Abstract
Many on-body delivery systems (OBDSs) for subcutaneous (SC) delivery require a change in primary container closure system (CCS). This necessitates compatibility and stability testing with original packaging materials and distribution and assembly, which are often laborious and time-consuming. Exploring new primary CCSs rather than using an original CCS can introduce risks, prolong timelines, and increase costs. In this study, 21 US-based combination product experts completed a double-blinded online survey between 6 October and 20 November 2023. The survey included 15 screening questions and 23 survey questions, including questions about compatibility issues between new CCSs and drug and stability testing for new CCSs. The largest proportion of participants (28.6%) reported that 5%–10% of the products that they had worked directly on had experienced compatibility issues between a new CCS and a drug, with a weighted mean of 11.9%. The most common compatibility issues were particulate challenges in 55.6%, sterility in 27.8%, and leachables in 16.7%. Most respondents (76.2%) rated the timeline showing that using an original CCS can save 12–24 months as somewhat (38.1%) or very (38.1%) representative. Most participants (57.1%) estimated that the range of direct costs, including development costs, drug product, engineering runs, line changes, and other costs, when using an OBDS with a new CCS is $10–15 million, 38.1% estimated <$10 million, and 4.8% estimated $21–25 million. Most participants (80.9%) reported that challenges in the primary CCS qualification/validation process delay entry of combination products into clinical trials or delay their commercial launch. The weighted mean of the delay was 9.7 months. Using an original CCS during combination product development would therefore be of significant economic benefit to the development of combination products in terms of time, cost, and risk.
1. Introduction
The development of subcutaneous (SC) biologic drugs such as monoclonal antibodies is surging, particularly in immunology and oncology (1⇓–3). However, biologic drugs have traditionally been formulated at low concentrations (<30 mg/mL) and large volumes convenient for intravenous (IV) infusion. This maximizes stability (4, 5) and reduces process development costs until drug efficacy has been demonstrated in humans, and challenges remain with the SC delivery of larger-volume formulations (6). SC formulations can be developed from IV formulations by increasing the drug concentration to 100–150 mg/mL and changing excipients (6). While efforts have been made to respond to the challenges of SC administration of large-volume formulations by increasing concentration, low-concentration formulations are easier and less costly to develop, are more stable, and do not require coformulation with excipients such as hyaluronidase to increase flow rate (6⇓–8). The trend toward less frequent dosing (extended dosing intervals) has also driven the need for higher doses. On-body delivery systems (OBDSs) circumvent the challenges of trying to increase drug concentration (to allow for lower-volume administration) with traditional, low-capacity SC devices such as syringes or autoinjectors (6). OBDSs can be used to administer high-concentration formulations, and the combination of higher concentrations with the larger volumes facilitated by OBDSs can result in less frequent dosing.
The use of large-volume OBDSs can also allow for extended dosing intervals with a single device compared with traditional SC devices or lower-capacity OBDSs, which may limit the weekly dose and thereby necessitate more frequent dosing and/or the use of multiple devices for the administration of each dose. For example, SC ravulizumab is delivered via an OBDS with a volume limit of 3.5 mL, therefore requiring the use of two devices to deliver a total dose volume of 7 mL. In contrast, SC pegcetacoplan can be administered at a 20 mL volume with a single device with a volume limit of 5–25 mL (9). Comparatively, if a ∼2.25 mL autoinjector was the only option available, the dosing frequency would need to be reduced to daily administration or require nine separate injections in one sitting to achieve the desired treatment. This would not only be time-consuming and uncomfortable but could also lead to reduced patient adherence (10) due to injection fatigue. Syringe pumps could also be an option, but they are almost unanimously inferior to OBDSs in terms of patient and healthcare provider (HCP) preference (11, 12).
Beyond convenience and adherence, the use of a single large-volume device also offers significant sustainability benefits over multiple autoinjectors and lower-capacity OBDSs. Reducing the number of devices per dose decreases the overall environmental impact by minimizing plastic waste, packaging materials, and disposal requirements. This is particularly relevant as pharmaceutical companies increasingly prioritize sustainability and track improvements in this area as part of their corporate social responsibility initiatives. In summary, large-volume OBDSs have several distinct advantages, delivering higher doses in a single administration, offering greater convenience, improving patient adherence and treatment outcomes, and aligning with environmental goals.
