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What is a drug-device combination?
US FDA calls these types of products combination products, in which they define them as: “A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity...” This is certainly the clearest definition provided and it really enables you to start to consider the device as a single entity but with two key components.

Current Good manufacturing Practices (cGMP) are industrial standards in which a drug or device are manufactured to minimise the risk to the end user. These practices get adopted by the regulatory bodies (MHRA & US FDA) and sometimes get published as a helpful guide for industry to aid in manufacture. These helpful guides eventually get absorbed into regulations. Therefore, with the development and manufacture of these combinational products, it is imperative to be aware of both the drug’s and the device’s cGMP`s.

The MHRA website has a useful line which explains virtually all about drug combination devices—consult the MHRA (using form NBA201)! This practical advice is fundamental as the MHRA governs the industry and protects the end user. But what about the dynamics in the relationship? What do the industrial pipelines have to do to get their drug-device combination approved?

In essence compliance is simple – you follow the guidelines and meet the requirements of the standards. However, the application of standards is not routinely applied to drug products. This is governed by the Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2007 (The Orange Guide). In the words of the MHRA, this guide “collates in one convenient and authoritative source European and UK guidance documents and information on legislation relating to the manufacture and distribution of medicines for human use.”

The guidance notes from the MHRA and the bulletin Number 17 (Medical Devices and Medicinal Products) suggest that the device combinations can be regulated by both, depending on the method of action, i.e. how the drug is administered to the end user through the device. If the drug system is active in a pharmacological mode of action then the Orange Guide would be applied.

Meeting the requirements
Contained within the Orange Guide are the defined rules for manufacture, which include quality system requirements, distribution practices and the legal requirements that companies require to manufacture a drug. There are several other supporting documents that are referred to by competent authorities and need to be adhered to when they are applicable. The ICH Guidelines are examples of these supporting documents. These mainly cover four areas: quality, efficiency, safety and multidiscipline.
The Quality ICH Guidelines are as follows:

1. Stability
2. Analytical validation
3. Impurities
4. Pharmacopeias
5. Quality of biotechnological products
6. Specifications
7. Good Manufacturing Practice
8. Pharmaceutical developments
9. Quality risk management
10. Pharmaceutical quality systems
11. Development and manufacture of drug substances
12. Cross-cutting topics

ICH’s mission is to work together with the drug regulatory authorities and the pharmaceutical industry of Europe, Japan and the United States to achieve greater harmonisation in the interpretation and application of technical guidelines and requirements for pharmaceutical product registration.

The reality
To comply with these regulations is a challenge and it is always recommended that the development department do a standards review with their regulatory affairs counterparts. This is a fairly simple task that takes time. All the applicable standards and GMP Guidelines need to be identified, read and discussed to distinguish which ones apply to the device in question. It is suggested that a fairly simple table is generated in which each standard is identified. The table should explain which section of the standard is applicable to the device. When compliance is not required, this should be discussed briefly in a column. This simple tool clearly identifies the regulatory strategy and allows the Quality Inspection Programme to be formed. This is a standard routine process in the formulation of Premarket Notification (510K) and Premarket Authorisation (PMA) applications in the United States.

The most obvious difference in the route to market between a medical device and a drug product is the use of Qualified Person (QP). For routine medical devices, regardless of the classification, the release to the market can be done by a competently trained person. If the drug-device has a pharmaceutical active then these will need a QP to release the product to the marketplace. QPs are available from the recognised Qualified Person List from the Institute of Biology or the Royal Institute of Chemistry. It is essential that you get a recognised QP to aid in this process.

Several common elements that are used routinely in the manufacture of pharmaceuticals and medical devices are those attributed to environmental control. ISO 14644: cleanrooms and associated controlled environments parts 1 to 4 is inclusively used by both industries to design and ensure compliance to current practices. This ISO standard applies to the Nonviable Particulates element of cleanroom control. For microbial control the GMP European Guide to manufacturing sterile medicinal products (Annex 1) can be used to support this ISO standard. This identifies just one of the gaps between the ISO standards and the GMPS—there are several others in which the standards review discussed above would identify.

Within the relevant GMPS to be used for the various drugs are the subtle differences to the routine standards we adhere to and follow in the medical device industry. For instance a few examples are:

• Stability batches are required each year for a drug product to ensure that the product has had no deviations in its routine manufacture and that the Active Pharmaceutical Ingredient (API) has not been altered or effective. This means one batch per year at real time and accelerated.
• API suppliers have to be audited inline as critical suppliers. If your device has exceipients within the drug element then you can determine the frequency of their audits depending on the risk of the device. Inadvertently this ends up being yearly as most drug combination products are a Class III. Patenting and IP ownership should be included in the technical or device history as usually patents on molecules only last seven years.
• The distribution chain of the drug element needs to be determined. If the drugs fall under the Drug Control Laws then it means that the type of packaging will be predetermined, unless it is an integral device. This also impacts on the stability life cycle and your stability samples should include this element of routine processing.

When it comes to meeting and managing the requirements for drug-device combinations, partnering with specialists in the field or training your team can help ensure that all essential variables are considered and effectively dealt with. While adhering to regulation can at times seem like a burden, consultants who have expertise in this area can work together with you to deliver on the business objectives so that compliance to standards becomes a gateway to commercial success rather than a hindrance.

Conclusion
There are some simple tips that help to address the issues that arise when developing and manufacturing a drug combination device.

1. Consider the device as a single entity with two components.
2. When discussing the design inputs during development, consider the cGMPs for both the drug and devices. Include these in your regulatory strategy.
3. Plan the stability studies on the drug and on the drug-devices combinations.

Remembering the general rule of thumb for GMPs will be critical to success: Pharmaceutical GMP is King, dependent on the mode of action of the device, and this brings the challenge of tackling all the relevant issues of compliance together.

Lee Simpson is
Regulatory & Quality Consultant
High Edge Consulting
BioCity Nottingham, Pennyfoot Street, Nottingham, NG1 1GF, UK
Tel. +44 1159 216 200
info@highedge.co.uk