Medical Device Link.

REGULATIONS & STANDARDS

Peter Haima, PhD, is IVD services manager at Eurogentec SA (Liege, Belgium). He can be reached at p.haima @eurogentec.com.

Primers and probes are critical components of IVD molecular diagnostic assays. Performance parameters like detection limit and specificity will vary significantly with variations in oligonucleotide quality. Despite the critical importance of oligonucleotide quality, many IVD start-ups seem to struggle with the quality and regulatory needs for oligonucleotides that are produced following good manufacturing practices (GMP). They are subsequently tempted to source less-expensive non-GMP oligonucleotides, which are verified for functional performance through an incoming quality control (QC) procedure.

Anne-Françoise Emontspohl, PhD, is quality system manager at Eurogentec SA (Seraing, Belgium). She can be reached at a.fr.emontspohl @eurogentec.com.

A need for written guidance on how to determine the quality and regulatory needs for GMP oligos has become clear from several communications between IVD manufacturers and the authors. Eurogentec SA (Liege, Belgium), a contract manufacturing organization (CMO) for IVD GMP oligos and compliance, and Xendo Pharma Services BV (Leiden, The Netherlands), a consultant agency for the health care industry, developed a series of articles that address whether IVD manufacturers need to source critical components from GMP-compliant CMOs from regulatory, legal, quality, risk management, and financial perspectives.

Marc Klinkhamer, PhD, is a senior consultant at Xendo Pharma Services BV (Leiden, The Netherlands). He can be reached at marc.klinkhamer @xendo.com.

Information included in the articles was obtained from legal documents, guidelines, and standards, as well as from discussions held with auditors from notified bodies who are involved in the daily regulation of IVDs and the application and enforcement of the legal requirements. Part 1 of this two-part series covers the necessity to provide guidance on maintaining GMP oligonucleotides standards from a European perspective.

Background

IVD products marketed in Europe must comply with the legal requirements set in the IVD Directive 98/79/EC, a document that has been transposed into national laws and approved by all member states of the European Union (EU).¹ When an IVD product complies with all IVD Directive requirements, the product receives a CE mark that allows the manufacturer to freely market the product throughout the EU. High-risk IVDs also require the involvement of a notified body to complete this process.

In the IVD Directive, the manufacturer is defined as “the natural or legal person with responsibility for the design, manufacture, packaging, and labeling of a device before it is placed on the market under his own name, regardless of whether these operations are carried out by that person himself or on his behalf by a third party.” Oligonucleotides and DNA polymerase are critical components that may affect the performance of an IVD and its compliance with the essential requirements of the IVD Directive. Any deviation from the specifications and manufacturing process of these critical components carries the risk of affecting the performance characteristics of the IVD. However, the IVD manufacturer is responsible for determining which components of the IVD product are deemed critical.

GMP is often used in reference to ISO 13485, a document that explains the quality management systems of medical devices and their requirements for regulatory purposes.² Additionally, GMP is specifically named and detailed in the quality system regulation (QSR) issued by FDA.³ In the case of high-risk IVDs, a regulatory inspection by a notified body serves as the only certification process for the IVD Directive.

For low-risk IVDs, there is no requirement for an inspection, and the IVD manufacturer can claim compliance to the requirements of the IVD Directive based on their own judgment. For those manufacturers, ISO 13485 certification of the quality system by an accredited certification organization can provide independent evidence for GMP compliance. In this situation, the certification organization can be other than a notified body.

IVD Directive Regulation

The IVD Directive, Annex 3, paragraph 4 states:

The manufacturer shall take necessary measures to ensure that the manufacturing process follows the principles of quality assurance (QA) as approp­riate for the products manufactured.

The IVD Directive does not have a specific protocol for establishing a quality system (QS) for the IVD manufacturing process, which includes control and evaluation of suppliers. Manufacturers have the option of setting up a QS that is compliant to ISO 13485, but other approaches are acceptable as well. Unfortunately, a manufacturer will not know if the chosen system is appropriate until after judgment by a notified body or a competent authority. However, IVD Directive, article 5, paragraph 1 offers IVD suppliers a helping hand:

Member States shall presume compliance with the essential requirements referred to in Article 3 in respect of devices, which are in conformity with the relevant national standards transposing the harmonized standards, the reference numbers of which have been published in the Official Journal of the European Communities.

Essentially, a manufacturer that has followed the IVD Directive requirements and can demonstrate compliance with a harmonized standard for setting up a QS will be presumed appropriate. ISO 13485 is a harmonized standard for QS, and, in practice, it is the standard guidance for the majority of European IVD manufacturers.

Legal Authority

In the field of IVDs, the authorities are responsible for the issuance of national laws, which must be based on the IVD Directive. If a major health and safety problem occurs with a specific product or similar products from other manufacturers, the authorities will contact the IVD manufacturer directly. In such a case, the authority of the member state where the problem occurred will follow a vigilance procedure and perform an assessment with the manufacturer.

The assessment largely consists of a root cause analysis of the problem in relation to the IVD product. The better the QA system performs during the analysis, the more favorable the assessment and the measures taken by the authority after the analysis is complete. For example, if the IVD manufacturer has exerted inappropriate control over a supplier of a critical component and this particular component is the cause of the problem, then the IVD manufacturer could receive the most severe consequence of an unfavorable assessment: exclusion from the European market.

Contrary to the responsibility of law issuance and vigilance duties, the EU authorities have delegated the process of IVD conformity assessment for high-risk IVDs (CE marking) to the notified bodies. Therefore, a notified body can also be regarded as an authority. Specifically, when an IVD is listed in Annex II, list A or list B of the IVD Directive (the high-risk IVDs), the product conformity assessment must be performed together with a notified body, which will issue a CE certificate if the product is found to be in compliance with the IVD Directive. The CE certificate must be issued before the manufacturer can affix the CE mark to the IVD.