Container closure systems (CCSs, also called packaging systems) are of paramount importance in the design of an OBDS. A CCS is defined as the sum of the packaging components (e.g., containers and container liners, closures and closure liners, administration ports) that contain and protect a drug (13). CCSs are composed of primary packaging components, which are those that do or may come in direct contact with the drug (13). An original CCS typically refers to the original packaging system, which is usually composed of a glass vial and an elastomeric stopper. In contrast, a new CCS generally refers to an alternative vial/CCS or a different packaging format, such as a cartridge with a plunger or a lined seal system.
Most OBDSs for SC delivery necessitate modification of the primary CCS to ensure proper drug delivery, which requires compatibility and stability testing with the new packaging material, typically a vial or prefilled cartridge. While both original and new CCSs require rigorous compatibility and stability testing, the process for original CCSs tends to be more streamlined because extensive shelf-life data from the original drug vial are already available. This allows for a focused evaluation of drug/device interactions over a shorter period (i.e., hours or days) compared to the comprehensive testing needed for new CCSs in OBDSs, which can last two years or longer.
One variable that contributes to the additional risk, increased development costs, and prolonged timelines with a prefilled OBDS employing a new CCS is the requirement to use multiple vendors. Figure 1 shows the vendor requirements for an OBDS using an original CCS versus one that is prefilled with a new CCS. When using a prefilled OBDS with a new CCS, multiple vendors may be required to manage the primary packaging, fill and finish, and final assembly. Management of multiple vendors necessitates a larger team and adds complexity to contracts in addition to substantial increases in overall cost, time, and risk. Nevertheless, there has been a historical tendency to develop prefilled OBDSs with a custom CCS rather than OBDSs that use original CCSs (Table I).
Vendor comparison between original container closure systems (CCSs) and prefilled (not preloaded) alternatives. Prefilled solutions typically require coordination with multiple vendors for fulfillment, including: (1) device manufacturer, (2) primary CCS supplier, and (3) fill-finish and final assembly partners, including line qualification. The time estimates shown are illustrative; actual timelines may vary based on prior experience with the CCS and whether contract manufacturing organizations (CMOs) have previously handled the specific components. While additional vendors and partners may be required beyond those depicted, this is more likely in the case of prefilled devices. This image assumes that original CCSs, such as vials and syringes, are typically verified and qualified during early stages of drug development, as is standard practice. Final assembly refers to the integration of the new CCS with the device and performance testing to ensure system functionality.
Subcutaneous Administration Devices
The objectives of this study were as follows:
To gather feedback from device experts regarding the challenges associated with new CCS drug/device combination products and the value of an original CCS;
To validate an example timeline for a combination product that allows use of an original CCS rather than requiring a new CCS; and
To create cost-savings estimates with an original vs. a new CCS using the feedback gathered from device experts and publicly available sales information.
2. Materials and Methods
2.1. Study Design
This was a double-blind, cross-sectional, online survey study.
2.2. Study Setting and Sampling
The survey was administered by a third-party vendor with a database of more than 1.5 million respondents, including experts from the biotechnology and pharmaceutical industries. All biotechnology and pharmaceutical industry experts in this database were sent an online survey to complete between 6 October and 20 November 2023. Excluded participants included those who had 1) no or very little familiarity with primary CCS validation/qualification, including but not limited to vials, autoinjectors, and cartridges; 2) no familiarity with SC combination product development for OBDSs; and/or 3) no experience working on SC combination products during their career.
2.3. Study Questionnaire
Participants were asked to complete 15 screening and demographic questions and 23 survey questions. In brief, survey questions covered compatibility issues between new CCSs and drugs; time required for stability testing, development, qualification, production, and release; engineering runs, changes, and time required for and challenges faced during fill line qualification for new CCSs; direct costs when using an OBDS with a new CCS; risk and cost of combination product development; and delays in combination product entry into clinical trials or launch due to challenges with primary CCS qualification/validation.
