The demand for biologics, and the ubiquitous use of highly potent ingredients, are forcing the industry to adapt their processes and consider alternative options, such as outsourcing and integrated solutions.
First published in Pharmaceutical Manufacturing and Packing Sourcer, May 2022, pages 46-50. © Samedan Ltd
Written by Tim Roberts at PCI Pharma Services
The biopharmaceutical landscape is evolving rapidly. Recent analysis predicts that the global biologics market will register a compound annual growth rate (CAGR) of 8.4% between 2021 and 2028 (1). Over the same period, it is anticipated that the small molecule drug discovery market will register a CAGR of around 8.05%, with around 25% of these containing highly potent active pharmaceutical ingredients (HPAPIs) (2).
Due to the growth in injectables, as well as highly potent materials, outsourcing the clinical and commercial supply of these precision medicines will become highly specialised. As such, drug developers must take into account many considerations, some of which are outlined in this article.
The innate complexity of biologics compared to their chemical counterparts is a major factor in terms of how they are handled. For example, strict thermal stability requirements demand expertise in cold- and ultra-cold chain management – particularly relevant in the handling of live vaccines. Such processes require very close monitoring, with rigorous control of ‘time out of refrigeration’ forming a vital part of the validated packaging process. Biologics also require additional packaging precautions when it comes to the shipment and distribution of these sensitive dosage forms, such as absorbent pads in the event of breakage.
There is an increasing need for intelligent packaging design solutions in response to clinical and commercial supply demands. The right packaging adds greater protection to sensitive biologic drug products, whilst also improving their shelf-life, and greatly improving overall time- and cost efficiencies. Regulatory bodies such as the FDA are placing more emphasis on the ability to create 2D or 3D packaging prototypes during the clinical development stages, as an early successful approach to this process can be extremely beneficial later in the R&D lifecycle in terms of commercial launch timelines.
Another consideration in terms of package design relates to situations where dosage forms require reconstitution by the end user, lyophilised powders being a good example. When the end user is a patient, this creates some challenges as they will not have the same level of experience or expertise as a healthcare professional. As such, there is a drive to create more patient-centric devices, such as prefilled syringes and autoinjectors. However, this can have an impact on the overall complexity of the assembly and packaging process, as well as cost, due to the end product’s unique nature.
In considering some of these factors, it is therefore clear that the demands placed on CDMOs for the clinical commercial supply of biologic therapies require the right experience, technical expertise, and facilities with a technology-forward approach to operations.
Highly Potent Small Molecules
Even though the biologics market has seen particularly aggressive growth in recent years, small molecule solid oral medicines remain vitally important. Oncology is at the forefront of this demand, accountable for around 38% of small molecule drug candidates, with almost 75% of these containing HPAPIs (3, 4).
A classification of high potency requires an operational exposure limit (OEL) of less than 10μg/m3, with many oncology therapies classified as being highly potent, registering an OEL of less than 1μg/m3. During the manufacturing process, contained engineering solutions are the gold standard when it comes to ensuring operator safety and environmental protection, along with the highest level of cleaning validation procedures to protect against cross-contamination, particularly in multi-product facilities. However, CDMOs must also pay close attention to their packaging operations to maintain this level of protection throughout the manufacturing and packaging cycle.
A well-designed facility that focuses on containment and control is essential. Standardised measurement for equipment particulate airborne concentrations (SMEPAC) testing as part of the qualification process, for example, allows a solid understanding of packaging processes and what levels of containment will be required. Additionally, heating, ventilation, and air conditioning systems provide an extra level of operator safety and product protection, as any highly potent airborne particulates are captured and drawn through high-classification filters.
As with biologics, a dedication to technologically-robust operations separates the good from the great. Pharma companies can assess a CDMO’s technical operations by asking questions such as:
- Does the CDMO use any digital printing technologies on their blister lines, such as HAPA, allowing for efficient multi-market production?
- How do they ensure accuracy in their tablet counting, desiccant insertion, capping, and labelling processes?
- Do they use smart camera technologies during their serialisation processes, to ensure compliance with the EU Falsified Medicines Directive?
- Are they able to produce small batches efficiently, whilst being able to scale-up to meet higher-volume clinical and commercial demands?
The need for a range of batch sizes covering both clinical and commercial supply is evident, as the drive to supply more targeted medicines to patients around the globe increases. A well designed facility, equipped with world-leading technologies, forms a strong foundation in this regard.
