IVDT Ask The Experts

Our company’s CEO assumes that IVDs are low-risk products and that ISO 13485 certification is merely a marketing tool for EU sales. Thus, satisfying the Notified Body (NB) auditors is important but establishing a functioning quality system is unnecessary. What accountability does the NB have to the MHRA and other EU regulators when they provide an overseas IVD manufacturer with the right to apply a CE mark to its IVD products for sale in the EU?

rpark — Tue, 27 Mar 2012 16:54:49 +0000

A compliant quality management system is a cornerstone of most global IVD regulatory systems, whether that be the QSRs in the U.S. or ISO 13485 in the EU. ISO13485 is the harmonized standard. However, the IVD Directive itself clearly states that all devices must have a quality system compliant with the requirements of Annex III of the IVD Directive, so a quality management system is essential to being able to place products on the European market.

A quality management system ensures that good manufacturing practices are established and maintained so that the product which is safe and effective and meets specifications is produced reproducibly. If a manufacturer requires a notified body to CE mark their product, then the notified body is responsible for auditing to the requirements of the Directive. Companies often choose to gain certification to ISO 13485. But manufacturers may choose not to apply ISO 13485. In this scenario, they will be assessed directly to Annex IV or VII of the IVD Directive. However, they must demonstrate a system with comparable solutions to the requirements in the Directive as described in ISO 13485.

If any manufacturer does not meet the requirements of the standard, a non conformity will be raised. If this is not addressed, it could lead to first the suspension and then withdrawal of a certificate, which means that the manufacturer may no longer be able to support regulatory approval if used to support a regulatory conformity route.

It is important to remember ISO13485 is entitled “Quality Management Systems — Requirements for Regulatory Purposes” and as such is a conformity route for many countries including EU, Canada, and Australia. It is therefore not a marketing tool but it is one of the key requirements needed to gain market access in these countries. A quality system appropriately applied will enable a company to make safe reproducible products, which is why regulators use it as a key tool for entry into their markets.

What is the regulation regarding the use of raw materials not made under GMP or tested by the supplier with non-validated test methods? Is it acceptable to mitigate such perceived issues at one’s supplier with risk analysis-driven performance verification protocols?

rpark — Tue, 20 Mar 2012 16:47:52 +0000

The first thing to consider is ISO 13485, which states, “The type and extent of control applied to the supplier and the purchased product shall be dependent upon the effect of the purchased product on subsequent product realization or the final product.” It is therefore essential to consider, evaluate, and document the potential risk and then determine how to manage this. Risk control measures may include selecting suppliers that use validated methods under GMP. However, when this is not possible, other methods of control may need to be considered. For example, can the product be tested on receipt, and can large batches be purchased and qualified for use in the IVD application? This assumes that processes can be subsequently verified on the principle that processes that cannot be verified by subsequent monitoring or measurement should be validated. When the incoming material or product cannot be verified, and there are no validated methods, for example if the product being purchased is sterile, then an alternative supplier may need to be found.
The GHTF Document Guidance on the Control of Products and Services Obtained from Suppliers is a useful source of guidance: http://www.ghtf.org/documents/sg3/sg3final-N17.pdf

I work for a local virus diagnostics services company, and we are aiming at validating a PCR method for hospital customer use as part of our education program (i.e., getting students familiar with quality issues and PCR methodology). This assay has been published, and we are aiming at using it in a modified form. Which issues would be most significant from an EU regulation point-of-view and also for customer acceptance?

rpark — Thu, 01 Mar 2012 18:49:42 +0000

There are two important things to consider. One, does the test detect a clinical parameter which could be used to diagnose a patient. If it does not, then the test does not meet the definition of an IVD as the device must have a medical intended purpose. The other important test is how is it “placed on the market.” If it is not described for a clinical use or sold in this way, it does not meet the definition of an IVD in the IVD Directive, and the Directive therefore does not apply. If it is not an IVD, local product liability/product safety legislation will apply in the normal way. It is essential that the instructions for use clearly identify the intended use of the device and that the product is sold and advertised appropriately. The technology alone does not make it an IVD nor determine what it is used for and how it is sold.

