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.

The first part of this two-part series (IVD Technology, June 2008) focused on the European regulatory, quality, and risk management aspects of sourcing critical components for molecular diagnostic assays. This second article will focus on the regulatory situation in the United States and the FDA perspective where it specifically differs from the European perspective as described in Part 1.

Peter Scott is a regulatory and quality consultant with 20 years senior management experience with medical devices based in the United States. He can be reached at psfs71@hotmail.com.

Some IVD manufacturers believe functional quality control (QC) testing on incoming critical components is an adequate replacement for good manufacturing practices (GMP) of those components. The Federal Register addresses this issue with the following statement:

The intent of §820.50 is to ensure that device manufacturers select only those suppliers, contractors, and consultants who have the capability to provide product and services. The quality of a product or service is established during the design of that product or service, and achieved through proper control of the manufacture of that product or the performance of that service. Section 820.50 thus mandates that products be manufactured and services be performed under appropriate [quality assurance] QA procedures. Finished device manufacturers are required under §820.50 to establish the requirements for, and document the capability of, suppliers, contractors, and consultants to provide quality products and services.¹

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

The following quote from the World Health Organization (WHO) supports the above statement:

Good quality must be built in during the manufacturing process. GMP prevents errors that cannot be eliminated through quality control of the finished product.²

As a consequence, incoming quality control (IQC) is not an adequate replacement for GMP manufacturing of critical components. Quality cannot be completely inspected or tested in products after implementation. For example, IQC is unable to detect or is likely to miss low-level cross-contamination, documentation errors, variations in impurities, and sequence errors (e.g. ACGT instead of AGCT). These variations could result in failing to meet the IVD performance characteristics required for use in certain patient samples (e.g., precision, specificity, and detection limit). GMP manufacturing in a GMP facility, including a proof of effectiveness of the quality system (QS) such as ISO 13485 certification, reduces the risks associated with such errors.

FDA Regulations

The regulatory framework for medical devices in the United States is different from the IVD products regulation in Europe. While the European Union has three separate directives (IVD Directive, Medical Devices Directive, and Active Implantable Medical Devices), the United States has one set of regulations applicable to medical devices which include IVD devices, such as molecular diagnostics.^3-5 The U.S. regulation system has no provisions concerning directives that need to be transposed into national laws, notified bodies, or different competent authorities. The regulations are clearly described in the Code of Federal Regulations (CFR). For example, 21 CFR 820 defines the GMP requirements, often referred to as the quality system regulation (QSR), which apply to medical devices. These regulations are similar to ISO 13485; however, they offer much more detail in the specific IVD device requirements. FDA is appointed to the task of enforcing the requirements.

The law is clear regarding the requirement for molecular diagnostic manufacturers to source critical components from GMP-compliant contract manufacturing organizations (CMOs). According to of 21 CFR 820:

The requirements in this part govern the methods used in, and the facilities and controls used for, the design, manufacture, packaging, labeling, storage, installation, and servicing of all finished devices intended for human use. This regulation does not apply to manufacturers of components or parts of finished devices, but such manufacturers are encouraged to use appropriate provisions of this regulation as guidance.

With this law in consideration, manufacturers of molecular diagnostics do not have any legal recourse to impose GMP on their critical-component suppliers. However, experience, with other FDA guidances implies that although FDA guidance documents are voluntary, implementation is highly recommended in order to facilitate a smooth product clearance and site inspection. Additionally, 21 CFR 820 requires manufacturers of molecular diagnostics to “establish and maintain the requirements, including quality requirements, which must be met by suppliers.” A practical way for a manufacturer to meet this requirement is to assure that a supplier has a QS in place that is either certified against the ISO 13485 standard or compliant with the QSR, or both. A QS based only on ISO 9001 could be regarded as insufficient because traceability requirements are lacking, and IVD requirements, such as documented procedures, are minimal (6 in ISO 9001 versus 20 in ISO 13485).

FDA Investigations

The depth and breadth of an FDA investigation depend on the rationale for the facility visit. Most FDA inspections are prompted by one of three situations: a routine inspection, a for-cause inspection, or a premarket approval (PMA) inspection. One of the requirements for FDA approval of a PMA device is an FDA facility inspection if an investigation has not recently occurred for a similar product.

A routine facility investigation will include a review of the corrective and preventive action (CAPA) system and several other major subsystems. In the absence of any concerns discovered during the review that would lead the investigator to request a closer evaluation of the incoming area (i.e., control over suppliers), the potential for a detailed review of the area is minimal. However, if the inspection is for cause and due to a reported field corrective action that directly relates to the product not meeting the package insert claims (i.e., the instructions for use), the investigator will evaluate the incoming area. During a PMA inspection, all areas of the production process, from incoming materials inspection and control to final product release, will be thoroughly evaluated.

As with most audits and investigations of an IVD manufacturer, the investigator will want to survey the entire facility. If an area appears disorderly or out of control, it will be noted and evaluated further by the investigator. Regardless of the rationale for the inspection, it is clear that the incoming area and supplier control will be either directly or indirectly evaluated during every FDA investigation.