Participants were also presented with a combination product development timeline (Figure 2) for an OBDS using an original CCS (drug vial) vs. an OBDS with a new CCS (custom cartridge) and asked questions about the accuracy of the timeline, any changes participants would make to the timeline, and their agreement with statements about time and cost savings associated with original versus new CCSs when new CCSs are prefilled but not preloaded. Space was offered to input free-text explanations for agreement or disagreement with the statements provided.
Development timelines. Assumptions for this timeline comparison: similar ease-of-use profiles; both on-body delivery systems (OBDSs) were at the same state of design controls; all human factors studies were successful; no changes were required; device and container closure system exist for new container closure system combination product, but container closure system requires qualification; manufacturing line and fill line for new container closure system requires qualification; new container closure system is a cartridge-based system that is prefilled, not preloaded.
2.4. Illustrative Cost and Time Savings Model
For the illustrative cost and savings model, the potential cost savings of an OBDS with an original CCS versus a new CCS were calculated using a simple prediction model in Microsoft Excel. The model included four incremental cost categories of using a new versus an original CCS: 1) the direct labor cost of the device team, 2) the opportunity cost of a delayed drug launch, 3) the direct cost of validation and qualification of a new CCS, and 4) vendor costs (costs related to validating and qualifying the new CCS). The direct labor cost of CCS work by a device team (1) was calculated as the number of full-time employees (base case: 2 employees; range: 1–3 employees) multiplied by mean salary cost per full-time employee (base case: $250,000; range: $187,500–$312,500 [±25%]) and months of work (base case: 18 months; range: 12–24 months). Mean salary cost per employee (i.e., total compensation) was calculated using reference values provided by authors who have hired employees for relevant positions. The opportunity cost of a delayed drug launch (2) was calculated as the weighted mean of delay time from survey respondents (base case: 9.65 months; range: 8.71–10.59 months) multiplied by expected average sales per month. Expected sales was based on the average total monthly sales in the United States in 2023 of eight autoinjector/OBDS immunology and cardiovascular drugs launched between 2002 and 2022: pegfilgrastim, risankizumab-rzaa, and evolocumab OBDSs and ustekinumab, secukinumab, ixekizumab, certolizumab pegol), and guselkumab autoinjectors. Because sales by type of device were not available, total sales were used but larger blockbuster drugs were excluded to make the model more conservative. The sales of the first three quarters after launch divided by nine were assumed to represent the average monthly opportunity cost of 9.65 months of delayed launch. The direct cost of validation and qualification of a new CCS (3) was assumed to be $15,000,000 and was not varied. Vendor cost (4) was assumed to be $2,000,000 in the base case (range: $1,000,000–$20,000,000). The vendor cost was calculated using reference values provided by authors with experience paying vendor costs in this context. Because the values used to create this model were generated from expert opinion and experience, this model was intended to be illustrative but not conclusive.
2.5. Ethics
Because this noninterventional study was comprised entirely of an anonymous online survey, institutional review board approval and informed consent were not required.
2.6. Statistical Analysis
Responses to survey questions were tabulated, and basic descriptive statistics were calculated from the survey data. Results for questions asked with Likert scale response options are presented as mean (standard deviation [SD]) or as number and percentage of participants (n [%]) choosing each category, and results for questions with binary responses are presented as number and percentage of participants (n [%]). No formal hypothesis testing was performed.
3. Results
3.1. Participant Characteristics
Participant characteristics can be found in Table II, and familiarity and direct experience working with specific SC OBDSs can be found in Table III. In total, 21 participants completed the questionnaire; all participants were located in the United States, and all were primarily specialized in combination product development. Participants held roles as Vice Presidents (23.8%), Senior Directors (19.1%), Directors (23.8%), Managers (23.8%), and Manufacturing Engineers or Project/Program Managers (9.5%) of combination product or device development. All participants self-identified as being involved in decision-making about SC combination product development, while 9 (42.9%) identified as the decision-maker.
