PACE – Pharmaceutical Acceleration in Clinical Excellence.

Using Manufacturing Innovation to deliver Just-In-Time clinical packing

A Catapult and large-Pharma supported project to bring together industry and academia innovation collaboration has delivered a modular Just-In-Time automated multi-product clinical packing capability, with integrated digitalised automated GMP verification – ‘PACE’.

The ‘PACE’ innovation project was conducted at CPI’s Medicines Manufacturing Innovation Centre, bringing together funding partners Scottish Enterprise, UK Research and Innovation, AstraZeneca and GSK, with collaboration partners National Physics Laboratory, Siemens and Automated Industrial Robotics a s system manufacturer, to deliver a truly agile and responsive innovative pharmaceutical supply chain solution. All companies worked side by side on the design, build and engineering of the automated platform in a unique multi-disciplinary industry-academia collaboration.

The PACE platform is a digitally-enabled automated GMP bottle packaging line that can fill tablets and capsules with custom amounts of drug compounds . One key innovation is the modular system design, allowing multiple drugs to be manufactured and packaged in the same facility without cross-contamination. Packed bottles are sealed and stored with a customised bar code that enables rapid labelling before distribution to individual patients. Additionally, a real-time Qualified Person (QP) release dashboard was created to accelerate the decision-making needed for legal certification, enabling automated rapid batch review, and Just-In-Time GMP batch certification. This innovative use of digitisation will enable the modular factory-in-a-box approaches expected for the future supply chain. Following the prototype OSD filling line, other formulation types of vial/ syringes are planned to be integrated into the line capability.

Traditional manufacturing challenges

Traditional clinical supply necessitates an inefficient ‘make to stock/Just-in-case’ over-manufacturing clinical supply chain to ensure study centres have access to medicines when they need them. This leads to waste, if for example trial parameters change such as safety / CMC data or patient enrolment. As pharmaceutical companies respond to accelerated clinical study timelines and increasing development costs, there is a growing need to adopt flexible and digitally-supported supply solutions. The rise of personalised therapies and small volume products is driving a commercial need to reliably and efficiently supply regulatory-approved small batches of tailored formulations.

The PACE system is designed to uniquely fulfil ‘make-to-order’ demand-driven supply. The Investigator can request re-supply via Interactive Response Technology (IRT), triggering PACE to schedule the order, fill and label each bottle in-line, executed within hours from the IRT to filling and labelling of the batch.

Batch sizes of 1 bottle are capable, thereby obviating inventory over-production waste, human errors and sustainability . Bulk stock will be held until demanded by a direct enumerated order; thus enabling the Sponsor to re-direct resources flexibly, based on actual demand to study centres.

Multi-product in-line bottle filling

Traditional GMP requires only one product per line to avoid cross contamination. The PACE system developed a patented sealed bottle fill capability. PACE can fill multiple-products on the same line for the first time in industry, using patented separate sealed fill heads. The PACE prototype was built with 4 fill-heads, however, the concept enables unlimited fill-head units, delivering sealed, filled bottles to the in-line labelling station. The powerful advantages are that in the clinical trials process, active, placebo or comparator can be filled and labelled on the same line at the same time. This enhances security considerably against such as unintended blind reveals, as the same bottles and same label printer create identical filled bottles, each with unique label. Plus this enhances sustainability of waste reduction and concurrent distribution of multi-trial kits.

From human Quality Assurance to automated Quality Verification

Traditional manufacturing systems are still designed for human workflow Quality Control checking, leading to potential human errors due to highly complex manufacturing steps and increasing data reviews. The PACE project took a truly digitalised approach, through innovative integration of sensor-controlled product fill and camera-verified in-line label printing.

Traditional labelling uses pre-printed label reels, which are sequentially applied to each bottle. The PACE system creates a digital pre-approved label mask, which enables each bottle to be uniquely printed in-line. Cameras verify the label quality and full wording (regulatory mandated data and variable data such as batch number, kit-id etc.) against the digital mask, delivering 100% in-line full label verification. This allows unique label printing on the line, per bottle, delivering batch-size = 1 bottle capability.

