From molecule to batch release: where the digital systems actually attach

If you are going to secure or digitalise a pharmaceutical plant, you need a map of what happens inside it. A marketing diagram will not do. You need the actual sequence of steps, each with the system attached to it and the record that system has to produce. That is what this article tries to draw.

This is part 2 of 3 of the “Pharmaceutical digital transformation” series; it follows part 1, why the sector is strategic and continues with part 3, the four stakes.

Part one: developing the substance

Long before anything is made at scale, a molecule has to be found, formulated and proved. Five stages, in order.

Pharmaceutical development. The active ingredient is synthesised, then comes the first formulation: the route of administration (tablet, injection, cream) and the excipients that will carry the active substance. Decisions taken here constrain everything that follows, down to which manufacturing equipment the product will ever be able to run on.

Preclinical development. Safety testing designed to find toxicity before any human is exposed, and efficacy testing whose results cannot be transposed directly to humans but give the first real signal. This is where Good Laboratory Practice applies.

Clinical development, in three phases:

1. Phase I: a small group of healthy volunteers, to assess safety and pharmacokinetics.
2. Phase II: a larger group of patients, to establish efficacy and bring side effects to light.
3. Phase III: a large patient population, to confirm efficacy, monitor adverse events, compare against existing treatments and gather the data that will support safe use in practice.

Marketing authorisation. Once safety and efficacy are demonstrated, the dossier goes to the regulators. Through the national route in France, the ANSM assesses it and grants the authorisation. Through the centralised European procedure, the EMA carries out the scientific evaluation and the European Commission grants an authorisation valid across the EU.

Pharmacovigilance. Approval does not close the file. Post-market surveillance runs for the life of the product, looking for adverse effects that a Phase III population was too small, or too short, to reveal.

Part two: manufacturing, by dosage form

The process changes with the form of the finished product. Three families cover most of it.

Solid oral forms: tablets, capsules. Receipt and testing of raw materials, formulation and blending, granulation to homogenise, then compression into tablets or filling into capsules, film coating where required, and packaging into blisters or bottles.

Liquids: solutions, emulsions, suspensions. Receipt and testing, a specific formulation, sterilisation where required, then filling and packaging into sterile containers.

Topicals: creams, gels, ointments. Receipt and testing, a homogeneous formulation with the actives added, then packaging.

What each unit operation actually does

Formulation fixes the exact composition, so that the proportions between components are right. Blending combines the active substance and the excipients into a homogeneous mix. Milling reduces particle size so that the active is evenly distributed. Granulation agglomerates fine particles into granules that will compress cleanly. Compression forms the tablets from the granulate; capsules are filled rather than compressed. Sterilisation eliminates micro-organisms where that is a safety requirement, and coating applies a protective or functional film to the tablet.

Packaging, primary, secondary and tertiary, carries the regulatory information and protects the content. Since the safety features of the Falsified Medicines Directive became mandatory in February 2019, the pack also carries the unique identifier that makes serialisation and aggregation possible.

Where the computerised systems sit

Lay the systems over that sequence and it becomes obvious why IT/OT convergence could not be avoided.

• Raw material receipt: the ERP holds the material master and the release status. Nothing moves without it.
• Dispensing and weighing: weighing terminals that should write into the batch record, not leave a figure for someone to copy.
• Granulation, compression, coating: PLC and SCADA control the critical process parameters, and those parameters are the quality evidence. A data historian collects them continuously.
• Sterile operations: environmental monitoring systems, plus the autoclave and lyophiliser cycle records that qualify the batch.
• In-process and QC testing: laboratory instruments under a LIMS, and chromatography data systems whose audit trails are among the most heavily inspected records in the industry.
• Packaging: vision systems, print inspection, serialisation and aggregation up to the national repository.
• Across all of it, MES and the electronic batch record, which ties the whole sequence into one document that can be reviewed.

Batch release: the step everything else exists to support

Quality control runs alongside production throughout. Every batch is documented in a batch record covering every step from raw material to final testing. Before distribution, the Qualified Person (in French practice, the pharmacien responsable or a pharmacist acting under delegation) certifies the batch, attesting that it meets every quality criterion and is fit for release.

That signature is what the whole apparatus is for. Every sensor, every historian tag, every audit-trail entry exists so that one named person can put their professional standing behind the statement that this batch is fit for patients. When you propose a change to a system in a GxP plant, the question that really decides it is whether the Qualified Person can still make that statement afterwards.

That is the practical difference between industrial IT in pharma and anywhere else. In most industries the data describes the product. Here it is part of what is released, and a batch whose record cannot be defended cannot be sold, however good the tablets are.

Two consequences for engineering

Real-time collection beats reconciliation. Data written straight from the equipment into a secured, central system at the moment it is created is far easier to defend than data transcribed, exported or reconciled afterwards. Every intermediary between the controller and the historian is a point where integrity has to be argued rather than shown. That is the technical case for OT/IT convergence, and it is a data-integrity case before it is an efficiency one.

The packaging line is a regulated data system. Serialisation turned the end of the line into a transactional system with legal obligations towards external repositories. When a packaging line stops because a serialisation server cannot be reached, the help desk may log it as an IT ticket, but what the site actually has is a supply interruption.

The next article moves up a level, to the economic, health and regulatory stakes that digitalising this process is supposed to address.

References

• EMA, Marketing authorisation: centralised procedure, EMA evaluation and European Commission decision.
• European Commission, EU GMP Annex 16: Certification by a Qualified Person and Batch Release, 2015.
• Commission Delegated Regulation (EU) 2016/161 on the safety features on the packaging of medicinal products, applicable from 9 February 2019.