SCALING MANUFACTURING - Collaboration Between a Device Supplier & Equipment Manufacturer to Meet the Needs of Patients, End-Users & Pharma Manufacturers

INTRODUCTION

Emerging trends in the pharmaceutical industry are posing greater challenges to the successful delivery of injectables than ever before. This requires innovation in drug delivery systems to address these challenges and meet the needs of pharmaceutical manufacturers, the drugs they are developing, and the end-users and patients that deliver them and benefit from them. But deliv­ering innovation in drug delivery is hard. Robust controls must be demonstrated to address the understandable aversion to risk. Pipeline drug programs continue or are terminated based on clin­ical data and evolving corporate strategies, requiring flexibility. New device programs are not fully funded until clinical success is probable, demanding speed to market once green-lighted. These factors require delivery systems that solve a wide array of chal­lenges with a breadth of variants, and a manufacturing capability with the flexibility to produce them.

Credence MedSystems, an innovator of drug delivery sys­tems, chose Mikron Automation, a leading partner for scalable and customized assembly solutions, to build an assembly system capable of producing over 150 variants of Credence’s Compan­ion® and Dual Chamber™ (DCS) Syringe Systems. The Flexible Clinical Line will operate under cGMP controls to support combi­nation product development activities, such as device verification and validation, stability studies, and clinical trials. The following discusses the industry trends driving challenges in drug delivery, how the Credence products produced on the Flexible Clinical Line address those challenges, and how the Mikron MiniCell automa­tion platform was leveraged to allow the flexibility and speed-to-market required to support Pharma’s needs.

EMERGING TRENDS & THE RESULTING CHALLENGES

Healthcare in the home. Ongoing safety concerns. Sustain­ability’s emergence as a priority. New formulations and combined therapies. Heightened regulatory scrutiny. Cost and efficiency pressures. These and other trends in our industry are driving new or intensified challenges in the delivery of injectable medications.

Chronic diseases are being treated with medications admin­istered by self-injectors and their loved ones. Hospital-At-Home legislation, implemented to address pandemic-driven healthcare capacity constraints, is continuing to allow acute care to be de­livered in the home under hospital-based requirements. As healthcare continues to move to the home, these injections are being performed by less experienced end-users with limited train­ing and support. Concurrently, formulations are becoming more complex. With pharma extending dosing schedules, higher con­centrations with higher viscosities are being injected in higher dose volumes. The difficulty of achieving liquid-stable solutions persists and pharma is moving toward combining multiple ther­apies in such areas as xRNA therapies, vaccines, and GLP-1s. This is driving increased development timelines and expense to target stable formulations or co-formulations, or alternatively, is causing pharma to compromise by launching therapies in inadequate configurations that burden users and pose safety and efficacy risks during administra­tion. Further, accidental needlestick injuries and syringe reuse continue to pose safety challenges. In short, drugs that are more difficult to administer are being adminis­tered by less-experienced users while re­quirements for safety, accurate dosing, and adherence are intensifying.

Additionally, the increased attention to sustainability, which seems to have finally arrived as an industry imperative, means that solutions to these challenges must come with reduced waste. And with inten­sified scrutiny on the performance of injec­tion systems, devices must perform to heightened levels to drive complaints down. All of this must be achieved under the specter of ongoing pressures for cost and expense containment.

SOLUTIONS TO THESE CHALLENGES VIA INNOVATION

New trends create new challenges, and new challenges require innovative so­lutions. First considering the patient and end-user, a preferred delivery system can promote proper use and support adher­ence, which is linked to improved out­comes. Antalfy et al cite a series of studies showing that poor medication adherence worsens outcomes.¹ The Credence Com­panion, which has numerous usability ad­vantages designed to promote adherence, has been demonstrated as preferred by self-injectors as well as HCP’s.² Key pre­ferred elements include the ease-of-use, ease-of-safety activation, and the end-of-dose cues in the form of a tactile and au­dible click at the end of injection when the needle automatically retracts into the plunger rod. The melding of user cues, passive integrated safety, and reuse pre­vention can promote adherence while ad­dressing the continuing safety and economic risks associated with accidental needlestick and syringe reuse.

While the Dual Chamber Syringe (DCS) includes the same usability and safety advantages seen in Companion, it further incorporates simplified administra­tion of drugs requiring separation of con­stituents during storage due to stability or co-formulation challenges. The DCS plat­form includes two variants; the Reconstitu­tion DCS allows transfer of the diluent from the rear chamber into the front chamber to mix with the lyo cake, powder, or liquid before injection, while the Se­quential DCS allows injection of two liquids in sequence. This simplified usability is vital to enabling delivery of medication in the home, where users ranging from naïve self-injectors to HCPs will administer the medication. Further, the prefilled na­ture of the DCS and the elimination of nu­merous user steps reduce the risk of mis-dosing and the wasted dead volume (estimated at 20%-30%) associated with conventional vial kits. Risk of contamina­tion and time to administer are also re­duced (Figure 1).

