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Conformity assessment procedures for immunohaematology reagents
Version 1.0, February 2012
Documentation to support applications for conformity assessment
Quality management system documentation
Manufacturers who apply for a TGA Conformity Assessment Certificate will be requested to complete a supporting data form and provide documents that detail specific parts of their quality management system. As a guide, documentation that is generally requested to be submitted includes:
- A copy of the latest version of the Quality Manual (as required under ISO 13485:2003, clause 4.2.2)
- Organisational chart (if not part of QM)
- Product requirements (specifications) for the products included in the scope of the certificate
- A list of critical suppliers and a description of how purchasing requirements are fulfilled (ISO 13485:2003, clause 7.4.1)
- Plans of the manufacturing facility or facilities
- List of critical processes and the status of their validation (ISO 13485:2003, clause 188.8.131.52). If the product is supplied sterile, a copy of sterilisation validation reports
- Procedure for a feedback system (ISO 13485:2003, clause 8.2.1; Regulatory requirements for review during the post-production phase)
- Procedure for the issue and implementation of advisory notices and notification of adverse events (ISO 13485:2003, clause 8.5.1, Uniform recall procedure for therapeutic goods).
- Any other information requested by the TGA, as a result of any issues identified during a pre-assessment meeting.
- Documents providing the basis for any abridgement of assessment fees applied for.
Manufacturers who apply for a TGA Conformity Assessment Certificate are required to have available technical documentation to demonstrate that each device complies with the Essential Principles. For Class 3 IHRs the technical documentation is generally referred to as a STED (Summary Technical Documentation). For Class 4 IHRs, the technical documentation should provide for a more detailed examination including a full review of the design aspects of the product and is often referred to as a Design Dossier.
Where an application for conformity assessment covers a number of IVDs, and particularly a range of Class 3 IHRs that are not subject to examination of the design, the TGA will review the technical documentation for a sample of the IVDs, either as part of a desk audit or on-site audit as required. The technical documentation to be assessed, and the level of detail required, will vary on a case by case basis depending on:
- class of the IVD
- complexity of the IVD
- period that it has been on the market
- whether the IVD has the following characteristics:
- it incorporates a novel technology
- it is an already marketed IVD type that is now being offered for an intended purpose different from the original one
- it incorporates novel or potentially hazardous materials
- the IVD type raises specific public health concerns
Following is a summary of each of the components of the design dossier or STED that is expected to be held by manufacturers of IHRs. For further information relating to the depth of detail required, please refer to the table 'Depth of information to be provided'.
A detailed description of the IVD must be provided, including information addressing each of the following points:
- Intended purpose;
- Intended user;
- Risk class according to Australian regulations;
- Acceptable specimen types;
- Description of principle of the assay(s) and methodologies that are suitable to be used;
- Description of the physical appearance of the reagent; and
- Description of individual components included in the IVD(s), including for monoclonal reagents and blends, the identity of the cell line(s) from which it is derived.
If relevant, the following should also be provided:
- A description of the specimen collection and/or transport materials required or recommended to be used;
- A description of the accessories, other IVDs and other products that are not medical devices which are intended to be used in combination with the IVD(s);
- For assays requiring instrumentation, a description of the relevant instrumentation characteristics or details of dedicated instrumentation to be used;
- A description of any software to be used; and
- A complete list of any configurations or variants of the IVD(s), other than kit size, that will be made available.
Where applicable, a review of all platforms/instrumentation and any other materials, including dedicated specimen receptacles, that are required (or recommended) to be used in combination with an IVD will occur in conjunction with the technical file review. Relevant information for every aspect of the IVD(s) should be provided to enable this to occur.
A summary of the product history in both the Australian market and any other jurisdiction(s) in which it is supplied will be requested to allow the TGA to make an assessment of the safety and performance of the IVD in the post-market environment. Details should include a list of countries or regulatory jurisdictions, approximate numbers of IVDs and/or period of time where it is supplied, a summary of any adverse events, recalls, corrective/preventive actions, or refusal to allow supply.
The inclusion of information clearly identifying products either as new to the Australian market, or as previously Registered, Listed or Exempt products transitioning to the requirements of the new IVD regulatory framework will assist the TGA in prioritising the assessment of new products, so as to reduce as much as possible any delay to the market caused by a backlog of IVDs transitioning to the requirements of the new regulations.
Essential principles checklist
A copy of the Essential Principles checklist that summarises conformity to each applicable Essential Principle by reference to appropriately applied standards, or other appropriate means will be requested. Evidence of compliance must refer to documents, reports, internal procedures, etc and should include a cross-reference to the location of the documents listed within the checklist. In order to establish that an IVD complies with the relevant provisions of the Essential Principles, the TGA may request further information in relation to any of the documents referenced or expected to be held as part of the product technical file.
The TGA will accept a European Essential Requirements checklist to IVDD requirements provided it is also accompanied by a short statement to provide assurance from the manufacturer "that the Australian Essential Principles, as described in Schedule 1 of the Therapeutic Goods (Medical Devices) Regulations 2002, have been met".
