Introduction
A manufacturing process is a series of steps and operations used to transform raw materials into finished products. It involves using equipment, reagents, tools, labour, and technology to produce items to specified standards and requirements. Manufacturing processes are formalised during the design transfer stage of design controls, which translates design outputs into products.
Medical device manufacturers must ensure their manufacturing processes incorporate the necessary controls to produce safe products that comply with all user, technical, and regulatory specifications. Process controls, verification and validation are essential to achieving this assurance:
- Process Controls provide the tools and methods to monitor and manage the manufacturing process.
- Process Verification uses these controls to check individual steps and components against specifications.
- Process Validation ensures that the entire process, supported by these controls, reliably produces products meeting all requirements.
Together, they create a robust system that ensures medical devices are manufactured to the highest safety and quality standards.
Production and process controls
Production and process controls are the mechanisms, procedures, and techniques used to regulate manufacturing. They are implemented to ensure that the manufacturing process consistently maintains product quality and prevents defects.
Process controls include monitoring, measuring, and adjusting process parameters to maintain product quality and compliance. Developing process controls involves a structured approach to identifying critical aspects of the manufacturing process and implementing measures to monitor and control them.
During design transfer, the detailed specifications and requirements of the product are communicated to the manufacturing team. Process controls are then established based on these specifications to ensure that the manufacturing process consistently produces products that meet the design criteria. Effective design transfer with robust process controls leads to a reliable, reproducible, and compliant manufacturing process, ensuring the production of high-quality medical devices. Key elements of process controls include:
Standard Operating Procedures (SOPs):
SOPs are detailed, written instructions for achieving uniformity in performing a specific function. Manufacturing process SOPs are included in medical device manufacturers’ quality management system (QMS). These documents provide detailed instructions for ensuring the manufacturing process is followed correctly and outline the necessary process controls. SOPs relevant to manufacturing are usually Level 2 or Level 3 documents, depending on the nature of the process. They are developed during design transfer based on the product design and the outputs of development activities.
In-Process Controls:
In-process controls are measures and checks performed during manufacturing to monitor and control the process parameters to ensure that the process operates within specified limits and that intermediate products meet defined criteria before moving to the next production stage. The purpose is to detect and correct deviations immediately to prevent defects from occurring in the final product. For example, it is common for raw materials and components to be tested upon arrival to ensure they meet predefined specifications before they are incorporated into products. In-process controls may also include monitoring controlled environments.
Quality Controls
Quality controls are the measures and tests conducted on the final product or at the end of the production process to ensure it meets all specified quality standards and regulatory requirements. These controls focus on the final output rather than the process itself. The purpose is to verify that the finished product meets all quality, safety, and regulatory standards and to identify and remove defective products from the supply chain.
Process verification and validation
As part of design transfer, process verification and validation demonstrate that the manufacturing process, supported by the implemented controls, can consistently produce products meeting the design specifications. In medical device manufacturing, process verification and validation are two crucial steps to ensure that the devices are safe and effective. They serve different purposes and occur at various stages of the manufacturing process.
Process verification confirms that manufacturing can produce products that meet specified requirements under controlled conditions. The primary goal is to ensure that the process, when followed correctly, consistently delivers results within predetermined specifications. A verified process demonstrates that it can consistently operate within established parameters and produce conforming products.
Process verification occurs during the development of the manufacturing process and periodically during production to ensure ongoing compliance.
Verification focuses on confirming that each step in the process meets defined standards and ensuring that the process inputs and outputs are within acceptable limits. Typical verification activities may include:
- Conducting tests on samples from the production process
- Using statistical methods to assess process capability
- Inspecting and calibrating equipment
- Reviewing documentation and records
Verification is documented through inspection reports, test results, and calibration records.
Process validation is the documented evidence that a process consistently produces a product meeting its predetermined specifications and quality attributes. The primary goal is to establish and provide objective evidence that the manufacturing process, operating within established parameters, can perform effectively and reproducibly to produce a product that meets its specifications and quality attributes. A validated process provides documented evidence that the process will consistently deliver products that meet all specifications and quality requirements.
