Contract manufacturing is a reality in the development, manufacture and distribution of medical devices in a global environment. Whether it is during design, purchasing, manufacturing, labelling, storage or distribution, ‘where in the world’ the medical device has been manufactured is important to the writers of standards and the crafters of regulations.
With respect to global harmonisation, there is still a key distinction between the legal manufacturer and where the device is actually manufactured in the minds of quality system experts and regulators.
This concern is a fact because in a global supply chain it matters (a) who is responsible for the device (whose name is on it) and (b) where it is manufactured. This concern is also relevant because product safety can be dramatically affected by the sourcing choices of the legal manufacturer.
The issue of sourcing is addressed at some level in key regulations from the US, the EU, Canada and Japan. The EU makes it clear in the MDD that in ‘duly substantiated cases’, the Notified Body will visit the manufacturer’s suppliers and/or subcontractors. In Canada, the CMDR states that the manufacturer must supply ‘the name and address of the establishment where the device is being manufactured’. In Japan the regulation is not quite as clear on subcontracting, but it is geared toward the inspection of finished devices and activities of design, manufacturing, sterilising, and storage and labelling.
DEFINING THE MANUFACTURER
In EU and Canada, it is clear that the manufacturer is the one whose name is on the label, even if all activities are carried out on the manufacturer’s behalf by a third party. In Japan, it is a little different as the term ‘manufacturer’ is not defined. But the Japanese still make clear that the concerns are (a) where the device is actually manufactured, and (b) that controls need to be applied primarily to finished devices. That said, the Japanese have concern over certain processes (design, manufacturing, sterilisation, labelling) regardless of whether it is a subcontract situation or not.
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In the US, manufacturer means any person who designs, manufactures, fabricates, assembles or processes a finished device, and is much broader than the strict definition of ‘name on the label’ in EU and Canada. Figure 1 explains the definitions of some of the key terms related to the key players in medical manufacturing.
Many people have put effort into harmonisation, with the Global Harmonization Task Force (GHTF) preparing key documents that are quite useful. They have published documents on regulatory auditing, market surveillance, clinical evaluation and quality systems. Two that are particularly useful are ‘Risk Management’ and ‘Process Validation’. The GHTF has unfortunately not published guidance on the subject of contract manufacturing and/or supply chains analysing the global processes mentioned above.
The reason that the GHTF needs to provide leadership is that ISO 13485:2003 provides requirements that are relevant to manufacturers and subcontractors. It requires the organisation to define: specifications and how they are obtained; mechanisms of material and process controls; how risk management is done; requirements for process and product validation; and inspection requirements. The new standard is recognised, but considered a requirement in Canada, voluntary in the EU, good but not sufficient in Japan, and not relevant in the US.
The Office of Regulatory Affairs in the US is trying to figure out a way to use ISO 13485:2003 but has not done so yet (with respect to PMAP, the FDA still uses EIR and not the ISO 13485:2003 report for inspection review.) Thus, global harmonisation is a good idea, but in shipping to the US, Canada, the EU or Japan, the organisation has to meet the country regulations which include requirements for subcontracting.
A MANUFACTURING CASE STUDY
ABC Medical Device Company in Toronto, Canada is developing a single-use sterile scalpel (for transient use, not used in the CNS or area of the heart), and it is to be sold in EU. The process and activities of the supply chain are outlined in Figures 2 and 3. The manufacturer has determined it is a class IIa in the EU and so will need to have Notified Body service and EC certificate. The manufacturer has checked with Health Canada and agreed it is a class II device in Canada so they will need to have an ISO 13485:2003 certificate.
Who is the manufacturer?
Since the device will be shipped to Europe and Canada with ABC’s name on it, ABC medical device company is the manufacturer.
Are the manufacturer and the subcontractors adequately controlled?
Simply speaking, with the process and activities of the company’s supply chain taken into account, the answer is ‘no’. However, an important consideration is the method of control and it must be determined whether this control is adequate for EU and Canada. This is demonstrated in Figure 4, which shows that location f is OK. Location a and e are not OK. Location b, c, and d are probably OK but bear further scrutiny.
One of the most interesting things that comes out of this analysis is that organisations are OK, probably OK, or not OK, for different reasons depending on the area in the world where medical devices are being shipped. This emphasises the idea that in some areas of the world, suppliers who are OK for shipping to one country, very likely could not be OK for shipping to another country and vice versa.
What are some resources for determining adequacy of control?
For Canada, there is an excellent document used for this purpose: GD210: ISO 13485:2003 Quality Management System Audits Performed by Health Canada Recognized Registrars. This document provides specific guidance on the supply chain, leading the manufacturer from ‘simple case, no subcontracting,’ to ‘multi-site, some subcontracting’, and ‘complex multi-site, extensive subcontracting’. The document also clarifies the expectations for control, records and data needed to demonstrate control of subcontractors.5
For the EU, there are also some excellent guidance documents available. Two of these are NB-MED/2.5.2/Rec1, which is ‘subcontracting –QS related,’ and NB-MED/2.15/Rec1, which is ‘Voluntary Certification at an Intermediate Stage of Manufacture’.
Both documents interpret the EU regulations and provide direction when considering the supply chain for a device.
Contract manufacturing is a foregone conclusion in today’s global environment, due to cost controls and supply line issues. The variation in global standardisation means that manufacturers need more than adequate guidance on regulation. Because of the concerns of regulators and quality system experts, manufacturers have to understand clearly the supply chain and the impact of manufacturing activities.
The manufacturer then has to make a clear decision on the adequacy of their controls and seek to understand the point of view of the regulators in the country where they are shipping their devices. Manufacturers have access to excellent documents that are publicly available to help them in the decision-making process.