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Applying cGMPs for Combination Products to Ophthalmic Devices

Are You Managing Your Combination Product Supplier Relationships Well Enough?

Unless you are a company that “does it all” (and at the time of publishing, that’s a unicorn company), the commercialization of combination products requires a biologic or pharmaceutical company to contract external partners for the build and assembly of the end product and its packaging. The quality of the raw materials and components can directly impact the safety and efficacy of the final product. The quality of a supplier’s project management can affect the timely delivery of the final product and the documentation needed for regulatory approval. Failure to manage overall supplier quality can lead to significant consequences, including imposed regulatory fines and penalties for cGMP non-compliance, product recalls, loss of revenue, and reputational damage.

This makes supplier quality management a critical aspect of combination product development. As the combination product “owner” (the company that owns the filing), you are responsible for the entire product, including purchasing controls and all regulatory, quality, and technical aspects of vendor activities. The quality management of suppliers involves a complex variety of factors, which we will review in this article, along with best practices tips for ensuring your success. 

How involved must your vendor relationship be?

There are a number of supplier or product types you may choose that will affect the level of co-development involvement that should be implemented with your device constituent manufacturing partner. In order of lowest involvement to highest:

1. “Off the shelf” products: the purchase of existing components or constituents that need no alteration (somewhat of a unicorn, but on occasion you find one).

2. Existing products with aesthetic changes: “off the shelf” products that will only need aesthetic changes and/or re-labeling.

3. Existing products with minor changes: “off the shelf” products that require minor design changes to accommodate your unique drug or biologic constituent.

4. Existing products with customization: “off the shelf products that require significant design changes to accommodate your unique drug or biologic constituent.

5. New product: the creation of a brand new component or constituent, designed in partnership with an external supplier.

On the regulatory compliance side of managing vendors, your strategy for supplier quality management should be mapped against the FDA’s cGMP requirements for combination products (21CFR4.4); specifically, drug cGMPs 21GFR210 and 211, plus device cGMPs for management responsibility (820.20), design controls (820.30), purchasing controls (820.50), corrective and preventative action (820.100), installation (820.170), and servicing (820.200). The FDA’s cGMP regulations establish the minimum requirements for the design, manufacture, and control of combination products.

Minimal compliance will involve:

  • Supplier Selection Controls: Having a risk-based supplier selection procedure with accompanying records.
  • Management Responsibility: Manufacturers must establish and maintain an effective quality management system, including supplier quality management.
  • Design Controls: Manufacturers must establish and maintain design controls that ensure the combination product meets its intended use, performs as intended, and is safe and effective.
  • Purchasing Controls: Manufacturers must establish and maintain procedures to ensure that purchased components and materials meet the quality requirements, such as spelling out requirements in specifications, purchase orders, and your purchasing agreement.
  • Audit Procedures: Establishing a supplier audit (and re-audit) procedure with documented reports of executed audits.
  • Inspection Procedures: Inspection of incoming materials against specifications and the monitoring of trends.
  • Corrective and Preventative Action (CAPA): Manufacturers must establish and maintain a CAPA system to identify and address quality problems through nonconformance procedures that include supplier corrective action reports and a system for supplier changes notifications.
  • Installation and Servicing: Manufacturers must establish and maintain procedures for installation and servicing to ensure that the combination product performs as intended and is safe and effective.

However, minimum compliance may get you the documentation needed by an FDA reviewer, but it will not provide the level of oversight needed to ensure that a safe and effective combination product gets launched according to your budget, timeline, and profitability expectations. For this, it is important to move beyond minimum compliance and take vested control of the holistic management of your external partnerships.

Below, we will review a handful of strategies we employ for our clients when setting up and supporting their supplier quality management systems.


Strategy #1: Establish a co-development partnership.

“Off the shelf” components require the least need, and also afford the least ability, for a partnership-style relationship. It is much more of a transactional relationship than those situations that require customizations or new device design. While purchasing “off the shelf” components or constituents may seem the easiest pathway, it comes with limitations. You may not get access to complete information and documentation for these items, particularly if you are using the item in a different way for which it was originally designed by the manufacturer. You may also have limited visibility to upcoming changes, quality concerns, or supply issues and limited ability to audit the supplier. To offset these limitations, it is a good idea to:

  • Conduct further testing to supplement incomplete information, including usability and incoming release testing.
  • Have an agreed upon change notification process and ALSO monitor for changes internally.
  • Consider safety stock inventory.
  • Conduct due diligence and quality monitoring in lieu of audits.

