As the life sciences industries have continued to evolve, the need for ever changing nomenclature has evolved along with it. It was once easy to understand the discussion amongst a group of industry and government professionals when referring to the “pharma” business. And by the late 1990s, after the implementation of the Quality System Regulation (QSR) (see 21 CFR Part 820), those in the device business had begun to adapt to the new language of design control requirements. Technology has developed in ways once unthought of, including the development of biosimilar drug products and complex cell and gene therapies. 

The contract manufacturing business has also changed. Once simply known as a contract manufacturing organization (CMO), has further expanded into contract development and manufacturing organization (CDMO). Contract organizations have been taking on more and more responsibilities in their partnership with the marketing authorization holder (AH). This, coupled with the expanding complexity of the global supply chain, has created an opportunity for gaps in the quality system oversight intended to ensure safe and effective products reach the market.

Combination products
One area of specific concern is the fast-growing business of combination products, particularly, integral combination products. In this instance, I am speaking of combinations of either drugs or biologics, combined with a medical device in an inseparable relationship. The growth in this market has been in using the device as the delivery mechanism for the drug or biologic. Examples include products such as metered dose inhalers (MDI), transdermal or subcutaneous patches, prefilled syringes (PFS), pens and autoinjectors.

In the past year, I have seen several instances where once uniquely pharma companies have decided to expand their product pipeline, primarily through introduction of generic combination products. Generic combination products bring many benefits to the consumer. First, any product which makes the delivery easier for the user to consume or provide can drive patient compliance up. Second, the partnering of the device with the drug can also help lower costs by supplying a single product rather than two or more. And third, combination products have allowed for more home use, allowing patients to have control of their medications without having to be in hospital or clinic. 

With the movement of pharma into the combination product space, there have been challenges. Medical devices and the QSR have unique aspects that do not translate exactly or sometimes even clearly into the usually well understood drug GMPs. Drug development, the bread and butter of the pharma industry, is very different from the development of molded, electromechanical, or even textile materials that medical devices are made from. Further, when you add complexity of the medical device incorporating software as part of the drug delivery system, things begin to get far removed from the usual view of software operating in a manufacturing, QA or QC system. Now, layer onto the novelty of materials and performance challenges, the lack of organizational structure and knowhow. Most pharma companies do not employ design engineers with medical device backgrounds or QSR expertise. 

C(D)MO partnerships
This is where the CMO/CDMO has been playing an ever-growing part in the combination product business. Pharma companies have been partnering with contractors for the design of the device. In the case of combination products, the device is referred to as the device constituent. Where the device constituent is not purchased as an already available finished device, such as a syringe already marketed under a 510(k) or premarket clearance, the device then needs to be designed for incorporation into the final product. Now design houses have been around for years, primarily in the context of supplying design support for medical devices to be marketed purely as medical devices, things such as catheters, orthopedic screws, and electrodes, for example. It is new to the design houses as well, to now be thinking of not just the device itself but, the interaction of the device with the drug or biologic it will be delivering. 

When we think about the applicant or the pharma company, they now must think about their new product in a different way. It is not just the drug they need to understand, but the design of the delivery device is critical to the product’s success. This is where the need for excellence in design control is a must, regardless of whether the design is outsourced to a contractor, or the design is developed in house. A syringe, already marketed under 510(k) for single use, was never intended to be the container closure system for a drug or biologic. The design must now be challenged to ensure that the syringe does not interact with the drug through the expiry period. Additional considerations include maintaining the integrity of the container closure, stability and extractables/leachable properties. And, if the drug is filled into the syringe, which is then terminally sterilized, there are additional considerations. These are only a few of the design considerations that must be developed in the design control process for the combination product. 

Now let us consider the CMO/CDMO. What is the role of the manufacturer here? It has been the case that the contract manufacturer has now established new manufacturing lines to accommodate the AH’s requests. This includes manufacture of PFS, autoinjector and MDIs, to name a few. The technologies are new for the CMO and pose their own challenges in complex manufacturing, handling of the device constituents and filling of the drug or biologic. The challenges get even more complex when you consider the requirements of design control under the QSR. 

The QSR requires certain activities in design control that involve the manufacture of the device constituent and/or the finished combination product. For example, part of the design control will be design requirements. Some of these design requirements will be directly related to the ability to manufacture within tolerances necessary to ensure proper performance of the device. Further, manufacturing can introduce risk to the device constituent, therefore a process failure mode and effects analysis (PFMEA) is an expected portion of the design history file (DHF) which is the compilation of all the work done to support that the proper design controls were applied.  Additionally, the design must be validated using production units manufactured under production conditions. And finally, the design must be properly transferred into the production environment for commercialization and translated into the Device Master Record (DMR). 

The AH is always responsible for the activities of its service providers. As FDA has made abundantly clear, the responsibility of the safety and efficacy of the device cannot be abdicated. Where the AH has outsourced the device design to a design house, and further outsourced manufacturing to a CMO/CDMO, the relationship becomes increasingly complex to ensure the design has been properly controlled, verified, validated, and transferred. Add into this the outsourcing of the drug substance or drug product manufacture and soon the critical composition of the drug and device constituents become scattered. 