Validation focuses on the production process and the end product to ensure long-term stability and capability. It examines the process under real-world production conditions and variability. Typical activities in validation include:
- Conducting process design studies
- Performing installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ)
- Running process validation batches to demonstrate consistency
- Collecting and analysing data from the process to demonstrate control
Validation activities occur at several stages of manufacturing:
- Before releasing a new product to the market (pre-market validation)
- Whenever there are significant changes to the process or product
- Periodically, as part of ongoing quality assurance
Validation documentation often requires comprehensive studies, protocols, and reports documenting the entire validation effort.
Verification and validation activities should be based on sound scientific principles and use risk-based approaches and statistical analysis techniques, with clear acceptance criteria defined a priori.
Process validation studies
Once the design is finalised, manufacturing processes must undergo rigorous validation to ensure consistency, reliability, and regulatory compliance. Process validation demonstrates that manufacturing processes consistently produce products that meet predetermined specifications and quality attributes. Validation is performed when verification is inappropriate or unfeasible for a particular process step and to evaluate the entire process.
Process qualification studies involve executing the manufacturing process under normal operating conditions to demonstrate its reproducibility and capability to produce products that consistently meet quality requirements. This typically involves conducting process performance qualification (PPQ) studies, where process parameters are systematically varied to assess their impact on product quality:
- Installation Qualification (IQ): Verifying that equipment and installations meet the required specifications.
- Operational Qualification (OQ): Confirming that equipment and processes operate correctly under defined conditions.
- Performance Qualification (PQ): Demonstrating that processes perform effectively and reproducibly in real-world conditions.
Process validation protocols must be designed, executed and documented to ensure compliance with regulatory requirements and industry best practices.
Resources
Regulatory Guidance
United States of America (USA):
International Standards
- ISO 13485:2016 – Quality Management Systems for Medical Devices
- ISO 14971:2019 – Risk Management for Medical Devices
- ISO/TR 24971 – Guidance on Applying ISO 14971
- IEC 60601 & IEC 62304 *(search required for specific documents)
Manufacturing Best Practices and Toolkits
Acceptance Criteria: The predefined standards and specifications that a device must meet during testing and evaluation to be deemed suitable for its intended use and to comply with regulatory requirements.
Adverse Event: Any untoward medical occurrence in a patient or clinical investigation subject administered a medical device, which does not necessarily have to have a causal relationship with this treatment.
Audit: A systematic, independent examination of a manufacturer’s processes, procedures, and products to ensure compliance with regulatory standards and quality requirements. Also see Internal Audit.
Authorised Representative: A natural or legal person appointed by a manufacturer to act on their behalf in carrying out specific tasks related to conformity assessment and regulatory compliance.
Biomedical Engineer and Technician: Personnel that maintain and repair medical devices to ensure their proper functionality.
Change Control: The systematic process of managing and documenting modifications to a device or its manufacturing process to ensure that all changes are assessed, approved, implemented, and tracked in compliance with regulatory standards and quality management systems.
Cleanroom: A controlled environment with a low level of pollutants, such as dust, airborne microbes, aerosol particles, and chemical vapours used in manufacturing and scientific research.
Compliance: Adherence to regulations, standards, and guidelines set forth by regulatory authorities.
Controlled Environment: A workspace where environmental conditions such as temperature, humidity, and particulate levels are regulated to ensure product quality and process integrity.
Corrective Maintenance: The process of diagnosing and repairing faults or failures to restore the device to its proper functioning condition. Design Transfer: The process of transitioning a product’s design from development and manufacturing into production while ensuring all specifications and requirements are met.
Distributor: A natural or legal person in the supply chain, other than the manufacturer or importer, who makes a medical device available on the market.
Economic Operator: Any person or entity engaged in the production, distribution, import, export, or supply of medical devices.
Enterprise Resource Planning (ERP) Systems: Integrated software platforms that manage and automate core business processes across an organisation, facilitating the flow of information and improving efficiency.
Equipment Management: The systematic process of acquiring, maintaining, calibrating, and retiring equipment to ensure it remains suitable for its intended use and complies with quality and regulatory requirements.
FDA Approval: The process by which the U.S. Food and Drug Administration (FDA) officially recognises that a medical device is safe and effective for its intended use.
Good Manufacturing Practices (GMP): Regulations that require manufacturers to ensure products are consistently produced and controlled according to quality standards.