It is relatively straightforward to con­nect enhanced usability with adherence, or to see how enhanced safety protects users and improves the overall cost of health­care by reducing downstream expense re­sulting from accidental needlestick or syringe reuse. Less obvious, perhaps, is that solving usability and adherence chal­lenges can lead to significant savings in development time and expense for drugs requiring separation during storage. As the usability and dose accuracy of dual chamber systems approach those of con­ventional single-chamber prefilled syringe presentations, new drug candidates can be introduced to the market faster because users can successfully use them. Reduced speed to market means the potential for market leadership and increased revenue, as well as significantly lower development cost that were traditionally directed at achieving stable formulations.

As the industry addresses the eco­nomic challenges associated with drug de­livery, both sustainability and cost of ownership should be discussed together. With elderly population growth and in­creased prevalence of chronic disease, along with the vast amounts of dispos­ables consumed by our industry, sustain­ability for sustainability’s sake should be enough to make it an imperative. But too often, sustainability and cost savings are presented as mutually exclusive proposi­tions. When innovation allows sustainabil­ity advantages to be a driver of cost savings, rather than of increased cost, sus­tainability becomes an imperative that is much more implementable.

The Credence Companion, with its integrated safety mechanism, has been evaluated against the conventional safety device, an add-on that wraps around the syringe barrel.³ In that study comparing the 1-mL Long format, Companion was shown to reduce the weight of added com­ponents by 54%, utilize 40% of the plastic, occupy 47% of the volume pre-use, and occupy 33% of the volume post-use (Figure 2).

Each of these has obvious connec­tions to an improved sustainability profile and has direct connections to cost savings. Large pharma manufacturers are paying for credits to offset their plastic waste. In addition to the cost, some experts believe this approach is less effective in reducing plastic pollution, and the only way to do so is to reduce plastic consumption, which Companion does.⁴ Reducing weight trans­lates to reduced cost of shipping through­out the supply chain. Smaller footprint means smaller secondary packaging, which translates to lower cost of materials, further reduced waste, and more effective use of shelf space – the latter being espe­cially impactful in drugs requiring cold-chain storage. These significant improvements will be notably enhanced in a 2.25-ml format in which the larger add-on device drives even more plastic, weight, and footprint while Companion has mini­mal change.

Companion’s cost-of-ownership ad­vantages extend beyond those linked di­rectly to sustainability. The conventional add-on device requires dedicated equip­ment to mount the safety mechanism on an already-filled syringe. That capital ex­penditure is not needed with Companion. Additionally, ongoing operational savings also result from the following:

• Any build-up of scrap associated with the add-on assembly machine includes an already filled syringe. The disposal or rework of that scrap, which includes the drug product, is costly. This expense is eliminated with Companion.
• For every pallet of syringes that will be paired with an add-on device, there will be an additional pallet of add-on de­vices. The expenses associated with the storage and material transport of the additional pallets are eliminated.
• When the add-on safety mechanism prematurely activates during transit or preparation, the medication cannot be injected, which is the ultimate failure of a drug delivery device. The cost of these complaints and associated customer dissatisfaction is eliminated with Com­panion because its mechanism of ac­tion dictates the needle cannot retract until the plunger rod has reached the bottom of the barrel.

INNOVATION EXTENDS BEYOND PRODUCT & INTO MANUFACTURING

With breakthrough products that will positively impact the drug delivery ecosys­tem, a robust manufacturing strategy is also required to support the production. The manufacturing strategy requires an ability to deliver a manufacturing solution that is optimized to what at times can be seen as conflicting requirements. Produc­tion of the Companion and Dual Cham­ber Syringe Systems requires the ability to assemble with extreme precision, allow for continued refinement of the medical de­vice, have the ability to accommodate a wide range of variants, but be capable of manufacturing to scale. Credence part­nered with

Mikron, an industry innovator for scalable and customizable assembly solutions, for this unique challenge (Figure 3).

Mikron has extensive experience manufacturing bespoke automation for medical device and pharmaceutical clients. Mikron’s automation philosophy de-risks and enables rapid deployment via the use of standard platforms and subsys­tem building blocks. This allows Mikron’s engineers to focus more on specific critical aspects of the medical device and assem­bly process. This automation strategy helped rapidly deploy the lowest possible risk automation solution for Credence – the Flexible Clinical Line (Figures 4 & 5).

