Erasmo A. Lopez and Atif Yardimci
|Figure 1: Biopharmaceutical delivery devices are often composed of multiple subsystems and require multiple steps during use. Defining subsystems is a practical approach to the development process. (All illustrations by Isaac Dosch, Exponent Inc.)
In recent years, demand has increased in the medical industry for drug-delivery technologies. In the case of biopharmaceuticals, or biologics, designers and manufacturers of delivery devices face the challenge of acquiring the in-house expertise required for designing, developing, and producing devices or systems that meet the expectations and needs of patients, clinicians, and regulatory bodies.
This article describes some of the considerations involved in developing drug-delivery devices. Focusing on system design and integration; material selection; chemical and biological interactions between the drug and the device; and manufacturing, regulatory, and usability concerns, it provides a brief and not all-inclusive overview of design and production issues associated with primary containers and closures, reconstitution and preparation devices, and infusion-pump delivery systems.
System Design and Integration
|Figure 2: Example of a software-embedded insulin-delivery pump.|
A typical drug-delivery system such as that shown in Figure 1 can be partitioned into the following subsystems:
- Packaging that facilitates final assembly, storage, and distribution, including labeling and instructions for use.
- Primary containers such as vials, cartridges, and syringes that are prefilled with a biologic in liquid or lyophilized form.
- Reconstitution or preparation subsystems such as vial access devices, dual-vial reconstitution systems, and double-chamber syringes.
- Fluid-propulsion subsystems such as disposable single-use pumps, autoinjectors, implantable pumps, and ambulatory infusion pumps. As shown in Figure 2, a range of wearable drug-delivery pumps are available, from disposable, single-use, and purely mechanical devices to full-featured electromechanical devices with embedded software that controls the delivery mechanism, processes data from auxiliary sensors, and contains multiple user interfaces for performing monitoring and managing functions.
- Access devices and accessories, including fine-gauge needles, subcutaneous bent-needle sets, IV catheters, and injection ports.
Because providers of drug-delivery devices commonly do not own all of the components or subsystems incorporated into their products, collaboration is necessary among developers of systems, internally developed subsystems, and third-party off-the-shelf subsystems.
Systems. At the system level, developers of drug-delivery devices should employ development processes that include defining requirements and specifications, conducting risk management, compiling documentation, and performing verification and validation. The system level development process must recognize and adapt to the development and design control needs of both the delivery device and the biological product it is intended to deliver.
Thus, the work product should demonstrate that system operation does not affect the biologic adversely or vary its potency or availability throughout the delivery process. For example, developers should ensure that the system does not cause shear-induced damage to proteins or crystallization of the biologic in the delivery line. Such system-level modeling tools as computational fluid dynamics may be used to shear-map the flow path in order to assess and mitigate identified risks.
Internally Developed Subsystems. For internally developed subsystems, appropriate design controls or container development practices can be followed. For example, the selection of a fluid propulsion subsystem is influenced by delivery accuracy, minimal basal and/or bolus dose, length of delivery or therapy, required device portability, and other factors. It is expected that during the feasibility phase or while assessing improvements over existing delivery mechanisms, intensive performance testing will be performed. Typical tests for a mechanical and software system include basal and bolus accuracy. Depending on the complexity of the device, tests involving mechanical and software interactions, such as occlusion detection, can also be performed. To define verification testing requirements, manufacturers typically refer to such published standards as IEC 60601-2-24.
Third-Party or Off-the-Shelf Subsystems. Third-party or off-the-shelf subsystems, including the biologic and the larger delivery system, should be qualified and documented. For example, the connection on an externally developed delivery set can be tested to ensure that it is compliant with ISO 594-2:1998, “Conical Fittings with 6% (Luer) Taper for Syringes, Needles, and Certain Other Medical Equipment—Part 2: Lock Fittings”, or an externally delivered vial access device can be tested to ensure that it can be docked with acceptable force, does not generate particulate matter through coring, and does not result in excessive residual volume.
The process of selecting adequate materials for storing and delivering biopharmaceuticals throughout the total product lifecycle of the system includes consideration of the risks associated with undesired biological and chemical interactions. Because interactions between the storage container and the delivery device are influenced by temperature variations, light, humidity, user conditions, and other factors, materials selection is critical during the early design phase. The choice of materials is rather small. Two commonly used materials are borosilicate glass and acrylonitrile butadiene styrene (ABS), both of which are well characterized, exhibit excellent functional stability and inertness, and have been used frequently in primary biopharmaceutical containers and reconstitution/delivery devices.
