An active pharmaceutical ingredient plant is a chemical plant that happens to be regulated as pharmaceutical. It has reactors, solvent inventories, distillation, filtration and drying, and it carries the process safety hazards that go with all of those. What makes it unusual is that the project team is frequently assembled around quality expertise rather than process safety expertise, and the DSEAR position is discovered late.

Projex Solutions provides engineering design, process safety studies and project delivery across API manufacture, secondary formulation and the non-GMP plant that supports both.

What makes this work different

Solvent inventory brings DSEAR and sometimes COMAH. Synthesis routes typically involve significant quantities of flammable solvent held in bulk, recovered and recycled. That requires hazardous area classification to BS EN IEC 60079-10-1:2021 and, where thresholds are crossed, brings COMAH 2015 duties onto a site that does not think of itself as a chemical establishment.

Containment for potent compounds. High-potency APIs require occupational exposure banding, containment strategy and verification designed in from concept, along with cleaning validation that can demonstrate carryover control between campaigns.

ICH Q7 governs the GMP boundary. Where GMP begins in a synthesis route is a defined decision, and it determines which parts of the plant carry qualification obligations and which do not.

Non-GMP support plant still has to protect the GMP envelope. Solvent recovery, effluent treatment and utilities are frequently non-GMP, but a failure in any of them can compromise the facility they serve.

Annex 15 shapes the project, not just the paperwork. URS, DQ, IQ, OQ and PQ should drive design decisions. Assembled afterwards, qualification becomes an expensive reconstruction exercise.

Drying and powder handling brings dust risk. Filter dryers, milling and powder transfer produce combustible dust and static generation in the same operation.

Where we help

  • DSEAR assessment and hazardous area classification for solvent and dust, with CompEx-certified engineers
  • COMAH tier determination where solvent inventory approaches threshold
  • HAZOP and HAZID facilitation, LOPA and SIL determination to BS EN 61511
  • Containment design for potent compounds, with exposure banding and verification planning
  • Reactor, distillation and solvent recovery design, including thermal hazard consideration
  • Commissioning and qualification to Annex 15, from URS through to PQ
  • Non-GMP support plant design that protects the GMP envelope
  • Feasibility, FEED, detailed design and EPCM delivery under ISO 9001:2015

Typical reasons clients get in touch

  • A DSEAR assessment is needed on a site whose team is quality-led rather than process-safety-led
  • Solvent inventory has grown and COMAH status needs establishing
  • A potent compound is entering the portfolio and containment has to be designed
  • Solvent recovery is limiting throughput or breaching emissions expectations
  • A new synthesis route changes the thermal or flammability profile of the plant
  • Qualification is being assembled retrospectively and is proving expensive

Related

Part of our work across the pharmaceutical sector and closely related to the chemical sector. See also life sciences and biotech processing.

Standards and regulations we work to

  • EU/UK GMP Annex 15, Qualification and Validation, in operation since October 2015
  • EU/UK GMP Annex 1, Manufacture of Sterile Medicinal Products, in force since August 2023 and fully applicable since August 2024
  • EU/UK GMP Annex 11, Computerised Systems (the January 2011 version remains the text in force)
  • ICH Q7, Good Manufacturing Practice for Active Pharmaceutical Ingredients
  • DSEAR 2002, with ACOP L138 (second edition, 2013)
  • BS EN IEC 60079-10-1:2021 for solvent vapour, and BS EN 60079-10-2 for dust
  • COMAH 2015, where solvent inventory crosses threshold
  • PSSR 2000, with guidance L122 (2014)
  • BS EN ISO 14644-4:2022 where classified space is involved
  • CDM 2015 and ISO 9001:2015

Frequently asked questions

Our quality team leads projects. Where does that usually go wrong?
Not in the quality documentation, which is generally excellent, but in process safety. API plant holds significant flammable solvent, and DSEAR duties, area classification and sometimes COMAH apply exactly as they would on a chemical site. Those obligations are commonly identified late, when design decisions have already been made.

How do we decide where GMP starts in our synthesis route?
ICH Q7 provides the framework, and the decision determines which parts of the plant carry qualification obligations. It is worth settling early, because it changes the specification of everything downstream of that point.

Is qualification cheaper if we design it in?
Considerably. When the URS drives design decisions, qualification documents what was intended. When it is assembled afterwards, it becomes a reconstruction exercise, and any gap between what was built and what can be evidenced has to be closed physically.

Can non-GMP plant be built to a lower standard?
To a different standard, not simply a lower one. Solvent recovery, effluent and utilities are frequently non-GMP, but a failure in any of them can compromise the GMP envelope they serve, so the design has to protect that envelope.

Talk to us about your plant. Request a call