COLLABORATION SOLVES THE CHALLENGE OF CONFLICTING CONSTRAINTS

With heritage in the Swiss watch-mak­ing industry, developing robust and preci­sion solutions is the norm for Mikron. Mikron has an extensive library of proven sub-system and design standards that can be leveraged to ensure the unique sub­components of the Companion and Dual Chamber Syringe Systems are assembled and processed to their specifications to en­sure patient safety and proper functional­ity. For the Credence products, this precision includes micro-component feed­ing, needle handling, precision welding, fine assembly, and vision inspection, just to name a few.

As speed to market is key for a novel product, Mikron needed to concurrently develop the automated manufacturing so­lutions, while Credence’s design was being refined. This required tight collabo­ration between the two companies’ engi­neering teams. As a benefit, some assembly techniques and device compo­nent designs were proven out on the Flex­ible Clinical Line as it was being assembled by Mikron. By utilizing the au­tomation asset to provide real-time feed­back, Credence was able to ensure a robust medical device design while Mikron was finalizing the automation.

The ability to accommodate a wide and varied range of products can run counter to automated manufacturing. However, one of Mikron Automation’s standard platforms, the MiniCell, was de­veloped specifically with this challenge in mind. This system provides not only the ability to rapidly deploy automation, but also the unique flexibility that Credence re­quired to manufacture an extensive range of product variations. Credence’s Flexible Clinical Line is a truly unique piece of au­tomation in its ability to produce more than 150 product variants (Figure 6).

With the understanding that the Flex­ible Clinical Line is one of multiple impor­tant steps in Credence’s product manufacturing journey, the two partners are using their experience to influence the design of a future high-volume system to support commercial adoption. This con­sists of using as many of the processes as possible from the Flexible Clinical Line and leveraging the concept of process equiva­lency to reduce validation overhead and burden. The teams are also working to­gether to evaluate and refine the manu­facturing processes as they look toward the eventual high-speed assembly solu­tion. Through developing subsequent process range capabilities studies and proof-of-principle experiments, Credence and Mikron are together developing the lowest-risk high-volume assembly system that can be deployed rapidly.

SUMMARY

Formulations are becoming more complex, and requirements for the per­formance and efficiency of delivery sys­tems are becoming more stringent. But the great news is that more effective therapies treating more and more diseases are being delivered in settings that allow pa­tients more comfort. Innovation and col­laboration across the supply chain are required to meet the needs of patients and healthcare providers. Credence and Mikron have worked closely together, using creative manufacturing strategies to produce a wide array of problem-solving drug delivery systems. This has been demonstrated with the Flexible Clinical Line’s completion of Factory Acceptance Testing at Mikron and its subsequent deliv­ery to its final destination, where it is un­dergoing validations required to supply GMP product to Credence’s pharmaceuti­cal customers.

REFERENCES

1. Antalfy A, Berman K, Everitt C, Alten R, Latymer M, Godfrey CM. The Adherence and Outcomes Benefits of Using a Connected, Reusable Auto-Injector for Self-Injecting Biologics: A Narrative Review. Adv Ther. 2023 Nov;40(11):4758-4776. doi: 10.1007/s12325-023-02671-2. Epub 2023 Sep 21. PMID: 37733212; PMCID: PMC10567963.
2. Companion Staked Syringe Formative Comparative HF Study (CD-003).
3. Credence Engineering Report #: ENG-0141.
4. https://time.com/collection/time-co2-futures/6691961/companies-offsetting-plastic-waste/.

John A. Merhige is Chief Commercial Officer at Credence MedSystems. Previously, he was Vice President, Market Development at Sanofi, having joined Sanofi upon its acquisition of Pluromed. Pluromed developed and commercialized rapid transition polymers delivered from prefilled syringes for use in surgical procedures. Prior, he founded Prelude Devices to identify early stage medtech ventures and gained general management and leadership experience at Ford and Avery Dennison. He graduated from Dartmouth College with a Mechanical Engineering degree and returned to Dartmouth for a Masters in Engineering Management from the Thayer School of Engineering and the Tuck School of Business.

William (“Bill”) Jaworski is the Sales Director and a member of the executive leadership team at Mikron Corporation Denver. Working at the intersection of healthcare, medical device, and manufacturing technology for 20+ years, he has explored market needs and developed solutions to meet those needs as Product Manager, Segment Marketing Manager, Global Marketing Director with GE Healthcare, and as a Business Development Director at ATS Life Sciences. He earned his BS in Mechanical Engineering and graduate degrees (MS in Mechatronics Engineering and a MS in Global Engineering Management) from the Northern Institute of Technology of Hamburg-Harburg, Germany, as well as an MBA from Marquette University.