A template Essential Principles checklist is available from the TGA website
Risk analysis and control summary
For Class 1-3 IHRs, a summary of the risk management activities performed by the manufacturer of the device must be provided. An example of such a summary is the Risk Management Report required by Clause 8 of ISO14971:2007, and should include as a minimum:
- a list of possible hazards for the IVD arising from false positive or false negative results;
- indirect risks which may result from IVD-associated hazards e.g. instability of test components, integrity of packaging, selection of specimens;
- the user/operator hazards such as any risks arising from reagents and specimens containing infectious agents; and
- the risk mitigation strategies that have been implemented to reduce unacceptable risks.
Taking into account risk mitigating activities, the results of the risk analysis should provide a conclusion that the remaining risks are acceptable when compared to the benefits. The risk analysis and control summary may be submitted either in a summary (text) format or as a reduced table.
For Class 4 IHRs, a full and detailed risk assessment report is required to be submitted for review.
Design and manufacturing information
A summary of the design and manufacturing processes at a level of detail appropriate to the risk class of the device should be provided. The summary should include a review of the design features that make the IVD suitable for its intended purpose, an overview of manufacturing processes and controls, manufacturing sites, a description of critical assay ingredients, a description of the major systems or critical processes, and details of any decision pathways or algorithms used, as appropriate.
Clinical evidence report
Every medical device requires clinical evidence, and for IVDs this represents the information that supports the clinical utility and the performance of the IVD as intended by the manufacturer. A clinical evidence evaluation report that demonstrates conformity with the applicable provisions of the Essential Principles (as specified in EP14) must be available for all IVDs, other than those that are exempt from inclusion in the ARTG. The Clinical Evaluation Procedures described in Clause 8, Schedule 3 of the Regulations set out the requirements, and focus on the manufacturer obtaining clinical investigation data through conducting performance evaluations and/or carrying out a literature review of published and unpublished scientific literature.
If a manufacturer considers that evidence of an IVDs clinical utility or its established usefulness is not required to be compiled and submitted for review due to it being a well developed and extensively utilised IVD, this decision is required to be documented and clearly justified as part of the clinical evidence report.
Evidence to support the clinical competence of the author (e.g. short curriculum vitae) must accompany the submitted clinical evidence report to provide assurance that the clinical evidence has been evaluated by a competent clinical expert.
Performance evaluation studies incorporate both the clinical and analytical performance characteristics of an IVD. Performance evaluation studies for IHRs include evaluation of serological blood grouping reagents, characterisation of reagent red blood cells, red blood cell genotyping assays, and production of calibrators (standards) and control material for use in an immunohaematology setting. Specific consideration should be given to the following aspects of the evaluation process, as appropriate to the type of reagent:
- Use of samples that reflect variants and weak antigen expression e.g. neonatal specimens, ABO variants, weak (Rh)D, partial expression of Rh(D);
- Ethnicity of test subjects expressing possible/probable phenotypes;
- Testing for prozone effect;
- Potency testing;
- Nature of red blood cells to be considered (e.g. washed/unwashed red blood cells (RBCs), RBC storage times, RBCs collected using different anti-coagulants/storage media)
- Range of methodologies to be considered (e.g. column, tube, tile)
Clinical performance is a measure of an IHR's ability to correctly group and screen human blood and blood products for compatibility purposes. Clinical performance characteristics include diagnostic sensitivity and diagnostic specificity.
For IHRs, providing data that has been drawn from clinical performance studies is an essential component of the clinical evidence. It is recognised that for some IHRs which have been in routine use for many years (> 10 years) and that have previously undergone the recognised equivalent1 of a design examination in other jurisdictions, the original validation data may no longer fully demonstrate all aspects now required of a Design Dossier. Where it is available in a suitable form, published literature or a review of experience gained during routine diagnostic testing, which includes post market surveillance data and on-going satisfactory performance in external Quality Assurance Programs should be used as supplementary evidence to support the clinical performance of an IVD. Full details of any investigations into anomalous results or unexpected reactions carried out by, or on behalf of the manufacturer must be provided.
Product validation and verification
Evidence to demonstrate the analytical performance characteristics of the IVD is a requirement under Essential Principle 15 and forms a critical part of the manufacturer’s performance evaluation studies, as required for clinical evidence.
The information presented for each study should provide sufficient detail for the assessor to understand how the study was conducted, the characterisation of specimens/samples used, acceptance criteria, explanations for anomalous results, and the outcomes/conclusions drawn. It is acceptable to combine two or more aspects of analytical/clinical performance into fewer separate studies provided each of the studies is well designed and all relevant variables and test characteristics are effectively demonstrated.
In Australia, the minimum acceptable numbers and range of characteristics to be assessed for validation and batch release testing for IHRs is consistent with requirements outlined in the:
- EU Common Technical Specifications for in vitro diagnostic medical devices (pdf,101kb), and
- UK Red Book
A list of all appropriate specimen type(s) suitable for use with the IVD must be provided, including anticoagulants, matrices or any special instructions or conditions associated with specimen collection. Information should also address specimen stability, appropriate storage conditions and where applicable, transport conditions. Storage includes elements such as different storage media, duration, temperature limits, maximum number of freeze/thaw cycles.
