Biomanufacturing: what changes between a test tube and a factory

Producing a molecule using cells involves more than increasing the size of their container. The culture environment, product recovery and operational consistency must remain controlled. Laboratory success demonstrates a possibility; industrial production must make that possibility repeatable, with a defined product and a quantity that is actually usable.

Biomanufacturing covers different activities. Here we consider cell or microbial cultures used to produce a substance. Requirements specific to biological medicines are distinguished from engineering principles: they do not automatically apply to every industrial fermentation.

Cells do not experience an average volume

Conditions in a large bioreactor are not necessarily identical everywhere. Forschungszentrum Jülich studies nutrient and oxygen gradients: cells may move through alternating rich and poor zones, unlike the more homogeneous environment of laboratory equipment. Its work includes flow models and small-scale devices that reproduce these variations. Forschungszentrum Jülich, bioprocess scale-up.

This suggests a useful question when assessing a project: which conditions were actually reproduced? The same temperature displayed on a dashboard does not fully describe what each cell encounters. An average measurement can be correct while concealing local variations important to the process.

That does not mean all large reactors work poorly. The task is to identify parameters that matter to the culture studied, then verify their control at the target scale. The effect depends on the biological system and process; a universal percentage loss during scale-up would be misleading.

Three quantities that should not be confused

When analysing a claim, we distinguish the quantity in the reactor, the quantity recovered and the quantity meeting requirements for the intended use. Here is a fictional arithmetic example, unrelated to any real facility.

A 1,000-litre culture contains 2 grams of product per litre at harvest. The crude product therefore amounts to 2 kilograms. If recovery retains 70% of that mass, the result is 1.4 kilograms. If the batch does not meet the specified criteria, that does not make it 1.4 kilograms of deliverable product.

Figure announced	Question it answers	Question it leaves open
Culture volume	How much liquid is processed?	What product concentration is achieved?
Mass at harvest	How much product is present before recovery?	What proportion will be recovered?
Recovered mass	How much remains after the selected operations?	Does the product meet the specified criteria?
Conforming mass	How much can serve the defined use?	How often and how consistently?

This table is a reading framework proposed by Pnebbula. It prevents tank capacity from being treated as commercial capacity. Comparing projects also requires matching scope: quantity per batch, per day and per year tell different stories.

Purification is part of the process

An announcement about a productive strain or high-performing cell does not complete the assessment. It must still explain how the product is separated from the medium, which steps are needed and how quality is measured. For non-specialist readers, the question is not which purification technique to choose, but whether the announced result concerns the final product or an intermediate state.

A precise request might be: “Does this quantity refer to harvest, purified product or a batch accepted against documented criteria?” A clearly bounded answer is more useful than a general scale-up promise. A step still under development can be named without invalidating progress already demonstrated.

For US pharmaceuticals, the FDA presents process validation as a lifecycle: design the process, qualify its operation, then verify that it remains controlled during production. This framework concerns drugs, including biological products; it is a methodological reference, not certification of all biomanufacturing. FDA, process validation principles, 2011.

Repetition matters as much as a single success

One successful production run can be a decisive milestone. To assess industrial capability, however, we suggest requesting a series of results: number of batches, acceptance criteria set before testing, observed deviations and handling of failures. A “best batch” does not answer the consistency question.

Imagine two fictional reports. The first announces a record concentration without stating the number of attempts. The second presents several batches, their results and remaining deviations. Without further data, we cannot declare the second process superior. We can say its repeatability is more directly open to examination.

The same reasoning applies to time. Annual capacity calculated assuming uninterrupted operation must be identified as a projection. To understand it, readers can ask what time allowances cover intermediate operations, checks and downtime. The aim is to make assumptions explicit, not invent a standard utilisation rate.

Changing the process requires comparing the product

For pharmaceutical biological products, ICH Q5E addresses comparison before and after a manufacturing process change. Its purpose is to examine potential effects on quality, safety and efficacy; retaining the same molecule name is not sufficient. FDA, ICH Q5E.

This does not mean every change requires restarting all clinical development. The evidence package depends on the product, change and available evidence. For our purposes, useful information is the existence of a comparison plan and a distinction between what was measured and what remains to be established.

The phases of clinical trials (in French) answer other questions. Clinical evidence and evidence of consistent manufacturing complement each other: neither removes the need to understand the other.

What an industrial announcement should make clear

A convincing dossier lets readers follow a simple chain: organism or cells used, tested scale, recovered quantity, quality criteria, repeatability and next step. It distinguishes achieved results from projected capacity. This approach also fits technology readiness levels, or TRLs (in French), without expecting them to summarise an entire factory.

The final question is therefore not just “how many litres?” It is: what usable product, obtained how many times, under which conditions and with what evidence?

Sources and scope

Jülich documents physical differences between scales. The cited FDA guidance concerns drugs and pharmaceutical biological products. Yield calculations and review situations are fictional; no real industrial cost or yield is inferred. Sources consulted on 22 October 2026.