The Atlantic KET Med (AKM) Project is bringing new, high tech, pilot production capacity to the EU Atlantic Area in support of SMEs and start-ups using the Key Enabling Technologies (KETs) to produce next generation medical devices.  Working closely with specific SMEs the Project is delivering  technical support via the pilot production network to enable key steps towards bringing a new product to market.  Further, the Project recognises that such technical support can be delivered in a way that is compliant with regulatory requirements, in other words, within the context of a Quality Management System (QMS).

At the point where medical products are to be used in human evaluations or clinical trials it is a legal requirement to have a QMS in place which meets the regulatory requirements.  Yet many SMEs which are focused on biomedical innovation fail to invest early enough in a Quality Management System.  Delaying QMS implementation until it is mandated by law often dictates elements of rework, and building a QMS from scratch is resource-intensive at a time when the business is focused on the demands of human clinical trials and associated fund raising.  Another significant consideration to bear in mind is that some aspects of new product development may be out-sourced to third-party suppliers. It is perhaps even more important that such external development is comprehensively recorded.

It is therefore best to get started early, so your company and technical partners begin thinking and acting in a GMP-compliant manner from the start.  To assist with this requirement the Atlantic KET Med Project has delivered a flexible, templated QMS, which is designed to meet the requirements of Good Manufacturing Practice (GMP) and ISO13485.  The GMP QMS meets the requirements for drug development, medical devices and combination therapies and crucially can be used by SMEs as a starting point to build their own dedicated QMS.  This article provides a general overview together with links to additional training materials and the QMS Procedures and Templates which are available to download.  But first let’s take a look at the basics.

What is Quality Management and why is it important?

To work in the Advanced Therapy Medical Product arena participants must comply with global regulations defined by national and regional regulatory authorities including the EU (EMA) and the US (FDA).  These regulations require projects to identify and comply with these regulations and conform to the appropriate recognised international standards.

Legally, the GMP Regulations do not apply to non-human use research, or feasibility activity.  But for products used on humans in clinical investigations or after approval, GMP is mandatory.  Developing a new medical device or advanced therapy is expensive in terms of costs and resources over many years, and as the product reaches maturity, the necessary regulatory approvals need to be sought.  The regulators will need to see evidence that the product has been developed in a way that is rigorous in terms of design, functionality and safety and that ethical considerations have been fully met.  The best way to encapsulate the development history of a product is to record the development steps, from the start, in a QMS.

Introduction to the AKM Quality Management System

An overview of the AKM QMS hierarchy is illustrated below.  The Atlantic KET Med Project has developed the top two layers of the triangle, the Quality Framework (which includes the Quality Manual and Document Control Procedure) and the Access Procedures and Templates to control the development steps. 

The blue layer is within the remit of whoever is delivering the actual technical support (either in-house or a third party) and constitutes the detailed Standard Operating Procedures, Work Instructions and Set-up Specifications etc needed for the specific equipment that will be used.

The bottom layer, Records, is fundamental to the Quality System as records provide the necessary traceability of actions, decisions, training etc that demonstrate compliance in action, when the Quality System is audited by a regulator.

  • The QMS has been designed to address the regulatory and quality requirements of medical device, pharmaceutical and advanced therapy medicinal products. 
  • The QMS creates a common way of working that bridges any system gaps within a collection of consortium and external members. 
  • The QMS achieves this through a framework of Procedures.  These Procedures are supplemented by a guideline that directs the work from start to finish through the application of a comprehensive series of Templates.  When followed they identify the work content of each individual project ensuring a rigorous, compliant approach is realised.
  • The QMS includes everything needed to control both development and manufacture and applies to both in-house resources and third-parties (for example the AKM technical consortium or indeed any other technical partner the SME chooses to work with).

The above concept translates into a hierarchy of documents as illustrated below

The Quality Manual is the top-level document. It defines the QMS scope, Organisational Structure, Management Responsibility, Resource Management and how products are developed, manufactured and released for their intended purpose.  The purpose of the Quality Manual is to ensure adequate oversight and control of all pharmaceutical and medical device regulated activities.  It is written to control technical development within Atlantic KET Med but can be easily adapted for an SME’s own needs.

The Access Procedure outlines how Project teams will define, plan and implement the technical development projects.  The documentation generated will culminate in a product file that may contain the device, pharmaceutical, ATMP or combination of these.  It could be adapted by an SME to manage third-party product development for instance if the work was being carried out by a research body that did not have a QMS of its own.

The 20 Templates set out in detail what must be recorded about the product and the project at each step defined in the Access Procedure.

The Document Control Procedure describes how documents are controlled within the QMS.  Documents may include procedures, plans, analysis and work instructions.  Documents are created with a unique identifier and have an Author, Reviewer and Approver and after approval a Document Owner is assigned to manage the future review of the document using change control after the first approval.

The flowchart below sets out clearly how the various Templates fit together to capture all the necessary information.

How has the AKM QMS worked in practice?