FDA’s general approach is to determine if the manufacturer has made every reasonable attempt to prevent the use of incorrect or suboptimal raw materials in an IVD product. FDA will hold the manufacturer responsible for the product that they produce and release on the market, regardless of the supplier, its data, or its certification. However, in some cases, the supplier may also be investigated should FDA believe it is warranted.

As previously indicated, FDA regulations state that the manufacturer shall “establish and maintain the requirements, including quality requirements, which must be met by suppliers.” In order to satisfy the FDA guidelines regarding establishing and maintaining quality require­ments, especially by suppliers, manufacturers typically set up programs that may include and combine any of the following: supplier audits, supplier ISO 13485 (or equivalent) certification, contract laboratory analysis of the raw material, in-house evaluation of the material, certificates of analysis, and certificates of conformance.

During a routine FDA investigation, many facility issues could result in a detailed review of the incoming inspection area, such as stability problems, complaints, or nonconforming-material reports relating to raw materials. The investigator’s review may evaluate the raw-material inspection procedures, quarantine, and holding areas.

At several meetings, FDA officials have expressed the opinion that IVD manufacturers and IVD service providers should preferably source their critical assay components from GMP-compliant suppliers. During an investigation, FDA will determine whether the raw materials provided by a supplier are adequately controlled by the manufacturer. Therefore, it is important to develop a detailed incoming-material inspection process. An ISO 13485 (or equivalent) certification of the supplier’s QS of critical components could be an essential part of the process.

Analyte Specific Reagents

In the United States, FDA has established a separate set of regulations for analyte specific reagents (ASRs) which are defined as the following:

Antibodies, both polyclonal and monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and similar reagents which, through specific binding or chemical reaction with substances in a specimen, are intended for use in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens.⁶

Critical components, such as primers and probes as defined in the first part of this article, directly delivered to a clinical diagnostic laboratory, can be considered ASRs. The laboratory will use an ASR for inclusion in an in-house–developed diagnostic test (i.e., laboratory-developed test (LDT)) and must comply with the Clinical Laboratory Improvement Amendments (CLIA).⁷ With respect to the supplier, if an ASR is not involved in any high-risk blood banking test or high-risk infectious-disease test (e.g., human immunodeficiency virus or tuberculosis), it can be considered a Class I medical device.

For some suppliers, the Class I classification is appealing because such devices are exempt from premarket notification. However, it is noteworthy that Class I device manufacturers are required to follow GMP. GMP are identified in the QSR and defined in 21 CFR 820. Contrary to the critical-component supplier for an IVD manufacturer, who is encouraged but not required to follow the GMP, the supplier of an ASR is obliged to follow such regulations.⁸

From the laboratory perspective, CLIA regulations are enforced by the Centers for Medicare & Medicaid Services (CMS). Therefore, certain diagnostic tests conducted in a U.S. clinical laboratory on a patient’s sample can be performed using two different types of molecular diagnostic assay: one that originates from an IVD manufacturer that is cleared or approved by FDA, or an LDT from a laboratory that is regulated by CMS.

Some primers and probes are sold in the United States as products for research use only (RUO). FDA requires such products to be labeled “For research use only, not for use in diagnostic procedures.”⁹ The required text makes it clear that the diagnostic aspect is not applicable for RUO products, and consequently, FDA does not require RUO products to be manufactured in compliance with GMP. RUOs are not regulated by CMS, because CMS only regulates lab testing performed on humans in the United States not intended for research testing purposes.

If a lab orders an RUO product, it cannot be used in any in-house–developed test or diagnostic assay. According to the label text, the laboratory may only utilize the material for research purposes, and even the most stringent IQC will not alter the status of the RUO.

Conclusion

Quality cannot be inspected in critical components that have been produced. A QS, preferably certified by an independent organization against an international standard such as ISO 13485, is an appropriate means to assess the quality of a supplier’s system and the component. With respect to FDA, there is no strict requirement for critical-component suppliers to comply with GMP; however, the agency encourages suppliers to embrace GMP.

FDA facility inspections routinely will not review the QC over suppliers in detail. However, if the inspection is related to a PMA filing, for cause (e.g., a field corrective action related to the product not meeting its claims), or a general production concern, this area will receive intensive attention from FDA.

Critical components, such as primers and probes supplied to a clinical laboratory, need to comply with specific regulations for ASRs and have to be manufactured under GMP. On the other hand, there are no specific regulations requiring a QS for RUO products in the United States. Manufacturers should use labeling according to the intent of the RUO product.

The regulations in Europe and the United States are complex and differ in several ways. However, it is clear that high-quality molecular diagnostic assays require high-quality inputs. Therefore, from a quality and risk management perspective, sourcing of critical components from a GMP-compliant supplier is a logical step, to be followed preferably by compliance with a widely accepted standard (e.g., ISO 13485) with independent certification.