Novel Digital GMP data verification and JIT automated QA batch review

Traditional batch GMP reviews are performed post batch packing, with extensive review of documents and data. The amount of data used to conduct human QC checks was calculated as over 1,500 data points per batch , which are held across up to 23 separate databases and 24 review steps per system to search for and access documents and data. Furthermore, this requires highly trained personnel to know what data is required, plus, data is held in documents (e.g. MS Office/pdf), which is designed to be reviewed only by the human eye. This is estimated to take 1-3 weeks, due to repeat and sequential human-QC data checks per batch. Multi-personnel checks are traditionally required of both manufacturing and batch review steps, due to the well-documented, known and acknowledged potential for human-errors, which still occur despite the highly trained expertise.

The challenge that the PACE project overcame was to accelerate the batch GMP and registration data review by using machine-automated data check and verification steps. Registration data is automatically pre-flight checked prior to order filling in real-time, direct from the digital data source. Sensor-driven automated verification of filling and labelling delivers an automatically verified batch record. All data is sent to the Siemens-designed ‘Automated QP Platform’ using a release by verification capability. All steps are auto-verified, making automated JIT- QA GMP batch review now capable. No need for human QC checks.

Delivering Sustainable, differentiated supply

Traditional clinical supply leads to waste, (50–75% costing some manufacturers between £10M–100M/year – Badman, C., Srai, J.S., 2018. ReMediES: collaborative research in action). It typically costs in excess of £75 million to run a clinical trial program for a new drug, only 25% make it to commercial production. Due to manufacturing processes, clinical teams are required to decide the doses of the drugs they are trialling – and hence how much needs to be manufactured – 12 to 18 months before they expect to use it. As a result, more drugs are made than are needed to cover contingencies; for example, when trial parameters change and pre-labelled stock has to be destroyed/reworked, patient enrolment does not meet forecast expectations. Modelling of stock implications for a made-to-order facility has demonstrated that the potential benefits could be savings of tens of millions of pounds per year per company (https://www.ifm.eng.cam.ac.uk/insights/global-supply-chains/remedies-collaboration-as-the-best-medicine/).

Furthermore, short shelf-life waste is high from both trial campaign stock (e.g. destroy <6months shelf-life stock) and expensive short-life comparator stock. As pharmaceutical companies respond to accelerated clinical study timelines and increasing development costs, there is a growing need to adopt flexible and digitally-supported supply solutions. The rise of personalised therapies and small volume products is driving a commercial need to reliably and efficiently supply regulatory-approved small batches of tailored formulations.

ClinicalTrials.gov has >350,000 national and international trials registered, which, using the average calculated by the Sustainable Clinical Trials Group, would give a carbon consumption of an estimated 27.5 million tonnes of carbon dioxide equivalent (MtCO2e). Almost half of the trials are of drugs, and drugs account for a fifth of the carbon footprint of NHS England. Most trials of drugs are performed by pharmaceutical companies, such as GSK that produces 17.7 MtCO2e, but is a company (like many others) that has committed to decarbonising.

PACE technology can enable the measurable overall operations effectiveness (OOE) benefits needed in a production setting as well as reductions in waste production, energy consumption and carbon emissions. A key differentiator is to move towards digital GMP verification over traditional human-checking methods. These will be enabled by innovation in data collection, utilisation of cloud, aligning with regulatory bodies, integration and interoperability.

The business landscape is increasingly shaped by regulatory demands to track and reduce carbon emissions. In the UK, the NHS, as the largest healthcare provider, has set ambitious targets to reach Net Zero by 2045, with an ambition to reach an 80% reduction by 2036 to 2039. For companies supplying the NHS, such as those involved in pharmaceutical manufacturing, reducing, tracking and reporting carbon emissions will soon be a regulatory requirement. The wider pharmaceutical and manufacturing industries face similar regulatory pressures. PACE serves as a model for how to integrate sustainability goals into the supply chain.