Cell & gene therapies (CGT) present an opportunity to fundamentally change the way diseases are treated. These personalized medicines present unique supply-chain and manufacturing challenges that differ from traditional pharmaceutical manufacturing of small molecules and biologics and new digital tools are required to support the scale up/out of CGT. Autolomous was formed by CGT experts to specifically address the challenges and bottlenecks facing CGT delivery to patients. The company is building a platform that uniquely supports CGT manufacturing across the entire value chain for both autologous and allogeneic therapies and its platform has gained early adopters from academia, clinical CGT manufacturers, CDMOs and the support of the UK Government via non-dilutive funding from UK Research & Innovation (UKRI). Autolomous has identified the need for support in batch verification of CGT products and is now actively engaged in a two-year project due to be completed by April 2023 involving the CGT community on developing AutoloMATE-Assist, its flagship module to support batch certification.

Manufacturing and certification requirements

Most commercially approved therapies have undergone a ‘growing-pain’ in the early days of commercial release to meet the market demand despite having commercial manufacturing facilities at onset. Solutions that enable rapid expansion into new markets, create easily transferable manufacturing knowledge, and allow CGT developers to have manufacturing insights on the production suite and on the drug product from early clinical phases up to commercialization. These insights into the early waves of commercial products can relate to some of the scenarios shown in Figure 1 as follows:

1. Expansion into Europe with a CGT product for clinical trial or commercial use via a US centralized manufacturing centre.

In the European Union and the UK, products destined for use in a clinical study or for commercial purposes must have a Qualified Person (QP) declaration. The QP certification for the EU market cannot be performed in the US. QPs would need real-time access in a digital manner to understand manufacturing related in process, input, and output data/insights. This secure online data stream enables rapid batch verification and subsequent certification by quality personnel based in target markets, in a remote manner, anywhere across the globe.

2. Technology transfer to European (or outside the US) manufacturing sites requires an appreciable amount of effort in training and a lot of oversight.

Paper batch records are restrictive in allowing manufacturing personnel to learn about the manufacturing method, acceptable ranges, manufacturing workflows, QP requiring on-site evaluations and days’ worth of work combing through data on hundreds of pages per batch. Digital tools such as electronic manufacturing batch records can assist in the instruction of manufacturing and analytic personnel, and QPs can quickly come up to speed and review.

3. Scaling to commercial production requires an intimate knowledge of manufacturing capacity and potential bottlenecks.

Digitization of the manufacturing process allows for real-time monitoring and assessment of CMC processes to optimize the utilization of facilities, materials, personnel and equipment.

4. Where are the knowledgeable QPs?

The low numbers of CGT-focused QPs in Europe is a challenge , and this lack of supply has created a bottleneck which in turn leads to significant reliance on expensive QP contracting services. In the UK, we estimate that less than 20 QPs are currently performing batch certification activities of CGT products. Digitization to enable rapid review of in-process and completed batches would streamline the batch verification process for QPs, enabling more batch releases by existing CGT-focused QPs, and utilizing methods such as remote verification and review by exception.

5. Where is my deviation? I just received a supplier quality notice, where was that batch of raw material used?

Inevitably, supplier quality notifications results in an investigation. Determining where the lot of questioned material was used could be a search query away or it could mean a full week combing through hundreds of pages across multiple batches.

6. Batch verification and certification requires combing through hundreds of pages of manufacturing documentation and requires days of work to release a single batch.

Finding even the simplest of data can be challenging. From our user studies, it would take days to find even the simplest of errors or deviations in the event of a specific reagent lot recall, across ~20 batches of a CGT clinical trial. ( 100 pages / batch x 20batches = 2,000 pages to be reviewed). In early clinical studies, few batches are certified; however, if a product is approved this becomes thousands of pages, resulting in an exponential need for staff and increased error rates.

7. Covid restrictions have highlighted deficiencies in data management tools used in CGT supply chains.

During the lockdown periods of the COVID-19 pandemic, CGT supply chains flexed to ensure continued CGT delivery to patients. Remote CGT certification using scanned paper batch manufacturing records have occurred, with some degree of risk. The need for digitization has been highlighted by many in the industry including, Curran Simpson, CTO and COO at RegenXBio, who comments as follows: “the digital documentation a manufacturing facility can provide indicates its compliance to cGMP and the efficiency of its processes.^[1] Indeed, eBMR could eventually be a requirement for approvals”^[2] : this allows for manufacturing and quality control data to be correlated and become key to efficient decision-making.

^[1]Raps.org. 2021. FDA officials, experts discuss impact of COVID-19 on cell and gene therapies. [online]

^[2]International Society Cell and Gene Therapy ISCGT, 2021. Impact of contracted manufacturing organization protocols on operationsin an academically based Current Good Manufacturing Practice facility. [online] Elsevier, pp.2,3.

Further Information 

Autolomous Business Intelligence 

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