International Medical Device Regulators Forum (IMDRF): A global regulatory collaboration focused on harmonising medical device regulations to facilitate patient access to safe and effective devices. This organisation was formerly the Global Harmonization Task Force (GHTF).
ISO 13485: An international standard that specifies requirements for a quality management system (QMS) specific to the medical devices industry.
ISO 14971: An international standard for the application of risk management to medical devices.
Lifecycle Management: The process of overseeing a product, service, or system from its initial development through its growth, maturity, and eventual decline or disposal, ensuring optimal performance and resource utilisation at each stage.
Manufacturer: A legal entity that designs, produces, assembles, or labels a medical device with the intention of placing it on the market.
Notified Body (NB): An organisation designated by a country authority to assess the conformity of certain products before being placed on the market, ensuring they meet applicable regulatory requirements and standards.
Process Controls: The tools and methods to monitor and manage medical device manufacturing processes.
Process Performance Qualification (PPQ) Studies:
-
Installation Qualification (IQ): Verifying that equipment and installations meet the required specifications.
-
Operational Qualification (OQ): Confirming that equipment and processes operate correctly under defined conditions.
-
Performance Qualification (PQ): Demonstrating that processes perform effectively and reproducibly in real-world conditions.
Process Verification: Uses process controls to check individual manufacturing steps and components against specifications.
Process Validation: Ensures that the entire manufacturing process, supported by process controls, reliably produces products meeting all requirements.
Quality Management System (QMS): A formalised system that documents the structure, responsibilities, and procedures required to achieve effective quality management.
Quality Management System Regulation (QMSR): The U.S. Food and Drug Administration (FDA) regulation that aligns its medical device quality system requirements with ISO 13485:2016 to streamline global compliance and enhance device safety and effectiveness.
Quality System Regulation (QSR): Outlined in 21 CFR Part 820, the U.S. Food and Drug Administration (FDA) framework requires medical device manufacturers to establish and maintain a quality management system to ensure their products consistently meet applicable requirements and specifications.
Record: A documented piece of evidence detailing activities, decisions, or results, created and maintained to demonstrate compliance with regulatory requirements and quality management standards.
Regulation: The rules, laws, standards, and requirements set by regulatory authorities to ensure the safety, efficacy, and quality of devices intended for medical use.
Regulatory Authority: An official body overseeing and enforcing laws, regulations, and standards within a specific industry or sector to ensure compliance and protect public interests. Also known as a Regulatory Authority. Also see Competent Authority and Notified Body.
Risk: The combination of the probability of occurrence of harm and the severity of that harm.
Risk Analysis: The systematic use of available information to identify hazards and to estimate the risk.
Risk Assessment: The overall process comprising risk analysis and risk evaluation.
Risk Evaluation: The process of comparing the estimated risk against given risk criteria to determine the acceptability of the risk.
Risk Management (RM): The systematic application of management policies, procedures, and practices to the tasks of analysing, evaluating, controlling, and monitoring risk.
Safety: The condition of being protected from or unlikely to cause danger, risk, or injury.
Software Validation: The documented process of ensuring that software performs as intended for its specific use within a regulated environment.
Standard: A document that provides guidance, requirements, or specifications established by regulatory bodies, industry organisations, or international consensus groups.
Supplier: An entity or organisation that provides materials, components, or finished products used in the manufacturing, assembly, or distribution of medical devices.
Supplier Management: Overseeing and controlling the relationships and activities with external suppliers to ensure the quality, reliability, and regulatory compliance of sourced materials and components.
Supply Chain: Activities, processes, and entities involved in the sourcing, manufacturing, distribution, and logistics management of these devices from suppliers to end-users.
Traceability Matrix: A document that maps and links requirements throughout the development lifecycle, ensuring that each requirement is tested and validated, thereby demonstrating compliance with regulatory standards.
User: Any individual who operates or interacts with a medical device, including healthcare professionals, patients, and caregivers.
User Requirements: The requirements and preferences of the intended users, which must be considered and addressed in the device design. Also known as User Needs or Customer Specifications.
Validation: Confirmation by examining and providing objective evidence that the particular requirements for a specific intended use can be consistently fulfilled.