical Ingredient manufacturing. The most common risk factor is temperature excursion. The majority of media, additives and growth factors have a specific range for storing (usually 2–8 °C; less than –20 °C for sensitive material or ambient temperature). If storage conditions are not optimal, then potency may decrease, although there will be no visible evidence of degradation. Light exposure is an important risk factor for photosensitive material like riboflavin, folic acid, tryptophan and HEPES formulations, which will produce peroxides when exposed to light. Protein degradation from freeze/thaw cycles is another common reason for unexplained loss of performance. Expiry/retest dates are challenging to manage when materials have a short shelf life compared to the production process. Cross-contamination and segregation failures, especially where animal-origin and ACF materials are stored in the same facility, are a point auditors specifically look for. And stock rotation failures, where first-expiry-first-out is not applied reliably, turn qualified stock into expired stock, which need to be disposed of.

Best practice maps quite directly to what an auditor expects. Storage equipment should be qualified, with continuous temperature monitoring, alarms, documented excursion handling, and mapping studies for freezers, cold rooms and fridges on a defined frequency. Segregation between quarantined, released, rejected and expired material should be physical where possible and logical (system-enforced) as a minimum. Labeling should travel with the material through its internal lifecycle, including retest or expiry date, status, and link to the released batch record. Controlled transport within the site, particularly for cold-chain materials moving between warehouse, dispensary and manufacturing suite, should be treated as part of the storage regime rather than as an afterthought. Excursion handling procedures should define thresholds for investigation, material hold and release-after-assessment decisions, with those decisions documented by QA rather than taken by the manufacturing team under time pressure.

The underlying regulatory expectation is straightforward: conditions of storage and handling must not compromise the quality of the material. For cell therapy developers transitioning from research to GMP, storage is often the weakest link, because research habits, unlabeled aliquots, undocumented freeze-thaw or exposure to light or temperature excursions, shared freezers, survive longer than they should.