Flexible, Integrated Services
Regardless of dosage form, CDMOs are required to display many fundamental qualities in the face of complex molecules including: stringent regulatory requirements, the time constraints of clinical trials, and the demands of a dynamic marketplace. Notably, these are not limited to technical expertise. Flexibility, agility, and speed are three such qualities, as is the ability to find creative solutions under pressure.
A common challenge in commercial packaging operations is the management of multiple stock-keeping units (SKU) across a wide range of global markets. Some projects may experience a demand for over 70 SKUs, each with their own distinct set of packaging and copy to consider. Successful management of such fragmented demand requires expertise in ‘brite stock’/late stage customisation methodology, allowing a CDMO to manage small to modest volumes for their target demographics in each region or country. Such an approach would enable many hundreds of copy changes on a single product in any given year.
Choosing a CDMO with a robust global network of sites capable of handling drug products to the same high standard is another important factor, whether for clinical or commercial supply. The most notable benefits of a strong global presence include:
- A higher available capacity for the onboarding of new products in the right location
- An integrated network of sites from which to package and distribute the vendor’s products
- Business continuity
- A wider pool of expertise to leverage support of each project
Such a network is highly valuable, for example, in situations where clinical products are assigned breakthrough status, which increases the pace of a project and adds significant pressure to the supply chain. A strong global depot network, the ability to find creative packaging solutions, and flexible and responsive project management, all contribute to the successful delivery of high-pressure clinical trial supplies.
The biopharma market may be growing rapidly, but it is also highly fragmented. With the top five CDMOs occupying just 15% of the market share, the number occupying the remaining 85% is vast. To avoid supply chain complications whilst enhancing the likelihood of long-term partnerships, there is an understandable desire to work with fewer outsourcing partners throughout a product’s lifecycle (5).
There are many benefits to working with a single specialist CDMO from development to commercialization. Firstly, it ensures a deep understanding of the drug product in terms of how it’s handled, from manufacture to clinical and commercial packaging. Secondly, the process of transferring between CDMOs at critical stages of the product lifecycle can be difficult, increasing both cost and risk. By choosing a partner capable of delivering end-to-end supply chain solutions, all product data and experience remains in one place, reducing the likelihood of knowledge gaps. Thirdly, the benefits of taking a more holistic approach to managing the clinical-to-commercial cycle as one seamless process are becoming increasingly clear; for example, planning your commercial launch during the clinical development cycle can reduce risk-to-launch timelines, therefore avoiding unnecessary delays.
Of course, not all CDMOs are able to provide this end-to-end, clinical to commercialization service. Some are more suited to smaller-scale, development-stage projects, creating a situation where commercialization may eventually need to be transferred to another CDMO. Conversely, others are more suited to larger-scale commercial supply, to the detriment of highly targeted therapies aimed at relatively small demographics. Small- to mid-capitalisation organisations are therefore well-advised to consider the position of any potential CDMO partners during the selection process, as this may improve the transition from clinical to commercial supply. Such forethought can greatly improve the transition from late stage clinical supply to commercial launch, thereby improving the speed-to-approval and ongoing market supply.
Executing high-value, high-complexity biopharma supply chain solutions to aggressive timelines is a formidable challenge in the current clinical and commercial landscape, regardless of dosage form. Experience, expertise, an integrated global network of technologically robust facilities, and the ability to commit to long-term partnerships are all major factors that drug discovery organisations must consider when choosing the right CDMO. In an ideal scenario, a partner CDMO will have the flexibility and agility to address any challenges presented to their clients, acting as a seamless extension of their team, whether it’s for manufacturing or packaging (or both). This level of flexibility can only exist when the CDMO has operated at a high level for many years. Careful consideration of the factors outlined here may help to establish a long, successful partnership, as projects move from the clinic to commercial launch and beyond.
1. Visit: www.biospace.com/article/biologics-market-growthat-a-cagr-of-8-4-percent-by-2028-/#:~:text=According%20to%20Emergen%20Research%2C%20the,forecast%20period%2C%202021%2D2028.
2. Visit: www.mordorintelligence.com/industry-reports/smallmolecule-drug-discovery-market
3. Visit: themedicinemaker.com/manufacture/small-moleculessizable-market-opportunities
4. Visit: themedicinemaker.com/manufacture/why-smallmolecules-are-still-a-big-deal
5. Visit: www.outsourcing-pharma.com/Article/2018/10/22/Top-5-CDMOs-hold-15-of-the-market-as-industryconsolidation-is-expected-to-continue