Participant Characteristics
Participant Familiarity and Direct Experience Working with SC OBDSs
Participants had a mean of 11.1 (SD 6.6) years of experience in primary container science and had worked on a mean of 7 (SD 5.04) SC combination products during their careers, with mean 4.33 (SD 3.72) of these products being with biologic drugs. On a scale from 1 (not at all familiar) to 5 (extremely familiar), participants reported themselves as being very familiar (mean 4.38 [SD 0.65]) with primary CCS validation/qualification (including but not limited to vials, autoinjectors, and cartridges) and very familiar (mean 4.29 [SD 0.76]) with SC combination product development for OBDSs. Syringes were the most common device format used with SC combination products (36.9%), followed by OBDSs (35.7%) and autoinjectors (27.4%).
The largest proportion of participants worked at an injection system provider (5 [23.8%]) or a large-cap pharmaceutical company (≥$10 billion market capitalization; 3 [14.3%]), while the rest worked at a midcap pharmaceutical company ($2–10 billion market capitalization; 2 [9.5%]), a small-cap pharmaceutical company ($250 million–$2 billion market capitalization; 2 [9.5%]), a microcap pharmaceutical company (<$250 million market capitalization; 2 [9.5%]), a large-cap biotechnology company (≥$10 billion market capitalization; 2 [9.5%]), a contract manufacturing organization (2 [9.5%]), as a consultant (2 [9.5%]), or at an unspecified type of organization (1 [4.8%]). No participants reported working at a mid- ($2–10 billion market capitalization), small- ($250 million–$2 billion market capitalization), or microcap (≤$250 million market capitalization) biotechnology company.
3.2. Survey Results
3.2.1. Beliefs About Maximum Drug Volume Injectable SC Without Permeation Enhancer:
The largest proportion of participants believed that a maximum of 2 mL (6 [28.6%]) or 4–6 mL (6 [28.6%]) could be injected SC without a permeation enhancer. A total of 5 (23.8%) participants believed that 7–10 mL was the maximum, 3 (14.3%) reported 2–3 mL to be the maximum, and 1 (4.7%) participant believed >10 mL can be injected SC without a permeation enhancer. These beliefs were based on expert or colleague opinion in 9 (42.9%) participants, familiarity with commercialized biologics that deliver volumes up to 100 mL subcutaneously without a permeation enhancer in 5 (23.8%) participants, peer-reviewed literature in 4 (19.1%) participants, a lecture at a conference or seminar in 2 (9.5%) participants, and another unspecified basis in 1 (4.8%) participant.
3.2.2. Compatibility Challenges:
The percentage of products participants had worked on with compatibility issues between a drug and a new CCS is illustrated in Figure 3. As shown, the largest proportion of participants (6 [28.6%]) reported that 5%–10% of projects that they had directly worked on experienced compatibility issues between a new CCS and a drug, with a weighted mean of 11.9%. Particulate challenges were the most common issue, reported by 10 (55.6%) participants, followed by sterility (5 [27.8%]) and leachables (3 [16.7%]).
Projects with compatibility issues between new container closure system and drug.
3.2.3. Stability Testing:
In relation to the level of stability testing typical for new CCSs for an OBDS before Good Manufacturing Practice (GMP) combination product clinical builds, 42.9% selected 5–6 months, 28.6% selected 3–4 months, 19.1% selected >12 months, 9.5% selected 7–12 months, and 0% selected 1–2 months, for a weighted mean of 6.6 months. The largest proportion of participants (47.6%) reported that it takes >9 months to produce and release the first GMP clinical batch with a new CCS for an established and qualified OBDS, with a weighted mean of 7.3 months.