Although efforts are made continuously to develop new materials, the associated costs and time to market are often prohibitive. Analytical testing and experimentation are necessary to demonstrate whether they are safe and to determine whether they ensure the stability of the drug. At the same time, new materials must meet tolerance, manufacturing, and sterilization requirements.
During the material selection phase, the manufacturer should also consider environmental regulations, which vary depending on the target market. Even in the United States, regulations can vary from state to state. For example, California’s Proposition 65 is an example of state legislation covering the use of chemicals in products that manufacturers should consider before marketing products in the United States.
In the European Union, the use of chemicals in products is regulated by the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) legislation. Some European countries are also introducing legislation that regulates such healthcare issues as sharps disposal. Because many delivery-device components are disposable, manufacturers should consider how they will be handled, disposed of, and recycled after use, if possible. During the development process, these issues can become decisive when choosing among design options.
It is useful to summarize in a single document the choice of materials and the rationale for selecting them. During the late development phase and the regulatory submission process, such a document—including design, manufacturability, and compatibility results—is especially useful. This approach can also be helpful when dealing with such life-cycle management issues as discontinuing the product, selecting a different material supplier, revising the manufacturing methods, moving to a new facility, or choosing improved materials.
Chemical and Biological Interactions
When developing a drug-delivery device, it is necessary to address the potential risk posed by the leaching of chemical compounds into the biopharmaceutical. Typically, extractables and leachables testing is performed during the verification phase of the development process. Testing should be performed on all delivery path components. Extractables testing is typically performed to ensure that the raw materials are of appropriate quality.
In particular, polymers should not contain unreacted species, and extracted chemical concentration levels should be within accepted toxicological limits and within the limits established by environmental regulations. Although exhaustive extraction may be useful during the initial screening process, extraction using milder solvents, with the actual drug, or with a substance similar to the drug can also be performed. Interpretation of the results by a toxicology expert can be an important part of the risk-benefit analysis for the end-user.
Another method for assessing chemical interactions is leachables testing. While leachables testing is preferably conducted using the drug, exceptions can be justifiable if a similar substance or solvent is used. However, in the case of certain biopharmaceuticals, the U.S. Pharmacopeial Convention and the National Formulary (USP/NF) monographs mandate the use of particular test methods and specifications. Analytical methods such as liquid chromatography and mass spectroscopy are utilized to identify compounds and concentrations of such substances as preservatives, impurities, particulate matter, and high-molecular-weight proteins.
Appropriate collaboration between testing laboratories, toxicologists commissioned to analyze and interpret data, and the R&D team is critical to plan appropriate and relevant tests. Because manufacturers generally do not possess the expertise and laboratory capabilities to conduct such tests in-house, they subcontract such services to outside laboratories. In such cases, the designer or manufacturer should participate in protocol development and determine acceptance criteria in collaboration with the testing laboratory.
In addition to conducting extractables and leachables tests, manufacturers should also evaluate the biocompatibility of prospective materials. Biocompatibility evaluation is described in ISO 10993, “Biological Evaluation of Medical Devices—Part 1: Evaluation and Testing within a Risk Management Process.” It is also discussed in “Use of International Standard ISO-10993: ‘Biological Evaluation of Medical Devices Part-1: Evaluation and Testing,’” an FDA guidance document that was issued in 1995 and revised and published in draft form in 2013. This guidance describes testing that should be performed for various types of medical devices depending on the nature and duration of the body contact. Intended to demonstrate the safety of a device during clinical use, ISO 10993 specifies the use of in vivo tests, in vitro tests, and acceptance criteria necessary for demonstrating biocompatibility for the international community.
Manufacturers commonly outsource biocompatibility testing to outside laboratories that have the infrastructure, personnel, and established protocols to perform evaluations. Close collaboration with the testing laboratory is critical to determine the appropriateness of testing protocols for the device in question, analyze initial results, determine acceptance criteria, and identify potential complications.
The process used to manufacture such primary containers as vials, cartridges, stoppers, and blow-molded ampules for biopharmaceuticals must be able to maintain stability while preventing denaturation, aggregation, loss of potency, and contamination. Because light and temperature can affect sensitive biologics, these parameters must be controlled from the moment the product is packaged in a primary container until it is delivered to the patient. In the case of equipment design, for example, the use of filling lines to manage product denaturation and minimize such process costs as ‘priming’ and testing has special relevance for biopharmaceuticals. The objective is to manage particle and bioburden risks at every step in the process.
