Citation: Franzese C, Rinaldi A “Co-Packaged Components Improve Patient Experience and Ensure Consistent Drug Delivery”. ONdrugDelivery Magazine, Issue 101 (Oct 2019), pp 86-88.
Chris Franzese and Amy Rinaldi explore the challenges and benefits of co-packaging for manufacturers, healthcare workers and patients.
A growing combination-product market and regulatory focus on patient-centred drug development has brought human factors engineering to the forefront of the pharmaceutical industry. Whereas the term “delivery device” previously signified traditional needle and syringe systems, today significant resources are allocated to ensuring drug delivery devices reflect user-centred design principles and can be used safely and effectively.
The prefilled syringe (PFS) developed to deliver UCB’s Cimzia (certolizumab pegol) was one of the first devices to exemplify this change, leveraging usability principles adapted from OXO’s kitchen utensils. Since then, many PFS devices, autoinjectors (AIs), on-body injectors (OBIs) and inhalation devices have been purposefully developed with the user in mind. Connected delivery devices that communicate with the user’s smartphone or other technology represent the next horizon for improving usability and patient-centricity.
“While device usability has made a step-change in recent years, device packaging has not always followed suit.”
While device usability has made a step-change in recent years, device packaging has not always followed suit. With few exceptions, parenteral medications – even those that are delivered with complex devices – are typically supplied in standard cartons with no additional design features or affordances. This is somewhat understandable, given the stringent labelling and child-resistance requirements for pharma packaging.
In lieu of altering the packaging design itself, some manufacturers of oral medications have adopted co-packaging strategies to improve the user experience. One of the most prominent examples is the Kisqali (ribociclib) and Femara (letrozole) co-pack from Novartis, which supplies one 28-day cycle of both medications in a single box for the treatment of metastatic breast cancer – Kisqali is supplied in weekly blister packs alongside Femara, which is supplied in a bulk bottle.
Novel packaging configurations, such as those that employ “poka-yoke”1 or “stepwise reveal” design elements, have been shown to improve usability,2 but these approaches often face substantial manufacturing hurdles. In other cases, “smart packaging” that incorporates video instruction and/or audiovisual feedback has been conceptualised.
Still another strategy is to use more commonplace packaging designs and supplement this approach with co-packing, whereby delivery devices are provided alongside ideal (and tested) supplies to facilitate a drug’s proper and intended use. Unlike other packaging strategies, co-packaging has the potential to impact medication administration directly, as opposed to strictly improving usability.
Including simple disposable devices (needles, syringes, transfer devices, vial adapters and closed-system transfer devices) in drug product packaging may confer several benefits, some of which are specific to the user and others to the manufacturer. Users may benefit most from co-packed supplies when their drug product requires some degree of manipulation (e.g. reconstitution, volume pooling or multiple transfers) before it can be administered. In these cases, several and/or specific types of supplies may be needed to facilitate the manipulation.
Some of the most well-known examples of this are found in haematologic conditions – such as haemophilia and hereditary angioedema – where many of the approved medications require reconstitution prior to administration.3-8 As a result, these drug products are often co-packed with supplies such as diluent vials, vial adapters, transfer needles and/or injection needles to aid in reconstitution and administration.9
When co-packaged supplies are not available, similar populations have been shown to require significantly more time and steps to reconstitute their medications, and deviate from the product’s instructions for use (IFU) more often.10 In addition, these populations may need to procure the appropriate supplies on their own, which not only increases the probability for error but can also create a burdensome supply excess, as they must often buy these items in bulk. In some cases, dispensing pharmacies (e.g. specialty pharmacies) may provide the components they deem necessary but these supplies may not be designed for non-healthcare provider user groups and/or may not have undergone human factors or compatibility testing with the drug product.
“Unlike other packaging strategies, co-packaging has the potential to directly impact medication administration, as opposed to strictly improving usability.”
For manufacturers, co-packing offers a means to direct users to supplies that have already been vetted for physical and chemical compatibility with a specific drug product and primary container. This is not only relevant for patient- or caregiver-administered medications but also particularly important in the acute care setting. In practice, drug products and primary containers are subject to an enormous variety of ancillary supplies, ranging from standard steel blunt and sharp needles of different lengths and gauges to large-bore plastic dispensing pins, plastic cannulae, stopcocks, vented needles and closed-system transfer devices (CSTDs).
Such variety can be problematic – a 2018 study found that variation in chemotherapy vial spike characteristics (e.g. dimensions and design) and user practices (e.g. off-centre stopper puncture) produced unpredictable stopper collapse when spikes were tested with different stoppers.11 This finding will be increasingly relevant as the regulations and recommendations for management of hazardous drugs (e.g. NIOSH, USP Chapter <800>) are enforced. For example, the prescribing information for some chemotherapy products specifically advises against the use of chemotherapy dispensing pins or similar devices, which is at odds with USP <800> recommendations for the use of CSTDs.