The Atlantic KET Med Project has developed a flexible, templated QMS as described above that with minor adaptations can be adopted by SMEs as an entry-level QMS for their own use going forwards.  The QMS has been used within the AKM Project itself to manage the technical support to ten SMEs which have engaged with the Consortium for in-depth technical support.  This engagement has very effectively ‘road-tested’ the QMS with real product development steps and it has worked well. 

Examples of procedures that have been developed in this way include:

Procedure TitleDescription
DMLS ProductionDirect Metal Laser Sintering preparation and production
Product Prototyping Using Additive ManufacturingProduct assessment and print method selection
3D Printing Using the Selected ProcessGeneric Printing Protocol
Data acquisition/ medical grade handling in a clinical environmentClinical protocol for diabetic foot ulcer imaging
Image AnalysisExtracting thermal readings from a FLIR (forward looking infrared) camera image for wound analysis
Rheometric analysis of a hydrogelDetermining viscosity to enable printing of a hydrogel
Peptigel printing trialPrinting a peptide crosslinking hydrogel using a polypico microdrop dispenser
Peptigel laser etching trialDetermination of parameters for laser material interaction with a peptide based hydrogel
Contamination conditions in a high TRL environmentDetermine bacterial and fungal contaminant load within a high TRL pilot production system capable of housing a 3D tissue printer
Multichamber biochip fabrication procedure.Production of a multi-chamber for 3D tissue-on-a-chip production
Bioprinting skin tissue modelsUsing a multi-chamber for skin tissue analogue on-a-chip
Bioprinting bone tumour modelsUsing a multi-chamber for a bone tissue analogue on-a-chip
Control of Non-conformities, corrective and preventive actionsEstablish a generalised system to control products  that do not conform to the specified requirement
Manufacturing TraceabilityDescribes the steps to be followed to ensure product identification and traceability from manufacture to delivery to the customer
Nanodevices – Organoid on-a-Chip Device Fabrication procedureMethodologies for the production and management processes of organoid based microfluidic devices
Risk Management on Medical DevicesMethodologies and responsibilities for the conduction of risk management processes associated to the production process of medical devices, according with ISO 14971:2019
Procedure for Control of Documented InformationDefine the methods and responsibilities concerning the creation of documents and the control of existing documented information, to ensure the availability of updated and approved documents
Medical Devices –  Risk ManagementMethodologies and responsibilities for the conduction of risk management processes associated with the production process of medical devices
Composite Materials Laser ProcessingWriting carbonised tracks in a composite material
Laser Pulse Energy optimisation for Materials processingOptimising laser energy for a particular application
Laser Frequency optimisation for Materials processingOptimising laser pulse frequency for a particular application
Laser Wavelength optimisation for Materials processingOptimising laser wavelength for a specific application
Integrating laser processing into existing production systemsIntegration of a processing laser into an existing production line
Graphene functionalisationFunctionalising a graphene sensor as a sensitive detector of DNA amplification
Testing EGFETs (extended-gate field-effect transistors)Testing a functionalised graphene sensor as a sensitive detector of DNA amplification

“Knowing where to start to implement a QMS is important for a small company like us especially as we don’t have a specialist person dedicated in this work. The QMS templates were very helpful to our company to initialize QMS implementation. With a QMS in place, we are more systematic which is important for us in product production and technical transfer.”       Phoenix DX

Takeaway messages

Implementing a GMP Quality System is challenging however:

  • It is a legal requirement when making medical products for human use.
  • It is best to get started early – so your company begins thinking and acting in a GMP-compliant manner.
  • The AKM GMP QMS has done all the ‘heavy lifting’  in terms of delivering a ready-to-use GMP Quality Management System for SMEs.
  • The Templates prompt for everything you need to record a technical procedure to advance a product towards the market.
  • That said, implementing a GMP QMS is complex and we recommend that any company  adopting the off-the-shelf AKM QMS also brings in some expert advice to ensure that the QMS is customised as needed during the implementation.

QMS Resources available to view and download

The Atlantic KET Med Project delivered three Webinar training courses addressing GMP in February and March 2021.  The training was delivered by Alastair Clarke, an expert in the field, and the webinars can be viewed at the links below.

Webinar:  Introduction to GMP – Key Concepts and Requirements   

A general overview of GMP   Download link for slides

Webinar:  Introduction to the AKM GMP QMS

Introduction to the AKM Quality Management System and GMP including the Quality Manual, SOPs (Access Procedure and Document Control) and Templates to define and control the product and process.     Download link for slides

Webinar:  Worked examples using the Atlantic KET Med GMP Template documents

A walk-through of the GMP Templates in depth.  Several example case studies are discussed, working through the completion of the various templates against project scenarios.   Download link for slides

Download the AKM Quality Management System

The Quality Manual, Procedures and Templates which constitute the Atlantic KET Med GMP QMS are also available to download.  With just minor adaptation, the QMS can be deployed into any SME wishing to implement GMP.      Download the QMS Procedures and Templates at link.

By Ian Mc Cabe, Diane Cresswell, and Richard Hall