Except for truly “off the shelf” components or constituents, most development should occur in partnership between your internal pharma/biologic CP team and the supplier’s manufacturing team. At times, when working with multiple component suppliers or with CMOs, additional parties should be included in this partnership. A unified definition of success and an understanding of how it can be achieved through teamwork between all parties will set the stage for success.


Strategy #2: Sign a quality agreement.

Once all parties are identified, the development agreement/contract should be used to clearly define purchasing controls, responsibilities, timelines, costs, and issue escalation and resolution processes. This type of agreement is not a requirement but is highly encouraged. In fact, regulators (particularly the FDA) will often ask for quality agreements in audits for combination products. While the FDA Guidance on Pharmaceutical CMOs is not designed as a template for drafting a quality agreement, the main points covered within are useful in crafting one. If using a purchased template, be sure to tailor it to the needs of your specific program…and don’t forget to update and maintain it throughout your combination product’s lifecycle. Circumstances change, and your agreement should change with them.


Strategy #3: Outline and obtain buy-in for an effective communication strategy.

Identifying appropriate counterparts, stakeholders, managers, and decision-makers will streamline communication to ensure the right people are getting the right information and are pulling through on goal-oriented decisions. Setting up preferred communication platforms to support documentation, information sharing, and filing efficiency will be the basis for strong collaboration. While sending emails and red-lined documents back and forth may result in quick turnaround, keep in mind that regular in-person or real-time video conferences and phone calls can often take the guesswork and misunderstanding out of reading between the emailed lines. It also supports coordinated adaptability and flexibility, as changes can and will happen during the combination product lifecycle.

It is likely that you will need to rely on a supplier’s proprietary information within their master files (DMF, MAF) or filings (NDA, BLA, PMA, 510(k)), or even nested master files of their sub-suppliers. The more information made available to you as the CP applicant, the more direct the picture of the product and the easier the audit and change burdens. However, protections for trade secrets will be a top priority of vendors. Defining up front a mutually acceptable level of information sharing (and including it in your quality agreement) is critical for avoiding conflicts or surprises during both development and post market phases. This understanding should facilitate the sharing of key pieces of information necessary to complete the project (such as design control deliverables) with appropriate confidentiality protections in place; for instance, noting that some proprietary specifics will be viewable only through on-site meetings or audit. Information-sharing arrangements should also include mechanisms to handle new information that may come up during the course of development.


Strategy #4: Start planning for technical, business, quality, and regulatory issues at the start of the partnership!

We can’t stress enough how important it is for all stakeholders and functional departments to be involved as the supplier relationship comes together. Their early input will build an adaptable foundation and their continued inclusion will provide key considerations for successful decision-making as the project progresses. This full-timeline involvement can save time and money later through issue avoidance. For example, a couple of common misconceptions and often overlooked functional inputs:

  • The Quality Team is not just there to review and approve documents. Their involvement should be at relationship-onset, setting up a Quality Agreement (or Quality section of the primary contract) that defines design and purchasing controls. From there, Quality teams on both/all sides of the partnership should build a relationship by establishing expectations, becoming familiar with and aligning each other’s standard QMS, and performing any desired due diligence to form levels of comfort with each other.
  • The Regulatory Team is not just there to write the filing at the end. A regulatory strategy should be created at the beginning of the partnership, with applicable content written into the primary contract. Part of this strategy should be identifying owners of each portion of needed regulatory data and/or filings (global considerations included), aligning on the “who will”, “within what timeframe,” and “how to” for fielding reviewer questions upon submission and agreeing on clinical and human factors requirements and responsibilities. In the case that one company owns the device design and the other is the combination product applicant, understanding intertwined responsibilities is also a factor.

Strategy #5: Create a review and approval strategy.

Key deliverables from your suppliers will require different levels of review by various functional team members on both the supplier and applicant sides of the partnership. It is imperative to clearly define and agree on who, from which party, will review and approve key deliverables – and add it to your contract! Once responsible parties are identified, alignment on DHF structure and development of a jointly standardized documentation and filing system (physical and/or electronic) should occur so both parties know where documents reside for easy access in the case of an audit. For “your” documentation and “their” documentation to come together seamlessly into one submission, even discussing formatting and font is a smart idea.

