Quality Manual

The quality management system (QMS) documentation per EN ISO 13485 that is required, shall include for the device part of the integral drug device combination product:

1. documented statements of a quality policy and quality objectives
2. a quality manual (QM)
3. documented procedures required by EN ISO 13485
4. documents, including records , determined by the organization to be necessary to ensure the effective planning, operation, and control of its processes
5. other documentation specified by applicable regulatory requirements

The purpose of the QM, as the top document of the QMS, is twofold:

1. It is the top document for internal and external auditors, inspectors, customers and top management with a focus on the scope of the QMS, including details of and justification for any exclusion and/or non-application, the documented procedures established for the QMS, a description of the interaction between the processes of the QMS and the outline of the structure of the documentation used in the QMS.
2. It is a guide for employees to facilitate using QMS procedures and associated work instructions, forms and other QMS-documentation on a need to know basis.

Furthermore, as manufacturer of a drug-device combination product, the QM shall:

1. Identify the processes needed for the QMS and their application throughout the organization, and define their sequence and interaction. Thus is advised to include in the QM a QMS-process flowchart
2. Apply risk based approach to the control of the appropriate needed processes by:

• • Providing resources and information needed to support these processes and to meet the QMS requirements
  • Monitoring, measure and analyse these processes
  • Implementing the review and the actions necessary to achieve planned results

3. Determine the responsibilities (including those of the person responsible for regulatory compliance of the device part) and scope of these processes

Examples of processes addressed with a risk based approach are: Document Control (gradation in document training requirements; change impact assessment), Project Management (projects versus tasks; risk management to manage project risks), Quality Objectives Management & Management Review (KPIs; different means to follow-up on MR-actions), Training (training verification depends on criticality of trained process), Software Verification and Validation (software risk assessment), Customer Order Handing (customer satisfactory level determines action), Design and Development Controls (output of risk management is design and development input), Device Risk Management (design, application and process risk management), Management of Suppliers (product-risk criteria), Purchasing (classification of spend; product-risk criteria), PQ (risk-based sample size determination), Handling and Storage (limited access; limited shelf life; special storage conditions; FEFO), Maintenance and calibration (scheduling, criticality of measurement), Statistical Techniques (risk-based sample size determination), PMS, PMCF & PSU (input for risk management), Internal Audits (risk-based audit program; gradation of findings), Nonconforming Product Procedure (input for risk management process; requirements for concession), Investigation of Returned Products (risk of contamination by returned product), Customer Complaint Handling Process (timelines; reporting criteria; input for risk management process), Corrective and Preventive Action (risk categories with associated action timelines; extension of target date)

It is also advised to include in the QM a Cross Reference Table with the EN ISO 13485:2016 requirements and for manufacturers that deliver to the US, to also include the FDA requirements for postmarketing safety reporting for combination products (21 CFR Part 4, Subpart B). That is, medical device reporting (21 CFR Part 803), corrections and removals (21 CFR Part 806) required for the combination’s product device part if device part is FDA-authorized or 21 CFR Part 314 Subpart 80 if the drug has received marketing authorization .

In the EU medicines vigilance applies for drug-device combination products.