Moreover, dead space is not consistent amongst supplies commonly used in the hospital environment and may result in persistently inaccurate drug dosing, depending on the product used and any adjustments made by clinicians to account for lost volume. While it is probably unnecessary and unreasonable to co-package supplies with every manufactured drug distributed to a hospital, drugs with high physicochemical sensitivities, those packaged in primary containers with stoppers prone to collapse or particulate generation, or those that require very precise dosing for therapeutic effect may be at risk when ancillary supplies cannot be controlled. This may be particularly relevant during investigational studies, where standardisation is critical to preserve internal validity.
In addition, there is a some evidence to suggest that use of CSTDs may reduce microbial ingress into primary containers and yield extended microbial stability.12,13
Although this has not yet been reflected in standards such as USP <800>, co-packing with CSTDs to increase in-use time without the need for antimicrobial preservatives or complex formulation changes may represent a competitive advantage in the future. Although co-packing offers tangible benefits to users and manufacturers, some manufacturers may be hesitant to employ a co-packing strategy, as it could present an incremental variable and potential risk in the drug development process that would need to be managed. While this is certainly a valid concern, new risks have emerged in recent years that may swing the balance in favour of co-packing.
“When co-packaged supplies are not available, similar
populations have been shown to require significantly
more time and steps to reconstitute their medications,
and deviate from the product’s IFU more often.10”
In addition to the usability/convenience benefits to users and compatibility/consistency benefits to manufactures mentioned previously, increasing human factors scrutiny may make co-packing a requirement for some products in the future. This is largely dependent on the clinical situation in which the product will be used and the reliability of safe and effective use with the supplies available in the use environment.
Examples include medications used in emergency situations, where access to appropriate supplies may be limited and delayed treatment would be deleterious, medications with narrow therapeutic indices that require precise and consistent dose preparation and administration, and medications that may present a high risk for the healthcare provider or patient harm if a specific supply is not used (e.g. a particular type of infusion set or a CSTD).
One such product is the Emergency Gynecologic Methotrexate Kit (EmGynKit), compounded and sold by Edge Pharma (Colchester, VT, US), a US FDA-registered 503B outsourcing facility. This system employs a CSTD to allow for closed transfer and disposal of unused methotrexate (after an appropriate body surface area-based dose has been set) in facilities without access to a USP <800>-compliant compounding area (e.g. obstetrics and gynaecology clinics).
CONCLUSION
All strategies to enhance patient and healthcare provider experience and usability inherently involve risk/benefit analyses, as well as time, cost, manufacturing and supply chain trade-offs. Overall, it will be interesting to see how this topic evolves moving forward, although it will not be surprising if more products begin to launch with co-packed supplies in the near future, especially as medical care continues to transition to the home, medication regimens become increasingly complex and the marketplace becomes more crowded.
REFERENCES
- Daws O, Robinson D, “Poka-Yoke-Inspired Medical Device Packaging Can Help Prevent Errors”. MDDI Online, April 2014.
- Powell R, “Improving device usability through understanding user needs and intuitiveness of device packaging”. The 2019 Symposium on Human Factors and Ergonomics in Health Care, March 24-27, 2019.
- Cimino E et al, “Patient preference and ease of use for different coagulation factor VIII reconstitution device scenarios: a cross-sectional survey in five European countries”. Patient Prefer Adherence, 2014, 8, pp1713–1720.
- Vidovic N et al, “Postmarketing surveillance study of KOGENATE Bayer with Bio-Set in patients with haemophilia A: evaluation of patients’ satisfaction after switch to the new reconstitution system”. Haemophilia, 2010, Vol 16(1), pp66–71.
- Fernández-Arias I, Kim H, “Factor VIII delivery devices in haemophilia A. Barriers and drivers for treatment adherence”. Farm Hosp, 2016, (6), pp579–603.
- Khair K, “Children’s preferences of transfer devices for reconstitution of factors VIII and IX for the treatment of haemophilia”. Haemophilia, 2009, Vol 15(1), pp159–167.
- Longhurst H et al, “Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor”. New Engl J Med, 2017, Vol 376(12), pp1131-1140.
- Dempster J, “Practicalities of a reduced volume formulation of a C1-INH concentrate for the treatment of hereditary angioedema: real-life experience”. Allergy Asthma Clin Immunol, 2018, Vol 14, Article 44.
- Package Insert, ADVATE (recombinant antihaemophilic factor), Baxalta, 2018.
- Franzese C et al, “The burden of at-home preparation of lyophilized parenteral medications: an analysis of contributing factors and implications for chronic disease patients and caregivers”. Expert Opin Drug Deliv, 2019, Vol 16(3), pp187–198.
- Zhao X et al, “A Case Study to Address a Gap in the Device-to-Vial Interface Stopper Push-in by Chemo Spikes – An Overlooked Oncology Safety Risk”. PDA J Pharm Sci Technol, 2018, Vol 73(1), pp92-109.
- Ho K et al, “Determination of Extended Sterility for Single-Use Vials Using the PhaSeal Closed-System Transfer Device”. J Hematol Oncol Pharm, 2016, Vol 6(2), 46-50.
- Uy M, Edwards M, Solimando D, “Sterility Duration of Single-Use Vials for Antineoplastic Agents or Monoclonal Antibodies Extended with a Closed-System Transfer Device”. J Hematol Oncol Pharm, 2019, Vol 9(1), pp 40-44.