Global Drug Development/Technical Research & Development
Introduction
Within the pharmaceutical industry the share of combination products has increased significantly during recent years. This is linked especially to the rise of biologics products. For the US, during fiscal year 2017, for the first time FDA received more biologic applications compared to small molecule applications.
Typically, combination products consist of a drug and a device constituent part. In most cases we see either a drug/device or a biologic/device combination. The typical case for pharmaceutical companies is to have combination products with a Primary Mode of Action (PMOA) of the drug or the biologic constituent part. For these, the device part is used as an application tool, only in some cases however as very sophisticated ones. For manufacturers of medical devices, combination products with a PMOA of the device are more relevant (e.g. drug coated stent), where the primary mode of action is the device functionality and the drug has a supporting function.
In Europe these products are considered as DDCs (Drug Device Combinations). Since a Combination Product (CP) or DDC consists of two constituent parts with quite different regulatory and GMP expectations both sets of regulation have to be considered.
For companies producing, assembling, handling, and distributing combination products this would require fulfilling the expectations of CFR 210/211 as well as for CFR 820. However, following the streamlined approach of CFR Part 4 for combination products, most pharmaceutical companies decided to fulfill the CFR 210/ 211 plus the relevant parts of CFR 820 in order to meet minimum expectations.
Compared to device regulation the application of risk management for pharmaceuticals is fairly new. For example, the ICH guidance for industry “Q9 Quality risk management” was introduced in 2006.
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Following that, the FDA Amendments Act of 2007 authorized FDA to require sponsors to develop and comply with a REMS (Risk Evaluation and Mitigation Strategy) program if it was determined necessary to ensure the benefits outweigh the risks. This type of REMS could be required pre- or post-approval.
On the contrary considering the device constituent part, ISO 14971, the standard for the application of risk management for medical devices, was harmonized and applied as of June 1993. Within the European Union Directive 93/42/EEC also known as the Medical Device Directive (MDD) defines these requirements. As of May 2020, the Medical Device Regulation (MDR) will finally replace the MDD with a complete set of additional, more strict expectations. This standard defines the minimum expectations for medical devices and device constituent parts of combination products. The most recent revision was during 2012.
How Do We Manage Risk?
We try to achieve the optimum risk reduction for all stakeholders. This does not automatically indicate that all risks are minimized under all circumstances. Reducing every risk as far as technically possible in one area might introduce risks in other areas and/or lead to very complex devices or devices with poor usability. The target is to develop devices and therapies where the risks are balanced well and that are proven effective. Risk management can be a very valuable tool to identify critical design, usability or manufacturing aspects and to optimize speed of iteration of existing systems.
The most important guidance for risk management for devices and device constituent parts is the ISO 14971. Figure 1 describes the iterative process to be applied.
ISO 14971 requires that devices must be safe when used as intended by the manufacturer. Additionally, risks have to be outweighed by the benefits of the treatment.
To achieve that the standards provide a framework for risk analysis, evaluation, control, and management, and also specify a procedure for reviewing and monitoring during development, production and post-production.
The main objectives of risk management are to investigate the risk and the underlying root cause to minimize risk and to finally determine the impact of the risk management initiatives taken.
For risk management all interactions of the user with the device need to be evaluated in depth.
Topics like:
- Normal, intended use
- Reasonably foreseeable misuse need to be taken into consideration and evaluated.
Design factors for use errors could be:
- Constricted visibility, audibility
- Confusing control system
- Ambiguous, unclear device status
- Displayed information unclear Use factors, such as user unable to perform task, or user completes task with difficulties or incompletely, as well as environmental factors like noise, heat, and lighting conditions need to be considered.
Current guidelines do not prescribe which tools to use. In most cases FMEA (Failure Mode and Effects Analysis) is being used for evaluation of medical devices and combination products. This tool is being used to evaluate the design, usability, process (e.g. assembly, packaging, shipping), and biocompatibility.
Which Information Needs to Go into the Risk Management File?
For all marketing applications and marketed products risk management needs to be documented properly. For the US this will be part of the Design History File (DHF) and for EU it will be part of the Technical File (TF) following the requirements of the medical device regulation (MDR) Annex I.
The following topics need to covered and documented accordingly during the risk evaluation:
- Risk Management Plan
- Hazard Identification
- Use related Risk Analysis
- Design Risk Analysis
- Process Risk Analyses
- Risk Management Report
Following this main structure, a significant number of additional evaluations need to take place.
Typically, the risk management plan describes the roles and responsibilities of contributing team members. It contains the risk acceptance matrix and lists all definitions related to the product evaluated.
For example, during the hazard identification step the potential hazards themselves as well as hazardous situations need to be evaluated and discussed. The sequence of events and potential harm to the user need to be taken into consideration.
During the use related risk analysis, all use steps have to be evaluated thoroughly using tools of human factors or usability. Of course, the instructions for use are at the center of this evaluation.
Also, reasonably foreseeable misuse has to be evaluated in depth.
For all topics above a well thought through ergonomic design will help to alleviate a significant number of the problems. Especially for combination products, during this step it is of utmost importance to consider the indication of the drug product or biologic. Based on the indication the patient population will be defined. For example, when developing a treatment for arthritic patients the ergonomic design might have to be completely different compared to the needs of young adults. Starting use related risk analyses early in the development process allows designers to address use failures by optimizing the device design which is the most effective risk mitigation.
During the design risk analysis, the ISO 10993 standard needs to be applied additionally, in order to evaluate biocompatibility. In most cases, for devices with skin contact (intact skin or damaged skin) this at least involves sensitivity, cytotoxicity, and skin irritation. Risk management tools are used to evaluate the overall impact considering the cumulated exposure time, location of exposure, release of potential toxins, etc.
Process risk analysis is evaluating the impact of all process steps on the quality of the device. During this step not only the device, but the combination product itself needs to be evaluated. All process steps need to be considered such as filling of the drug product or biologics into primary packaging, assembly of the drug constituent part with the device constituent part(s). Filling of drug products is fairly straightforward, if state of the art methods for aseptic filling are being used. In case the drug constituent part is biologic, this might complicate the matter. For example, a number of pump types can’t be used because of shear forces they create. A significant portion of large biologic products are susceptible to this problem. For this reason, the correct type of pumps has to be chosen or filling speeds have to be reduced to an acceptable level. This property of biologics, susceptibility to shear forces, also needs to be considered in the design of the device, as very thin needles, which clearly is a current trend, would also exhibit this problem. Furthermore, packaging and shipping need to be evaluated thoroughly, as they typically bear some surprises. During all processing steps the heat exposure of any biologics have to be controlled. This is especially true for the compounding, filling, and packaging step. To consider and implement a temperature control during compounding and filling is very straightforward, however during packaging the heat-sealing process is easily forgotten.
Finally, the risk management report should summarize the overall risk/benefit analysis and also point out the residual risks.
Why are We Implementing Risk Management Tools for Combination Product Development?
Clearly, the proper implementation of a risk management process can be a win-win for both, the patient and the company.
It is an expectation that the patient has a product in his hand, which is easy to use and has been designed properly. It is important to realize for combination products, at least for the device constituent part, there is a similarly high expectation as for consumer products.
As a patient, I can’t make a judgement on the quality of the drug or biologic, but I can draw a lot of conclusions on the functionality and design of the device.
In turn, for any company being able to create inspiring, reliable devices easing the treatment for the patient there is a huge competitive advantage especially in the field of generics and biosimilars, where there is by definition no difference in the drug part.