When vial adapters, pooling bags, and compounding systems are used during reconstitution and preparation, managing air and unintentional foaming becomes crucial. Moreover, understanding the physics of delivery or the dissolution rate to shorten the preparation time without compromising component potency and availability is critical. Knowing such unique properties of a biologic as viscosity, surface tension, or porosity in lyophilized form enables manufacturers to create custom reconstitution systems that add clinical value to the therapy and the device/delivery mechanism.
In addition to developing adequate manufacturing systems, manufacturers of drug-delivery devices should understand the importance of documentation to keep track of changes in equipment, manufacturing processes, and raw materials. Because the involvement of external suppliers increases the manufacturing challenges, adequate protocols, audits, and an effective document control system are essential for ensuring that changes are identified and risks are evaluated before modifications are implemented.
Ranging from the simple to the complex, biopharmaceutical delivery devices are available in prefilled formats or may require the use of vials to manually fill syringes or cartridges. A device’s usability also depends on whether it is used at home or in a clinical setting, whether it is administered by the caregiver or the patient, and whether its use requires a series of workflow steps.
|Figure 3: User interaction with an autoinjector pen used for delivering a biopharmaceutical agent.|
Although manufacturers design products based on usability and human factors engineering standards, and FDA has published draft guidance on human factors engineering and position documents on combination products, designing for usability in this rapidly evolving field is not straightforward. For the sake of the patient, a balance must ultimately be struck between technological complexity and therapeutic needs, with the expectation that technology should facilitate patient compliance. In the case of type I diabetes, for example, patient compliance with insulin administration regimes, as presented in Figure 3, has been shown to minimize hypoglycemic events, helping to reduce such comorbidities as macro- and microvascular disease.
Examples of human factors that manufacturers should consider for improving the usability of drug-delivery devices include:
- Risk management activities are expected to include Use, Misuse, and Abuse of the Device Failure Modes and Effects Analysis. During this analysis, a complete set of use environments, users and workflows are explored not merely for use cases but also for foreseeable misuse cases. The latter requirement demands adequate knowledge not only of the physical environment in which the device will be used but also of the cognitive context in which it will be placed, including off-design conditions.
- The ability of the user to activate connections using axial (push-pull) force and torque must be well characterized. Understanding the users’ capabilities will ultimately help to define the engineering requirements for specified workflow actions. Because the target user population may lack the dexterity or acuity required to use a device as a result of such conditions as neuropathy or rheumatoid arthritis, the characterization of user ability and its translation into requirements is often important.
- In the case of software-embedded devices, it is critical to develop appropriate user interface designs that display errors, occlusion alarms, delay-of-therapy messages, or delivery interruptions. Ultimately, the end-user level of clinical knowledge will determine most user interface requirements, which could eventually encompass communication with other devices for data storage and analysis, access to bolus and basal rate modifications, and biologic-dosing adjustments.
Regulating Infusion Pumps
In its guidance document “Infusion Pumps Total Product Life Cycle” issued in 2010 and reissued in 2014, FDA introduced the concept of a safety assurance case for evaluating the safety claims that manufacturers make about their devices. As described in the guidance, “The safety assurance case (or safety case) consists of a structured argument, supported by a body of valid scientific evidence that provides an organized case that the infusion pump adequately addresses hazards associated with its intended use within its environment of use.” Typically used in other industries in which safety is critical, this approach is now followed by the agency when it evaluates new submissions.
FDA separates infusion pumps into subsystems depending on their complexity and recommends that manufacturers analyze eight hazardous situations, including operational, environmental, electrical, hardware, software, mechanical, biological and chemical, and use-related sources. While the guidance document addresses Class II infusion pumps—that is, devices requiring 510(k) premarket notification for sale in the U.S.—such devices can also be considered Class III or combination devices depending on their specific biologic or system characteristics. In such cases, the devices must undergo premarket notification approval. Another FDA guidance document, published by the Office of Combination Products in 2013, offers recommendations for pen, jet, and related injectors that are used to dispense drugs and biologics.
The development of biologic-delivery devices requires input from a variety of disciplines, including materials science, biology, chemistry, toxicology, human factors, drug/biologic development, biomedical engineering, mechanical engineering, and software engineering. In addition, effective leadership and experience are critical for coordinating this multidisciplinary team effort in order to design, manufacture, and support the lifecycle of safe and effective products that will improve patient health.
Erasmo A. Lopez is senior associate, Biomedical Engineering Practice, at Exponent Inc. Reach him at email@example.com.
Atif Yardimci, is manager, Biomedical Engineering Practice, at Exponent Inc. Reach him at firstname.lastname@example.org.