In addition to key deliverables, you will also need a strategy for reviewing and approving changes that occur during development and post market lifecycle management. Identifying decision-making roles, timeframes, processes, and socialization for change management is also critical to your supplier management success.

Strategy #6: Align on risk management.

Where to walk the line between business risk and patient/user risk is generally decided based upon many factors and your company’s own weighted priorities. It is important to align on this “line” with your suppliers to ensure your products risk is managed appropriately and that both communication and decision-making fall within agreed upon boundaries. Defining the below elements within your quality agreement will support both clarity and accountability for aligned risk management activities:

  • The structure of the risk management file, including design, user and process risks. Risk identification, benefit-risk analysis, controls, and responsibilities for each party should be addressed.
  • Processes for the alignment of risk files, which will be dependent on the responsibilities of each party.
  • Change management processes and periodic update procedures to ensure requirement compliance through both development and post market lifecycle phases.

Strategy #7: Prepare for commercial success.

Your initial supplier relationships will be focused on design, but these development-focused contracts should set the stage for future supply agreements. With commercial success as the ultimate goal of both parties, design development supplier relationships should be focused on preparing for clinical and ultimately commercial supply relationships. This can be accomplished by:

  • Being conscious of design transfer and scale up during the design phase.
  • Including plans for Human Factors summative studies and design validation along with your design transfer.
  • Using clinical studies as part of scale-up and preparation for launch.
  • Setting up systems to handle post market changes, safety reporting, and investigations.

Strategy #8: Remember that your combination product’s lifecycle (and your supplier relationship) includes post market activities.

Nonconformities can and will happen during development and post market. You will need a collaborative relationship and established systems in place to successfully investigate and address issues with corrective and preventative actions and to document them through supplier corrective action reports.

Without proper safety reporting of the collection, investigation, and corrective/preventative actions of adverse events, complaints, and malfunctions, you can run into regulatory issues post market. The FDA’s Post Market Safety Reporting (PMSR) for Combination Products Final Rule provides data-sharing requirements for cross-labeled combination products that have received FDA marketing authorization. We recommend using this guidance, and/or guidance provided by other relevant countries, to support consistent compliance and to assign ownership and communication/filing of the reporting tasks required to appropriate parties.

Post market changes may result from collected adverse effects, complaints, and malfunctions, or they may come from life cycle management decisions for improvements, supply issues, and other technical, business, regulatory, or commercial reasons. They will not only impact product supply and continued commercial success, but also regulatory filings and all parties’ master files, DHF, and RMF. Setting up and socializing agreed-upon systems for change management (notification processes, timing requirements, filing structures, etc.) during early development will provide a clear pathway to efficient solutions.

To assist with the development of your change management systems, consider reviewing ICH Q12, Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, and the accompanying FDA Draft Guidance Document. This guideline applies to drug-device combination products that meet the definition of a pharmaceutical or biotechnological/biological product and introduces the concepts of Established Conditions (EC), Post-Approval Change Management Protocols (PACMP), and Product Lifecycle Management (PLCM). Not all of the guidelines included will apply globally in a consistent manner, so be sure to consider geographic variations.


Final Thoughts…

While purchasing controls are minimum requirements for regulatory compliance, commercial success requires more. It requires efficient and effective collaboration. The entire product life cycle should be considered, and key functions such as Regulatory and Quality should be included in the planning of supplier relationships as early as possible. This kind of cooperative, holistic, and preemptive thinking will steer you to defined, adaptable, and documented (don’t forget to put it in the contract!) supplier quality systems that promote a smooth and easier-managed vendor relationship.

Should you wish to run your supplier quality management system by our experts for a best-practice second pass or think you might want some support in developing and/or installing a supplier QMS, please contact us at [email protected].


Jonathan Amaya-Hodges, Director, Technical Services, Suttons Creek, Inc. – Jonathan has over 16 years of multidisciplinary experience in regulated medical products (drugs, biologics, medical devices, and combination products) at multiple global companies. He has practical experience in Development/Engineering, Quality Assurance, and Regulatory Affairs for various types of combination products with a focus on drug delivery. Additional background includes digital health (including smart packaging/connected devices and software as a medical device, or SaMD) and in vitro diagnostics, along with clinical development (bridging) and lifecycle management for combination products. Jonathan engages with the global combination product community by speaking at conferences, lecturing in courses, serving key roles within prominent industry organizations, and interfacing with regulators on a variety of topics.