3.2.4. Qualification:
The largest proportion of participants (47.6%) reported that it takes ≥12 months to develop and qualify a new CCS for an OBDS, with a weighted mean of 9.7 months. Two-thirds (66.7%) of participants reported that ≤3 engineering runs are typical during fill line qualification for a new CCS and one-third (33.3%) reported that >15 runs are typical. The most common challenges faced when qualifying fill lines for new CCS development were equipment issues (reported in 61.9%), drug incompatibility (52.4%), CCS challenges (47.6%), fixture issues (42.9%), unacceptable reject rate (23.8%), and other unspecified challenges (4.8%). Five to six was the most commonly reported number of changes (CCS material, fixture redesign, equipment changes, and others) during new CCS and fill line qualification (47.6%); the need for change in parts lengthens the qualification process and the potential for failure. The largest proportion of participants (38.1%) reported that it takes 6–12 months to complete qualification of a fill line for new CCSs when working on an OBDS, followed by 19.1% each reporting that it takes <6 months or 13–18 months, 14.3% reporting that it takes >24 months, and 9.5% reporting that it takes 19–24 months. With respect to the length of time required to complete CCS qualification for a new CCS for an OBDS, 38.1% reported that it takes 6–9 months, 28.6% reported that it takes 12–18 months, 23.8% reported that it takes 9–12 months, and 4.76% each reported that it takes <6 months or >18 months. The majority of participants (90.5%) reported that in their experience, primary CCS qualification is done in parallel with development of the fill line for new CCSs.
Most participants (80.9%) reported that challenges in the primary CCS qualification/validation process delay entry of combination products into clinical trials or delay their commercial launch. Participants who responded positively to this question reported that the major challenges that led to these delays were drug compatibility and CCS changes (27.6% each), unacceptable rejection rate (20.7%), equipment issues (17.2%), and fixture issues (6.9%) (Figure 4). The largest proportion of participants reported that the commercial launch timeline was pushed out by 4–6 months (35.3%) with a weighted average of 9.7 months (Figure 5).
Challenges leading to delay in entry into clinical trials or delay in launch.
Delay in launch or clinical trial timeline due to challenges in primary container closure system qualification/validation process.
3.2.5. Risks, Costs, and Time Required for Combination Product Development Processes:
Participants were asked to evaluate the risk associated with various combination product development processes on a scale from 1 (no risk at all) to 5 (high-risk). The mean risk score was 3.62 (SD 0.58) for CCS development, 3.38 (SD 0.79) for device platform development, 3.24 (SD 0.75) for product assembly line development, 3.14 (SD 0.64) for fill line development, and 2.00 (SD 1.00) for other processes.
Most participants (57.1%) estimated that the range of direct costs, including development costs, drug product, engineering runs, line changes, and other costs, when using an OBDS with a new CCS is $10–15 million, 38.1% estimated <$10 million, and 4.8% estimated $21–25 million. Participants were asked to evaluate the costs of various combination product development processes on a scale from 1 (low-cost) to 5 (high-cost). The mean cost score was 3.90 (SD 1.02) for device platform development, 3.62 (SD 0.79) for CCS development, 3.52 (SD 0.73) for combination product line development, 3.38 (SD 0.72) for fill line development, and 1.00 (SD 0.00) for other processes.
Finally, participants were asked to rate the time commitment required for various combination product development processes on a scale from 1 (low time commitment) to 5 (high time commitment). The mean time commitment score was 3.76 (SD 0.92) for CCS development, 3.71 (SD 0.82) for device platform development, 3.67 (SD 0.89) for combination product line development, and 3.05 (SD 0.79) for fill line development.
3.2.6. Development Timeline Accuracy:
Accuracy ratings for the timeline shown in Figure 2 are displayed in Figure 6. Most respondents rated the timeline as somewhat representative (38.1%) or very representative (38.1%). Suggested changes to the development timelines are presented and categorized in Table IV. Specific suggested changes included more overlaps, more compression, formative studies with mockups in parallel to CCS development and characterization, design review phases, starting the change part earlier by one quarter to shorten the timeline for a new CCS, and real-time and accelerated stability studies. The need for extension of the timelines was frequently referenced, with specific extensions suggested for CCS development, retesting, issues with compatibility and equipment qualifications, device and drug compatibility characterization, combination product verification, GMP qualification, product development runs or engineering runs to assure high-quality main production runs, a slightly larger gap between formative 1 and 2 for both timelines, production materials shortages, and allowance for negative surprises. A few participants commented that they needed additional information to accurately evaluate the representativeness of the timelines or that a minor change to the assumptions could dramatically influence the time difference between the two timelines. Finally, four participants included comments that they felt the timeline was representative and did not require any changes.