My company produces mouse monoclonal IgM antibodies, and we want to use them in an enzyme immunoassay (EIA). Can you suggest the best way to label them with an enzyme like HRP, or do you have any other enzyme suggestions?

rpark — Thu, 23 Feb 2012 18:23:52 +0000

The two enzymes used widely in EIA are HRP and alkaline phosphatase (ALP). HRP has a rapid turnover rate and gives high sensitivity over short incubation times, while ALP has a linear reaction rate enabling increased sensitivity over extended incubation times. From the feedback that we receive, the best way to label your antibodies is to conjugate using heterobifunctional crosslinkers such as those supplied by Thermo Scientific–Pierce Protein Research Products.

I am looking for sources of diaphorase with high specificity for NADh and low reactivity with NADPH. Can you suggest some sources?

rpark — Fri, 17 Feb 2012 18:20:53 +0000

The best source for such a diaphorase is probably Asahi-Kasei (www.asahi-kasei.co.jp/shindan/eng/list/index.html). Their enzyme is claimed to be four times less reactive with NADPH than NADH.

Will the label on an IVD product need to change to designate compliance with the new IVD Directive regulations?

rpark — Thu, 16 Feb 2012 17:43:46 +0000

The labelling may change to meet new essential requirements and may now include a Notified Body number to identify that a conformity route requiring a Notified Body has now been applied. However, if neither of these are affected by the new regulations, there may be no obvious change to the labels.

Ask a Question

admin — Thu, 16 Feb 2012 06:57:50 +0000

How will the revised IVD Directive regulations affect the CE mark that may already be on the label of a given IVD product?

rpark — Thu, 02 Feb 2012 21:37:53 +0000

Once the new IVD Directive regulations come into force, IVD manufacturers must meet any new labeling requirements. The CE mark shown on an IVD product reflects the regulations at the time the product was placed on the market, as reflected in an IVD manufacturer’s declaration of conformity. Once an IVD manufacturer applies the new IVD Directive regulations, it must meet any new labeling requirements and apply appropriate conformity routes such that the declaration of conformity denotes the regulations applied not specifically to the label.

We want to improve our assay. How can an enzyme supplier help us?

rpark — Mon, 30 Jan 2012 19:54:22 +0000

There is constant pressure on IVD manufacturers to develop new diagnostic assays which deliver improved performance and accuracy, but which remain cost effective.

Enzyme suppliers can assist in this process by working with customers to develop superior products, for example with higher activity or in different formulations, which enable improved assay performance.

Tests for novel diagnostic markers may require the development of new enzymes. IVD manufacturers may wish to collaborate with enzyme suppliers that provide a custom development service.

Today, there are some recombinant enzymes that are used to formulate reagents. However, these raw materials are very costly, which drives up the price of these reagents. Could you please make a prediction about the future use of and pricing for recombinant enzymes in the diagnostics industry? Are there any technical hurdles that need to be overcome to drive down the cost of producing recombinant enzymes?

rpark — Mon, 23 Jan 2012 19:06:04 +0000

Today’s diagnostic reagents use a wide range of both naturally derived and recombinant enzymes. In many cases the available natural enzymes provide appropriate performance at a reasonable cost, however where there is no natural enzyme readily available, or its performance is inadequate, then a recombinant enzyme is required. The majority of natural enzymes already employed in diagnostic reagents have well managed supply chains and are manufactured to produce consistent performance from lot to lot, so it is unlikely that they would be need to be replaced by recombinant enzymes. The use of recombinant enzymes is likely to increase therefore, due to the demand for 1/ particular improved performance criteria in existing reagents or 2/ the measurement of new analytes requiring the development of novel enzymes.

The pricing of today’s recombinant enzymes is largely driven by the scale of the fermentation hence if the demand volumes increase then there should be a concomitant decrease in pricing. Aside from volume, technical advances such as optimised vectors producing increased expression levels, greater control of protein folding and glycosylation levels, and the secretion or compartmentalising of functional enzymes to make harvesting easier should all combine to drive down the costs of production. However enzyme manufacturers will have to account for substantial research & development costs to overcome such technical hurdles so while a significant reduction in the pricing of recombinant enzymes is on the horizon it is unlikely to take place in the near future.