Pharmaceutical engineering and bioprocesses

Engineering projects: Quality by Engineering Design

Axys-Network has structured its Engineering department, headed by Mongi Sakly, to support laboratories across all their industrial projects.

Front-end phases

Site master plans, feasibility studies and conceptual designs.

Project audits at key milestones

Audits at each milestone to ensure, through to handover, that the five pillars of project management are respected:

• quality by design;
• safety;
• performance;
• schedule;
• final cost.

Proven methods

Fast Track Project, Quality by Engineering Design and Quality by Construction, to prevent schedule overruns during qualification and validation. Projects are led by project management experts with 30 to 40 years of experience in major pharmaceutical groups.

Monoclonal antibodies (mAb)

Our experts have taken monoclonal antibody processes from clone to commercial manufacturing, at manufacturers and at CDMOs alike. They work on projects in development as well as on commercial processes that need to be brought back under control or run end to end.

Development and scale-up

Choice of cell line and culture mode (fed-batch, perfusion), scale-up from laboratory bioreactor to commercial volumes, identification of critical parameters and construction of the design space using the QbD approach (ICH Q8 and Q11). Development and deployment of cell banks (MCB and WCB), their storage and protection.

Characterisation and control strategy

Critical quality attributes (glycosylation, charge variants, aggregates, fragments), analytical strategy, process control strategy (PCS), comparability after a process or site change (ICH Q5E).

Viral safety

Viral risk assessment of raw materials and cell banks, choice of inactivation and removal steps, small-scale clearance studies (ICH Q5A).

CMC, transfer and inspections

Writing and reviewing the CMC sections of the dossier, technology transfer to a CMO and management of the interface, process validation, preparation for pre-approval inspections. Securing the value chain and supply chain, transport validation.

Antibody-drug conjugates (ADC)

Antibody-drug conjugates (ADC) combine a monoclonal antibody with a highly potent cytotoxic payload. Our network has strong expertise in their manufacture and in setting up qualified supply chains. Our experts have taken part in several conjugate manufacturing campaigns, at clinical and commercial scale, for global supply.

Design

Choice of linker and cytotoxic payload, conjugation chemistry (lysine, cysteine, site-specific conjugation), control of the drug-to-antibody ratio (DAR) and its distribution, definition of critical quality attributes and analytical strategy.

Production

Design and set-up of conjugation and purification in a containment facility suited to highly potent products, operator and environmental protection, removal of free species, formulation, then aseptic filling and freeze-drying of a cytotoxic product.

Qualified supply chain

An ADC often involves several sites: antibody, linker-payload, conjugation, filling, testing and release. We select and audit contract manufacturers, draft quality agreements, organise transfers between sites, the cold chain and traceability of intermediates, through to batch release for several markets, to ensure your processes comply with international regulations.

Downstream

Purification weighs heavily in the production cost of a therapeutic protein, and it determines the purity and viral safety of the product. We build or review your purification train starting from the molecule and the way it is produced.

Choice of purification systems

Harvest by centrifugation or depth filtration, capture by affinity (protein A for antibodies, specific ligands for other proteins) or ion exchange, polishing by ion exchange, hydrophobic interaction or mixed-mode chromatography, ultrafiltration and diafiltration, final sterilising filtration.

Assessing the alternatives

For each step, a comparison of the options: resins or membranes, bind-and-elute or flow-through chromatography, batch or continuous processing with multi-column capture. Each scenario is assessed on yield, purity, capacity, cycle time and cost per gram produced.

Equipment suited to the type of molecule

An antibody, a coagulation factor, a fragile protein or a viral vector do not impose the same constraints: sensitivity to shear, temperature and interfaces, molecule size, potential viral load of the starting material. The sizing of columns, chromatography skids, tangential flow filtration systems and tanks follows from this.

Single-use, stainless steel or hybrid

The decision is made process by process: volumes, number of products in the facility, frequency of campaign changeovers, cost of cleaning and its validation, cross-contamination risk, extractables and leachables studies, security of supply and supplier dependence. The outcome may be a fully single-use process, a fully stainless-steel one, or a hybrid.

Viral safety and established processes

Positioning of inactivation (low pH, solvent-detergent) and nanofiltration steps, clearance studies. For a process in production: optimisation, comparability, troubleshooting and technical investigations.

Biological molecules

Beyond antibodies, our experts support the production of other families of biological molecules, each with its own process, quality and regulatory constraints.

Immunoglobulins

Plasma fractionation and purification of polyvalent or specific immunoglobulins, dedicated viral safety steps, control of aggregates and anticomplementary activity, formulation and aseptic filling.

Coagulation factors

Plasma-derived or recombinant factors: fragile, low-concentration molecules, high-yield purification, viral inactivation and removal, freeze-drying and control of biological activity.

Recombinant proteins

Microbial or mammalian cell expression, removal of process-related impurities (host cell proteins, residual DNA), prevention of aggregation and stability studies. Implementation at clinical and commercial scale.

ATMP

Gene, cell and tissue therapies: viral vector production, closed-system and single-use processes, small batch sizes, application of the GMP specific to advanced therapy medicinal products (Part IV of EU GMP).

Maintenance

In a cleanroom, every maintenance intervention affects the validated state of equipment and premises. Annex 1 makes preventive maintenance part of the contamination control strategy. Our experts help you organise maintenance that keeps your lines available without weakening sterility assurance.

Maintenance strategy and plan

Equipment criticality analysis (FMEA, RCM approach), balance between preventive, condition-based and corrective maintenance, review of your plan against GMP and manufacturers' recommendations. Sterilisers, air handling and water systems require qualification, monitoring and planned maintenance, and their return to use after an intervention must be approved.

Maintaining the validated state

Preparation and supervision of interventions in cleanrooms, isolators or RABS. Work is done outside the room whenever possible; otherwise, restricted access, a written protocol, then enhanced cleaning, disinfection and environmental monitoring. Unplanned maintenance on equipment critical to sterility is subject to a recorded impact assessment, and specific maintenance such as changing terminal filters triggers requalification of the room. Maintenance staff receive the same training and gowning qualification as operators.

CMMS, audit and KPIs

Selection and validation of your CMMS as a computerised system, audit of the maintenance organisation, KPIs tracked in management review: MTBF, MTTR, preventive maintenance completion rate, work order backlog. Isolated but repeated excursions above action limits after each preventive maintenance form a trend that Annex 1 requires you to monitor.