Accuracy of development timeline.
Categories and Example Responses to Question About Needed Additions or Changes to Proposed Development Timelines for On-Body Delivery Systems with Original vs New Container Closure Systems
3.3. Time and Cost Savings with Original vs. New CCS
After being presented with the model, participants were asked to rate their agreement with a series of statements on a scale from 1 (strongly disagree) to 4 (strongly agree). The mean agreement score for a statement that “an OBDS with an original CCS/vial would save 12–24 months of time compared with a new primary CCS OBDS that is a cartridge-based system and prefilled but not preloaded due to no new primary CCS qualification and other associated work” given that the drug was formulated in a vial for IV use before development as an SC formulation was 3.38 (SD 0.90) (Figure 7). The mean agreement score for a statement that “an OBDS with an original CCS/vial would save >24 months of time compared with a new primary CCS OBDS that is prefilled and preloaded due to the fill-finish assembly requirement” was 2.86 (SD 0.83).
Agreement with economic benefits of original container closure system during combination product development.
The inputs and results of the cost savings model comparing the cost savings associated with the use of an OBDS with an original CCS versus a new CCS are summarized in Table V. As shown, in the base case, the model returned an estimate of $299,593,078 (range $32,112,090–$764,912,388) in total cost savings. In a scenario including only on-body injectors, the total cost savings were $353,047,987 (range $66,899,464–$655,801,667), while in a scenario including only autoinjectors, the total cost savings were $267,520,132 (range $32,112,090–$764,912,388).
Cost Savings Model of On-Body Delivery Systems with Original vs New Container Closure Systems
4. Discussion
This survey study was completed by 21 US-based combination product experts in the pharmaceutical, biotechnology, and drug delivery industries familiar with primary CCS validation and qualification, including but not limited to vials, autoinjectors, and cartridges; familiar with SC combination product development for OBDSs; and experienced working on ≥1 SC combination product.
In summary, the results of this study suggest that most experts have experienced challenges in the primary CCS qualification/validation processes that have delayed entry of combination products into clinical trials and commercial launch. Compatibility issues between new CCSs and drugs, challenges when qualifying fill lines for new CCS development, direct costs incurred when using an OBDS with a new CCS, and delays in commercial launch timelines due to challenges with the primary CCS qualification/validation process are common. Timelines may also be extended for a new CCS compared with an original CCS due to the availability of contract manufacturing organizations (CMOs) for handling new CCSs. This reflects the information in Figure 1, which demonstrates the need for multiple vendors when using a prefilled OBDS with a new CCS. CMOs for fill and finish and final assembly are in high demand, leading to extended timelines. These results suggest that using an original CCS during combination product development would be of significant economic benefit to the development of combination products in terms of time, cost, and risk.
Although new CCS testing is necessary, if the materials and composition remain consistent, the incremental risk can be low. However, addressing the challenges can vary based on factors such as a company’s level of sophistication, budget, and evolving regulatory requirements. Well-resourced or more experienced companies may be able to minimize delays and costs if they begin stability testing in advance and have well-coordinated implementation plans. Still, even in such cases, the availability of validated data from the original CCS generally results in lower overall risk, direct and indirect costs, and time investment.
There are several potential reasons for the historical tendency to develop prefilled OBDSs with a custom CCS rather than OBDSs that use original CCSs, such as the use of existing platforms across a product portfolio, prevailing processes or capabilities that are geared toward prefilled OBDSs, a perceived risk-averse approach, or preference for familiar methods. While the first OBDS program and costs associated with a primary container or CCS may be high, subsequent development costs may be lower. Using an original CCS requires patient or caregiver filling and may therefore necessitate some training for patients or caregivers and may increase the risk of treatment failure or complaints. Although there are reasonable benefits to developing prefilled OBDSs rather than OBDSs that use original CCSs, this approach has several important drawbacks, including substantial challenges with fill-finish operations and sterilization obstacles. Fill-finish challenges are common with changes to the primary CCS; if a CMO or other manufacturing site are not familiar with the primary CCS, they may resist the change and will typically have challenges that could lead to the need for upgraded equipment or change in parts.