In my experience, the most difficult part of this process is for the AH to be able to understand the unique requirements of bringing a medical device into the pharma quality system. Everything from properly qualifying the supplier/contractor, to establishing the initial design and development plan, to ensuring proper execution by each player, has been creating some uncomfortable situations. What follows are a few very recent case studies.

In the case of the AH outsourcing the manufacturing of the finished combination product to the CMO, or in this case, the unknowing CDMO, the Supplier Agreement between the parties is key. The CMO, working in partnership with the AH who seeks to bring a combination product to market, unfamiliar with the depth and breadth of the design control requirements, does not clearly delineate in the Supplier Agreement the responsibility for the design control of the device constituent. The Agreement notes that the CMO will be responsible for the development of the design and the maintenance of the DHF. Fast forward to marketing of the finished product. When complaints begin to arrive, the CMO, in cooperation with the AH, makes a good quality decision to halt production while investigation can be performed. Meanwhile, enter FDA for inspection. FDA, while interested in the complaint management being handled by the AH, has a greater interest in the CMO for the manufacture of the finished product. Further, because the AH can point to a Supplier Agreement placing the design control responsibilities on the CMO, FDA wants to discuss this with the CMO as well. I do not need to elaborate on the outcome. 

The lesson here is that as the CMO, you need to clearly understand what design control includes, and ensure in your Supplier Agreement that you have been precise in describing your roles and responsibilities. If it is not your intent to be completely responsible for the design and development of the device constituent, it is best to limit your role in the Supplier Agreement to those steps necessary to support the application and manufacture. Such steps, as stated above, include participating in the PFMEA, providing the finished products manufactured in the production environment for design validation, and ensuring proper transfer of the design to manufacturing and establishing the DMR in coordination with the AH. There will be a continuing role in working with the AH to incorporate any changes through the device total product lifecycle, which involves updating and maintaining the DHF in current state, which should be an expectation further outlined in the AH’s Quality Agreement with the CMO.

Next, consider the case of the “virtual” company. In this instance, the AH is only that.  It owns the intellectual property, and if it is an innovator product, perhaps the patent, of the combination product. However, being virtual, the AH contracts the manufacture of the API and drug product, the design of the device constituent, and the final production of the combination product. The question is, who is responsible for the DHF, the design and development, the verification, validation, and transfer? Moreover, who is responsible for ensuring the design is maintained through the total product lifecycle?

In this case, the AH got the sense that it may not have a quality system established to answer these questions. In fact, the AH had been “virtually” manufacturing and distributing combination products for years, including transdermal and transcutaneous patches, and had recently developed PFS, autoinjectors, MDI and nasal sprays. Being proactive, in-depth training in combination product GMPs, and specifically, workshops in design control, were sought to bring the quality and regulatory teams of the company up to speed with expectations of the regulations. What was discovered is that the Quality Agreements between the design houses, the CMOs and the AH did not clearly delineate the roles and responsibilities of the design process, nor did it indicate who would be the holder of the DHF and how communications were to be handled to maintain the DHF. The quality system in place for the AH was not developed, nor was it sufficient to manage medical devices or the interaction of the devices with the drug in the case of the combination products. There was no one on the staff that had medical device or design experience. The AH is now developing a project plan to ensure applications going forward will have the design controls and the DHF to support the design process and, will develop a risk-based remediation plan to bring the legacy products up to current state. Further, personnel with design and device experience will be hired and Quality Agreements will be revised to ensure clear delineation of responsibilities.

What we have experienced is that FDA has been inconsistent in the review of the design controls for combination products. In the instances where the application is an NDA, ANDA or BLA, the design controls are not necessarily well established in the submission. Some reviewers have made information requests to try to ensure the design controls were put in place in the development of the combination product, while others have not. In fact, in instances where the device constituent is a pre-existing 510(k) device, the expectation is that the applicant has completed the design controls relevant to the interaction of the drug/biologic-device combination and those have been less often questioned. 

We have seen that applications have made it to the pre-approval inspection where the design controls have been challenged, with no questions in the review, only to find that the design control was not done at all, or was very far removed from meeting expectations. Applications have been withheld on these grounds for ANDA, NDA and BLA submissions.

The combination products market is going to continue to grow. And the market is going to get increasingly complex with new device technologies which can deliver drugs in a safer, more convenient manner. As this market grows, and as FDA sees more of these types of products coming to review, the questions involving the design will begin developing more at the review stage. Further, as combination products take their place in the market, more post-market data and unfortunately, more adverse events, will highlight the need for more stringent oversight of those responsible for ensuring the design is properly developed at the earliest stages and managed through the total product lifecycle. 

If you are a contract design house or a CMO/CDMO, your role is integral to the design, and as is evidenced by FDA’s willingness to inspect and hold CMOs accountable, it will be even more important to ensure you are prepared. This means establishing a quality system that provides for your role in the design process and lifecycle, and clearly negotiating your Supplier Agreements to ensure those responsibilities are documented. If you are an AH, your expectations of the supplier also need to be clearly delineated and the Quality Agreement should outline the role of the AH, the design house, if applicable and the CMO/CDMO in the design process.