Intelligent Logistics: Key Considerations Of Manufacturing Biologics
The art of manufacturing biologics is best summed up in the adage — ‘you only get out what you put in’. As biologics are produced from living cells, the drug product you get out of a bioreactor is only as good as the cells and critical reagents you put in.
The key challenge to manufacturing biologics in a commercial environment stems from the need to maintain and control living, enzymatically active systems within both an optimised and tightly regulated manufacturing environment.1
hile responsibility for research, development and CMC remain largely in the US and Europe, manufacturing is being increasingly outsourced to places such as India.2 Therefore, master and working cell bank production, maintenance and distribution logistics have become critical in biologic manufacturing.
This need arises from the sensitivity of cGMP cell lines to many factors including, but not limited to, temperature excursion, genetic instability and contamination among many others. It is, therefore, of utmost importance to ensure that clear temperature-controlled logistics ensuring the chain-of-condition and custody of all cell lines and critical reagents is maintained to ensure quality and maximise manufacturing efficiency.
The response to the criticality of and risks to cGMP manufacturing logistics in a commercial environment is largely two-fold; first, evolving good distribution practice (GDP) standards primarily centring on maintaining a digital pedigree regarding all materials involved in manufacturing from the bioreactors themselves to the finished product;3 and second, technological advancements in temperature-controlled packaging combined with real-time condition monitoring and regulatory compliant data-management and logistics IT platforms — ‘intelligent logistics’.4
efore discussing the benefits of intelligent logistics in commercial manufacturing, it is important to note that concerns over increased regulatory burden from the adoption of GDP standards and the infrastructure needed to maintain chain-of-condition and custody monitoring over long logistics networks, not only for critical reagents, but also for drug product, are very real and understandable. First and foremost, because there is no codified standard, participation in and compliance with GDP standards is largely voluntary at this point and thus varies wildly based on the physical (stability, formulation, etc.) and economic characteristics of the biologic being manufactured, leading to justifiable disagreement as to what the best practice throughout the industry should be.3
Second, the availability and scalability of monitoring technology can be rather limited. For instance, technologies such as RFID tags and bar codes, while inexpensive in themselves, require a significant amount of infrastructure investment in RFID tag/barcode readers, estimated to be between $10 million and $25 million per supply chain. This technology is also limited in that while it will record the location, provide security and confirm authenticity of material in transit, it offers nothing by way of changes in condition of the material being shipped.5
Barriers aside, there are strong scientific, medical and economic incentives to adopt stringent GDP standards, powered by intelligent logistics. First, manufacturing biologics is very expensive. In 2011, the average price per gram of drug product from a small mammalian cell culture project was estimated to be $280,000.6 Market pressures to lower costs of biologics have combined with advances in manufacturing technology, such as improved production techniques coupled with the move within the industry to smaller batch, multiple product and even single use facilities. These advanced techniques are dependent on tightly controlled conditions, and thus are highly sensitive to the effects of confounding factors on critical reagents and cell lines that result in sub-optimal production.7 Therefore, advanced temperature-controlled packaging and logistics solutions that limit these confounding factors while critical reagents are in transit should be a front-line risk mitigation and cost-reduction strategy.
For example, exposure to temperature instability or excursion can reduce cell viability. Cells subjected to room temperature of 21 oC, as in the event of a failure of temperature controlled packaging, will undergo caspase dependent apoptosis.8
Cell viability has been studied under dry ice conditions as well, with cell viability dropping by more than 90% when stored at –80 oC over a 72-hour period following cryogenic storage.9 In fact, a recent collaboration between Cryoport, Kansas City Analytical Services and Heat Biologics, performed a logistics study investigating the effects of shipping a GMP working cell bank via dry ice shippers vs cryogenic dry vapour shippers.
The results indicate that transportation of GMP cell lines via dry ice shippers at a temperature above the glass point of –135 oC, leads to a marked decrease (up to 60% in this study) in cell viability, regardless of whether the shipment is domestic or international.10
The consequences of a failure of a GMP cell line to meet release specifications, which is generally set at 70–80% viability after transport, due to inadequate cold chain management, can lead to the loss of the cell bank, millions of lost dollars of CMC development and ultimately billions of dollars in lost product and revenue.
Short of a loss of viability, GMP cell lines can also show the effects of improper cold-chain logistics management in other ways, namely performance. Confounding factors can lead to deviations from established process controls such as time in bioreactor, pH sensitivity, O2 requirements and biomass formation. This can lead to a manufacturing run being sub-optimal, failing to meet acceptance criteria and even result in run termination. Therefore, the key logistics challenge to front-end biologics manufacturing is keeping cell quality to the highest possible standards.11
Companies that have adopted intelligent logistics have already seen dramatic improvements in their manufacturing process and the global distribution of biologics.12 As opposed to RFID tags or barcodes, cellular enabled condition monitoring equipment depends on existing telecommunications infrastructure, dramatically reducing the investment required to implement global track and trace supply chain systems.
Coupled with existing, regulatory compliant data-collection and logistics management IT platforms, global commercial manufacturing logistics has the potential to enjoy never before seen improvements in manufacturing efficiency and drug product quality over global logistics supply chains.
Ultimately, the continuing transition to biologically based pharmaceuticals is driving the growth of what is already a $12.6 billion temperature-controlled pharmaceutical logistics industry.13 Market expansion worldwide of both the contract manufacturing as well as the consumer market for biologics is already the primary driver for innovation into technologically advanced manufacturing methods.
Intelligent logistics technology will ensure that clear visibility on product quality is maintained over long and complex supply chains as well as improve commercial biologic manufacturing efficiency, patient access to biologics as well as clinical outcomes alike.
Original Source: https://www.epmmagazine.com/opinion/intelligent-logistics-key-considerations-of-manufacturing-bi/
Original Date: Sept 21 2017
Original Author: Robert L. Moore, PhD