Even among these combination product experts, there was a notable lack of awareness regarding the volume capacity possible for SC injection without permeation enhancer coformulation, with only one participant reporting that they believed >10 mL to be feasible without a permeation enhancer. This misconception appears to be common across the industry; our research suggests it is shared by formulation; chemistry, manufacturing, and controls (CMC); commercial; medical affairs; and clinical development professionals (14, 15). Volume and duration are related when it comes to SC volume limitations. As a bolus, the SC volume limit is 2–3 mL; however, over a timeframe of several minutes, the volume administered can go up to 100 mL and has done so in several commercial drugs without use of any permeation enhancer (6, 16, 17). This question did not delineate between a bolus (all-at-once) limit or a perceived limit over several minutes, but our future studies will query this in two parts (8, 14, 15, 18). Another interesting observation is that the participants’ beliefs were mostly based on colleague or expert opinion rather than knowledge that there are several biologic drugs that deliver large volumes SC without any permeation enhancer, such as SC immune globulin, evolocumab, and more recently, pegcetocoplan, ravulizumab, rozanolixizumab, and crovalimab. Pegcetacoplan is administered as a 20 mL formulation via OBDS or SC syringe pump over 20 minutes and was approved in 2021. Similarly, SC human normal immunoglobulin (Hizentra) was approved in 2010 for the treatment of primary immunodeficiency syndromes, secondary immunodeficiencies, or chronic inflammatory demyelinating polyneuropathy and is available in a range of vial and prefilled syringe sizes from 5 to 50 mL (16). This lack of awareness indicates a significant requirement for education within the industry, as it may result in the underuse of OBDSs or pumps and large-volume SC formulations due to the incorrect assumption that large-volume SC administration is not possible without permeation enhancers (14). Misconceptions about SC volume limits may also lead to missed drug development opportunities (19).
The most common delaying challenges identified included drug compatibility issues and CCS changes. Compatibility between a drug and its packaging components refers to a lack of unacceptable changes in the quality of the drug or packaging due to interaction between them, such as a loss of drug potency due to absorption or drug degradation due to a chemical entity leached from a packaging component (13). Interactions between drugs and packaging components may be detected during qualification studies or stability studies (13). Compatibility assessments may include coating integrity testing for coatings on metal tubes, evaluation of swelling effects for elastomeric components, and physiochemical and plastics tests for plastic components, including tube and plunger coatings (13). Stability studies are conducted to monitor the consistency of the compatibility of a CCS with the drug and the degree of protection provided to the drug over time (13). The impact of conducting stability and compatibility assessments for primary CCSs on development timelines is often overlooked by commercial, clinical, and executive leadership within the biotechnology and pharmaceutical industries. Stability and compatibility assessments are also subject to several challenges, including extensive labor requirements and often extended timelines. For example, Gilead Sciences, Inc. had to conduct product recalls and pause 10 clinical trials evaluating injectable lenacapavir, a long-acting HIV-1 capsid inhibitor, due to CMC issues relating to the compatibility of lenacapavir with the proposed borosilicate glass container vial (20, 21).