Analytical performance study reports should include information about the nature of the specimen types tested (e.g. spiked, pooled etc) and the source of specimens obtained, as appropriate.
The term accuracy refers to both trueness and precision (reproducibility and repeatability).
Demonstration of trueness requires utilisation of an acceptable reference method or comparison with reference material of a higher order.
Reproducibility should include information about studies to estimate total variability and may include, as appropriate, between-day, between-run, between-sites, between-lots, between-operators and between-instrument variability.
Repeatability should include information about studies to estimate total variability and as appropriate, within-run variability.
Analytical & clinical sensitivity & specificity
Demonstration of analytical sensitivity should provide as part of the study design, the analyte tested, how the levels were established, specimen characterisation and number of replicates tested. Calculations used to determine the assay sensitivity should be included.
Positive specimens used in the performance evaluation for IHR IVDs should be selected to reflect heterozygous and homozygous phenotypes, variant and weak antigen expression. Specimens types tested in these studies should include:
- clinical specimens
- neonatal specimens
- cord blood specimens
Performance evaluation should be consistent with relevant standards and guidelines such as the Requirements for Conventional Blood Typing Reagents, as specified in the UK Red Book. Where relevant, blood grouping reagents should be assessed against international standards such as the WHO International Reference Preparations to ensure minimum potency titres are achieved.
For reagent red blood cell manufacture, a sample from each cell population should be tested using at least 2 antisera prepared from different donors or cell lines, in order to confirm the presence or absence of every antigen specificity claimed.
Information relating to studies conducted to determine the effect caused by potentially interfering or cross-reacting substances or agents on test results should be provided. Consideration should be given to both exogenous and endogenous factors expected to be encountered.
Where relevant, analytical and clinical performance evaluation studies for IHRs should address:
- detection of red blood cell (RBC) phenotypes from different ethnic groups;
- determination of antibody potency;
- determination of haemolytic activity; rouleaux formation; prozone effect;
- RBC sensitisation studies (e.g. IgG sensitised RBCs for testing reagents for use by a direct agglutination method, sensitised RBCs for the assessment of anti-complement activity);
- RBC treatment - e.g. washed versus unwashed RBCs, proteolytic enzyme treated RBCs (for enzyme-treated reagent red blood cells, information should be provided concerning those antigens which are rendered inactive or less active by the enzyme treatment used);
- Specificity of polyvalent antibodies and polyclonal reagents - e.g. testing against a wide range of antigens to confirm specificity and exclude the presence of potentially interfering antibodies.
Traceability of calibrator and controls
Information establishing the traceability of calibrators and trueness control materials should be provided, when applicable. Methods used to determine traceability to reference material of a higher order, acceptance criteria, and the assignment and validation of values should be included.
The phenotype of red blood cells used in the control of blood typing reagents should be confirmed using an established reference standard.
Controls and calibrators that are manufactured for use in immunohaematological testing should be assessed against international reference preparations to ensure minimum potency titres or standards are being achieved.
Determination of assay cut-off
Where applicable, a summary of the process used to establish the assay cut-off should be provided. Information provided should be based on the population studied, method(s) used to establish the true status and any statistical methods used to generate results.
Verification and validation of instrumentation/software
For verification and validation of instrumentation and/or software IVDs, the study report should include a summary of performance testing undertaken conducted in a valid end-user environment.
Stability studies to support the claimed shelf-life under closed, in-use and transport conditions must be provided.
For closed shelf life studies, data must be generated by testing at appropriate storage time intervals using a minimum of 3 separate production batches of IVDs, with at least one batch of real time data extending beyond the claimed shelf life. Temperature ranges assigned for testing should encompass both the upper and lower storage temperatures claimed. For new products where real-time studies are not yet completed, the initial expiry dating may be determined using accelerated stability studies, and experience gained by the manufacturer with similar reagents that can reasonably expect to be comparable with respect to stability characteristics. Ongoing real time studies for those products where the shelf-life has been assigned on the basis of accelerated data should be monitored closely, and the manufacturer should reduce the shelf-life in line with the real-time data as appropriate.
In-use (open vial) stability and transport simulation studies should be conducted using at least one batch of product, with a study design which includes conditions appropriate to the intended use and expected conditions likely to be encountered for the product.
For further information refer to CLSI standard EP25-A, Evaluation of Stability of In Vitro Diagnostic Reagents.
Information to be supplied with the IVD
The sponsor is required to provide clear, legible copies of representative information that is to accompany the kind of IVD medical device when supplied in Australia, including:
- Instructions For Use; and
- Advertising material (e.g. brochures, web-pages, published advertisements, etc.), where available.
- Labelling and instructions for use are not necessarily required for every model or variation, unless there are significant differences in content. However, the copies provided are required to be representative of what will be supplied in Australia.
- The sponsor's name and address must be provided with the IVD in such a way that the user can readily identify the sponsor. Labelling requirements are prescribed in Regulation 10.2 and Essential Principle 13.2 in Schedule 1.
- All representative information must be provided in English.