Unpacking the complex challenge of biologics 

Biologics are drugs that are derived from – or contain parts of – living biological organisms. Unlike chemically derived, small-molecule drugs, which are more stable, large-molecule biologics are highly sensitive to manufacturing, packaging and storage conditions.

Though some biologics are more demanding than others – many cell and gene therapies, for example, must be stored at cryogenic temperatures to remain potent – all must be packed, sealed and stored to ensure they work exactly as intended once they reach the patient.

Responsible for keeping a drug secure and stable until it is administered, primary packaging is the first line of defence against pharmaceutical contamination. The chief concern when it comes to packaging biologics is reducing the risk of extractables and leachables, says Philippe Lauwers, director of technology development at pharmaceutical solutions company Terumo Europe.

“Extractables and leachables coming from some of the raw materials that make up the container closure system can have an adverse effect and negative impact on the stability of such sensitive biologic drug products,” Lauwers says.

“That's why Terumo, and I would say primary container suppliers in general, over the last few years have proactively investigated innovative technologies and solutions for prefilled syringes (PFS) to overcome some of the challenges related to the impact of silicone oil, adhesives, glue, tungsten residues and heavy metals.”

Silicone oil is commonly used to lubricate the inside of glass prefilled syringes and reduce the force needed to inject their contents, but the substance can interfere with the sensitive proteins in biologic medicines.

“[Silicone oil] could lead to protein aggregates, which can impact the stability of the drug product, and the consequence of that is that it potentially lowers the efficacy of the treatment for the patient,” Lauwers says.

To avoid the risk of silicone oil altering these structurally complex medicines, he says, Terumo has developed and implemented a fully silicone oil-free primary container for biologic drug packaging.

Other measures the company takes to reduce the risk of contamination include using an insertion moulding process instead of glue or adhesives when attaching needles to prefilled syringes and using steam sterilisation to minimise the introduction of unwanted molecules. Alternative sterilisation methods, such as ionising radiation, can generate free radicals that have the potential to negatively impact a biologic’s stability.

Additional challenges that are unique to packaging biologics include refrigeration time and process inspections, says Alex Weaver, director of engineering at PCI Pharma Services.

“Since biologics must be refrigerated and can only be out of those temperatures for a certain amount of time, it becomes more costly when equipment fails or is found to be defective, because, in this scenario, the drugs are no longer usable most of the time,” he explains.

“Performing destructive testing on biologics is also more costly, so it is crucial that the right tests are being performed, as well as identifying areas where testing can be taken out.”

While commonly used biologic medicines like insulin or anti-inflammatory drugs can be produced and packaged on a relatively large scale, personalised and highly engineered biologics for less common conditions present yet another challenge for packaging manufacturers.

“There we are looking at smaller batch sizes, and rare diseases or orphan diseases are often in scope,” Lauwers says. “We are talking about sometimes just a few dozen, up to a few thousand, syringes on an annual basis for a specific therapy, compared to millions of syringes, for instance, for heparin products or vaccine products.

“So, obviously, the scale of production should be adapted to those lower annual quantities and requirements, and this is what the industry and the fill-and-finish equipment manufacturers have shifted to and developed.

“We are looking at small scale, highly flexible fill-and-finish lines, which allow for swift changeover between vial presentation and prefilled syringe container presentation.”

Lauwers adds that implementing syringe-by-syringe processing – rather than an automated, nested approach, in which multiple syringes are filled and sealed at once – can help to reduce drug product waste when processing small batches of specialised biologics.

“For instance, when there is a deviation or rejects on the line, you don't have to throw out an entire nest of filled syringes, which could be 100 or 160 syringes,” he says.

“I think it's widely understood that the manufacturing costs of those kinds of orphan disease drugs and biotech products, in general, is a multifold of what a generic chemical drug product would be,” Lauwers says. “And therefore, the industry had to look for sensible solutions to avoid overfill drug wastage and rejects on the line, higher flexibility, shorter downtime, and so on.

“Those are some of the changes that have been already implemented, and more development and innovative technologies are coming up as we speak.”

While the self-administration of injectable drugs isn’t a new concept, the at-home delivery of biologic medicines is considerably more complex. For biologics that are self-administered by patients, such as treatments for chronic diseases like asthma, diabetes and rheumatoid arthritis, packaging solutions that ensure the drug’s stability and maximise its shelf-life are all the more crucial.

