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EDITORIAL: Combination Products and their Regulatory Pathway

Combination products are becoming increasingly important to pharmaceutical CDMOs like Alcami, said Jacque Uribe, VP of Quality Operations, who was speaking at a recent company webinar. Alcami has developed its own internal implementation programme reflecting this.

In September 2009, Uribe noted, the FDA published a proposed rule (74 FR 48423). This was the first part of its still ongoing effort to improve the consistency of, and aid industry in, implementing the regulatory requirements for combination products. The final rule, 21 CFR Part 4, cGMP for Combination Products, became effective in July 2013. A final guidance document, ‘cGMP Requirements for Combination Products’ was released in January 2017.

Under 21 CFR Part 3.2(e), a combination product is defined as a product comprised of two or three of the regulated components of ‘drug’, ‘device’ and ‘biological product’. These three terms are defined under FD&C Act (21 USC 321(g) and (h)) and Section 351(i) of the PHS Act (42 USC 262(i)) respectively.

One important element of these definitions relevant to combination products, Uribe noted, is that a device “does not achieve its primary intended purposes through chemical action” in the body and “is not dependent upon being metabolised for the achievement of its primary intended purposes”.

Combination Products

Combinations of two drugs, two devices, two biologics or combinations of all three with a food or cosmetic product are not considered to be combination products. Within the category of ‘combination products’ are:

  • ‘Single Entity Combination Products’, which are physically, chemically, or otherwise combined or mixed and produced as a single entity

  • ‘Co-Packaged Combination Products’, where two or more separate products are or packaged together in a single package or as a unit, such as a first aid kit

  • ‘Cross-Labelled Combination Products’, which are a drug or product packaged separately and are intended for use only with an approved, individually specified device, where both are required to achieve the intended use, indication or effect, and where, upon approval of the proposed product the labelling would need to be changed, e.g. to reflect a change in intended use, dosage form, strength, route of administration or significant change in dose; or any investigational drug (IND), device or biological product packaged separately that is for use only with another individually specified IND, device or biological product, where both are required to achieve the intended use, indication or effect.

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Application in Practice

When it comes to applying the regulation at company level, the drug and the biologic must follow the existing applicable sections of cGMPs (Parts 210 and 211 and 600-680 respectively), while the device constituent must follow the applicable sections of the Quality Systems Regulations for medical devices (Part 820).

“If there is any conflict or ambiguity when you are working in situations where these regulations seemingly overlap, what we are looking for is the ‘most specifically applicable’ regulation,” Uribe said.

The constituent parts of a combination product retain their regulatory status even after they are combined, and the cGMP requirements that apply to each of them continue to apply throughout their lifecycle. Organisations have two options to meet their compliance requirements.

The first is to comply with all parts of the relevant cGMP requirements for each constituent of a combination product. However, Uribe said, “as we look across our organisation and our manufacturing and compliance landscape, we find that it is very rare that any one organisation is licensed to meet all of those requirements”.

Alcami itself takes the alternative, streamlined approach, in which it complies with a primary set of requirements for one constituent part and with a specific sub-set of the regulations applicable to the other(s). 

Company Case Study

Currently, Alcami is producing a single entity product, a prefilled syringe, at its steriles facility at Research Triangle Park (RTP), North Carolina. To do this, it needed to review and incorporate some applicable elements of Part 820. The company, she added, is not currently working with any type of software, so installation and servicing was not applicable in its implementation plan.

The initial focus in this project, said Brian Dillion, who joined the company as VP of Regulatory Affairs and QA in June 2020, was implementing a quality management system compliant with the requirements for a drug-device combination product.

Alcami already had established quality systems in place specific to drug product manufacturing in accordance with 21 CFR Parts 210 and 211, so it first turned to the regulations specific to devices. This included management responsibilities, design controls, purchasing controls, and corrective and preventative actions

“The next stage will be to focus on augmenting quality management systems in support of other types of combination products, starting with co-packaged and cross-labelled products,” Dillion said. “Our future state goal is to be fully compliant with ISO 13485 and the EU Medical Device Regulations.”

For each section of the regulations that had to be integrated into its quality management systems, Alcami identified teams from various different internal functions and appointed a leader an executive sponsor to each. These met on a weekly basis for about six months.

The basic plan for each team began with creating a ‘SIPOC’ (Supplier, Inputs, Process, Outputs, Customers) to help them to understand each of these elements and the required linkages within the organisation. The next goal was to identify future state process mapping and where the company wanted to end up with the new process.

“The meat of the project was to develop and revise SOPs, policies, forms and work instructions,” said Dillion. “Here is where you get into the nuts and bolts of what you are actually going to be doing. Once that’s done, you develop training materials, finalise your forms and SOPs, and identify the relevant metrics to measure against the new process to make sure it works as you expected it to.”

Dillion shared an example of CAPA process optimisation in one team, where implementing compliance was also an opportunity to streamline an extremely complex process. Changes were therefore made. “In the future state mapping, we basically decided that he wanted to take a more holistic CAPA plan rather than individually issued CAPA documents.”

The CAPA process optimization was demonstrated using retrospective data against the new process to show increased performance potential. CAPA data from January 2019-January 2021 using the existing CAPA process was compared against the optimized process flow. The output of that assessment revealed a 29% reduction in the CAPA-related documentation issued if the new process had been used over the last year, demonstrating an overall reductonin terms of the numbers of requests submitted, InfoCards created and workflows processed.

In addition, although the new process is more comprehensive and overall processing takes longer to close each CAPA, it is anticipated to greatly reduce the total time needed by eliminating process steps and the number of CAPAs needed, potentially over 4,400 hours less of processing and review time over almost two years.

“The CAPA Plan in the future state will be developed and approved in parallel with the deviation and non-conformance document,” Dillion said. “Under this approach, the CAPA Plan is a lifecycle document and final CAPA closure in the streamlined process closes the full CAPA lifecycle.

“This eliminates the potential for any auxiliary activity to remain open when the CAPA is closed. It also reinforces the importance of the CAPA. The final process that Alcami ended up with was considerably simpler, as well as being more compliant.” 

FDA View

When the FDA decides whether to classify a combination product as a drug, biologic or device, it looks at the primary mode of action (PMOA). This, in Uribe’s view is the essential element in determining a regulatory strategy for combination product submissions, including which FDA review centre will be the primary one for the application review.

“What they are looking at is action of a combination product,” Uribe said. If the PMOA is that of a drug, the agency centre charged with the pre-market review will be CDER; for a device, CDRH; for a biologic, CBER or possibly CDER. Where the PMOA is not clear, the FDA will look at past precedents, primary safety concerns and its own expertise.

For companies who have little experience of working with combination products and who wish to understand how product classifications and jurisdictions are assigned, Uribe continued, there are three sources of informal advice. This is usually where such companies start.

“You can simply email the FDA Office of Combination Products, who deal with simple issues, uncertainty and process concerns,” she said. “They can help in determining whether a request for designation (RFD) or a pre-RFD meeting is needed.”

The pre-RFD is the most common option for firms routinely working the combination product space. It leads to feedback but this is non-binding. The last stage is the RFD, a formal, binding determination process that generally takes about 60 days. This is the preferred option where complex issues are involved or if there is any dispute and/or uncertainty associated with the combination.

Exerted from Speciality Chemicals Magazine, May/June 2021 Edition
Written By: Andrew Warrington

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