According to our cost-savings model, an OBDS with an original CCS may save 12–24 months of time and $10–25 million in additional costs related to validation and qualification work compared with a prefilled, not preloaded OBDS with a new CCS. This conservative cost-savings model used a base case of inputs with respect to direct effort from a device team (only two full-time employees and 18 months of work with a mean annual salary of $250,000 per employee), opportunity costs of delayed drug launch (delay of 9.65 months and average sales of $29,206,537 per month), direct costs ($15,000,000), and vendor costs ($2,000,000). Given that these inputs are conservative and that most of the surveyed respondents indicated that the timeline presented should be longer, and because we neglected to include the cost of handling at final assembly, the actual time and cost savings associated with using an OBDS with an original CCS rather than a new CCS are likely to be significantly greater than estimated here. It is important to note, however, that these savings depend on several factors. For example, a drug launching without competitors (first-to-market advantage) has more flexibility in timelines compared to one that is second to market, where delays could significantly impact market share and revenue potential. Additionally, whether the drug is considered best-in-class or not can influence the financial and strategic implications of any launch delays. The drugs used for this calculation, as shown in Table V, varied in terms of competition, but the conservativeness of the calculation was maintained by excluding certain blockbuster drugs like infliximab, etanercept, adalimumab, ravulizumab-cwvz, and dupilumab, which would have skewed the results due to their extraordinary sales volumes. Unfortunately, differentiated sales figures for OBDSs vs. autoinjectors were not available. While these estimates may seem high, they reflect key cost drivers, including the complexity of device validation, additional stability testing, extended regulatory review timelines, and vendor-related expenses. In real-world scenarios, companies with robust contingency plans, such as backup device stock keeping units (SKUs) or alternative packaging formats, can reduce the risks and costs associated with device-related delays. For example, companies with well-established processes or larger resource pools may be able to launch with alternative devices or packaging systems, mitigating the impact of any delays. However, in cases in which a company lacks such redundancy or is focused on first-to-market advantages, the financial stakes are much higher. The strategic positioning of a drug—whether it is best-in-class or competing in a crowded market—can greatly influence the significance of any delays. An additional consideration is that vendor costs can vary significantly depending on the company's infrastructure. Organizations with a less robust infrastructure may incur higher vendor costs than projected, while larger companies with internal personnel to handle key activities may experience lower vendor costs than projected. These variables should be considered when applying this model to different market scenarios.
This study had several important limitations, including its small sample size, potential self-report bias, and the risk of an anchoring effect for some of the survey questions. Although only a few experts completed the survey, their responses provide valuable insights and impetus for further research into the economic benefits of using an original CCS during combination product development. As with all survey studies, the responses reported here may have been subject to self-report bias. Finally, some of the survey questions may have had an anchoring effect, such as the provision in the timeline (Figure 2) of an estimate of 15 months’ delay; this anchoring effect may have affected responses, and providing a variety of projected timelines with a range of delays may have resulted in different delay estimates. Notably, some additional steps associated with a new CCS (e.g., drug-device compatibility characterization, new fill-finish runs, co-pack engineering runs) are not included in the timeline scenario; the comparison between original and custom CCS options may therefore be considered conservative. Inclusion of these activities would likely extend the timeline further for a custom CCS, thereby reinforcing the value of leveraging the original vial or primary container when feasible.
5. Conclusions
Most experts (81%) surveyed in this double-blind survey study reported that challenges in the primary CCS qualification/validation processes delay entry of combination products into clinical trials and their commercial launch. Compatibility issues between new CCSs and drugs, challenges when qualifying fill lines for new CCS development, direct costs incurred when using an OBDS with a new CCS, and delays in commercial launch timelines due to challenges with the primary CCS qualification/validation process are common. While capital investment can be used to fill a new CCS, it remains an expensive and resource-heavy process and does not guarantee compatibility with the drug product. An original CCS during combination product development would therefore be of significant economic benefit to the development of combination products in terms of time, direct cost, and risk.
Conflicts of Interest Declaration
This study was funded by Enable Injections, Inc. M. Desai and D. Waites are employees of Enable Injections, Inc. W. Rich is a paid consultant for Enable Injections, Inc. and other pharmaceutical and device companies. L. Laurence is an employee of Apellis Pharmaceuticals, Inc. with monetary and stock-based compensation. F. DeGrazio and S. Ingawale report no relevant conflicts of interest.
Acknowledgements
Terri Levine, MSc, PhD, CMPP, and Kate Booth, BSc, PGCE, provided writing and editorial support for this manuscript. The authors would like to thank the participants who completed the survey.
Footnotes
i Equal contribution.
ii Equal contribution.
iii Relative difference = (average measured – certified He-Flow) / certified He-Flow in percent.
iv Probability of microbial ingress was <0.10 at this limit.
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