PFSs are the most common delivery method for patients self-administering injectable drugs in their own homes. PFS containers are filled with the exact treatment dose required, minimising drug wastage for manufacturers and reducing the risk of dosing errors by the patient.

As one of the most widely self-administered biologic drugs in the world, the insulin space offers plenty of room for delivery device innovation. One company looking to improve diabetes patients’ at-home experience is Medtronic, the US-based medical device group behind the first and only FDA-cleared smart insulin pen for people requiring multiple daily injections.

Medtronic’s InPen, which tracks active insulin while delivering short-acting insulins, is integrated with a real-time continuous glucose monitor that transfers insulin dose data wirelessly from the device to a smartphone app, allowing individuals to manage their diabetes with enhanced accuracy and convenience.

The ultimate goal for manufacturers developing drugs and delivery devices for long-term medical conditions is to minimise the number of doses required by the patient – but this usually means increasing the volume of the drug being delivered, which can be too painful for administration via conventional needles or auto-injectors.

This problem is exacerbated by biologics; highly viscous, they often require large doses that must be administered slowly over time, making consistent and regular dosing a challenge for patients outside of a hospital setting.

Enter: the wearable injector, a device that can be adhered to the body to provide higher doses and volumes of medicine, over a longer period of time, than is possible with traditional delivery methods.

Swiss technology company Sonceboz, for example, has developed wearable drug delivery devices that dispense high volumes of viscous medicines subcutaneously, without the wearer having to manually operate the device. The company offers on-body injector models with varying features and cartridge settings depending on drug type, volume and viscosity, that are compatible with a range of primary container designs.

The incentive to innovate in the injectables space is clear: the global prefilled syringes market is predicted to be worth as much as $22.5bn by 2025, and patient demand for safe and convenient at-home biologic delivery devices is only set to grow.

When it comes to biologics packaging, there’s no universally superior design – some drugs will be more compatible with one type of syringe or device than others, and what works for one individual will be less convenient or effective for someone living with a different condition. As Weaver explains, packaging material and design decisions must be made on a patient-by-patient basis.

“In packaging design, questions such as ‘what is the treatment?’ and ‘who is the end user?’ are all considered before development begins,” he says. “For example, if arthritic patients are the target audience for a product, it is likely glue will be used instead of a tamper-resistant seal, since it would be much easier for the patient to open.

“As a contract packager, PCI factors in the patient’s ability to use the packaging based on information we receive from our customers, versus directly canvassing patients. The patient is at the centre throughout the entire design process and their ability to use the product is paramount."

A crucial aspect of ensuring that at-home drug delivery devices are user-friendly and intuitive, Lauwers says, is to “keep it simple”.

“For an untrained patient population, it's not always well understood how they should use their auto-injector or their body-worn device, or how the safety device operates,” he explains. “Keeping that in mind already at the very beginning of your drug development process is key.”

For Lauwers, the measures that should be taken to maximise the useability of a device include clearly written instructions, instruction videos, and service desks that provide immediate assistance to patients with questions about their drug delivery technology.

“In addition, any initiative or technology that can help reduce the pain perception by patients will further help them gain confidence and feel more comfortable to inject themselves at home,” he says. “These technologies can range from larger needle gauges, as well as specific needle technologies such as ultrathin wall needles and double tapered needles, to safety and self-injection devices that help to prevent the occurrence of needle stick injuries.”

When it comes to the limitations of current biologics, Weaver says the cost of biologics – from the drugs themselves to the secure packaging they require – makes the list.

“The market must re-evaluate its current process and determine how to reduce costs, as well as ensure the correct risk calculations are being applied at each step of the development and packaging process,” he says. “Currently, many companies use the same risk scale for primary and secondary packaging, which inhibits improvements and cost reduction.

“Primary packaging requires a sterile environment and more restrictive FDA regulations since it makes direct contact with the product. Secondary packaging is less restrictive because it involves labelling and assembly, and no direct contact with the drug is made.

“The industry will truly start to evolve as more companies begin to improve their risk scale strategies – namely, no longer applying the same risk strategies to both primary and secondary packaging –which will lead to more innovation due to saved time and resources.”

The biologics market is expected to reach a value of more than $509bn by 2026 – and as more of these complex drugs are developed in the coming years, the packaging processes that make their delivery possible will have to evolve, too.