Paragraph 3.3 of Annexes 4 and 7 of the IVD Directive stipulates that the notified body must audit the manufacturer’s QS for the assessment process, and “the assessment procedure must include an inspection on the manufacturer’s premises and, in duly substantiated cases, on the premises of the manufacturer’s suppliers and/or subcontractors.” Whether or not an inspection of a supplier is substantiated is further outlined in the notified bodies consensus document of February 2000.⁴ An inspection of a supplier of critical components may be necessary, but the notified body will base this necessity on various factors, such as the certification status of the supplier (e.g., the ISO 13485 standard).

Aspects of Quality

The ISO 13485 standard becomes an obvious choice when it comes to ensuring product quality. Section 7.4.1 of ISO 13485 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.

In the case of critical components, it is clear that the extent of control should be maximized because of its potential effect on the IVD performance. Therefore, requiring a QS process during the manufacturing of critical compo­nents would be logical.

If a critical-component supplier is ISO 13485 certified by an independent organization, the IVD manufacturer could consider using this certificate as sufficient proof of supplier evaluation, thereby minimizing costly supplier audits. Alternatively, a highly similar quality system, such as the U.S. QSR, can be used. However, a QS based on ISO 9001 could be seen as too minimal or broad.⁵ For example, ISO 9001 lacks a requirement for traceability, but it is mandatory in the ISO 13485 standard. On top of the supplier’s QS, the manufacturer will have to further control the supplier and supplier components by use of its supplier monitoring system. Other IVD requirements are clearly mentioned in ISO 13485, which is reflected in the increased number of required documented procedures (6 versus 20).

Risk Management Process

The newly revised ISO 14971:2007 standard is a widely accepted tool for medical device risk management.⁶ IVDs undergo a product risk analysis that examines the IVD’s function in normal and fault condition modes. Annex H of the ISO 14971 standard lists hazards associated with IVDs in fault condition modes, which could result in the product failing to meet the performance characteristics required for medical use (e.g., trueness, precision, specificity). The listed hazards could result in within-batch inhomogeneity, batch-to-batch inconsistency, nonspecificity, sample or reagent carryover (contamination), and stability failures.

Critical components, largely identified in a production process risk analysis, can be involved in many of the listed hazards as well. Depending on the fault condition’s impact on the patient, risk reduction measures would be required to warrant an acceptable IVD. The risk reduction and control focus on, but are not limited to, the critical components of the IVD. An appropriate QS (ISO 13485 or similar) for the production of the critical components, including a proof of the quality system’s efficacy (such as ISO 13485 certification), is an effective and acceptable risk reduction measure. The absence of an appropriate QS may result in an increased risk level, possibly to a level that cannot be acceptably justified by the IVD manufacturer.

It should be noted that the classifications listed in the IVD Directive Annex 2 (list A or B) do not play a significant role in performing IVD risk management. The essential requirements and others, as defined in the IVD Directive, are similar for Annex 2 and nonannex 2 IVDs. If an IVD manufacturer decides to outsource the manufacturing activities, the IVD company should make sure that the outsourcing partner adheres to the essential requirements of the IVD Directive, such as supplier control.

Financial Consideration

Figure 1. (click to enlarge) GMP oligonucleotide manufacturing: quality system, documentation, and environmental control.

GMP manufacturing of critical components for IVDs requires significant investments in GMP facilities (mainly class 100,000 clean rooms) and the set up and maintenance of an ISO 13485–based QS. Additionally, the extensive quality procedures and documentation for traceability add fixed costs to the overall process. The scope of the QS spans the manufacturing chain for the entire GMP oligonucleo­tides manufacturing process (see Figure 1).

Figure 2. (click to enlarge) Relationship between price (per nmol) and purchased amount for a GMP and non-GMP oligon­u­cleotide (40-mer FAM labelled molecular beacon).

The financial impact, however, is largely dependent on the scale and final yield of the critical components. Figure 2 shows how the cost of producing a FAM-labeled molecular beacon is affected when a manufacturer has the freedom to upscale the production. Costs are shown as percentages of the GMP oligonu­cleotide at the lowest yield delivered (5 nmol). At higher yields, the price curves approach each other at levels far below the initial prices for the smallest yield. The prices for GMP and non-GMP oligonucleotides clearly demonstrate the economy-of-scale effect.

Conclusion

As a leading principle, the IVD manufacturer is responsible for its CE-marked molecular diagnostic assays and the quality of critical components supplied. The IVD Directive and corresponding laws require the manufacturer to implement a quality system for molecular diagnostic assay production, including control of suppliers and supplied components. The ISO 13485 standard is not required, but it is generally accepted to set up an effective QS.

Any interaction between the IVD manufacturer and the authorities (both national authorities and notified bodies) will benefit from the ISO 13845 certification process with all critical component suppliers. The vigilance and conformity assessment procedures will pose fewer hurdles to the manufacturer than without an ISO 13845–based system.

From a quality and risk management perspective, sourcing critical components from a GMP-compliant supplier using an ISO 13485–based or similar QS is required. GMP components like oligonucleotides are not necessarily more expensive than non-GMP components if ordered at higher yields.

Although the above conclusions are based on European standards, they largely apply to U.S. standards as well. At several meetings, FDA officials have expressed the opinion that IVD manufacturers and IVD service providers should source their critical assay components from GMP-compliant suppliers. The next article in this two-part series will address the same topics from an FDA perspective.