4M Change Management in Medical Device Manufacturing Processes

Introduction

In the medical device industry, ensuring product quality and safety is the most critical challenge. Changes in manufacturing processes can directly impact the quality and performance of the final product, requiring strict management. Among these, the concept of “4M change management” is a core approach in managing manufacturing process changes.

In medical device regulations, the term “design change” is commonly used, but in practice, it often refers to changes in the manufacturing process, or “manufacturing changes.” In other words, the primary purpose of making design changes is, in many cases, to modify or optimize manufacturing methods. This article provides a detailed explanation of 4M change management in medical device manufacturing processes, taking this point into consideration.

What is 4M Change?

In medical device regulations, 4M change refers to changes in the following four elements of the manufacturing process:

Machine: Changes to manufacturing equipment, inspection devices, jigs, tools, etc.
Material: Changes to raw materials, components, auxiliary materials, packaging materials, etc.
Method: Changes to manufacturing methods, procedures, process parameters, work instructions, etc.
Measurement: Changes to inspection methods, acceptance criteria, measuring instruments, calibration methods, etc.

This differs significantly from the 4M (Man, Machine, Material, Method) referenced in general manufacturing industries. In general manufacturing, the human element (Man) is included as a target for 4M change. However, in medical device regulations, changes related to the human element (Man) are excluded from direct regulatory control, and instead, the Measurement element is emphasized.

These four elements are fundamental components of the manufacturing process, and changes to any of them may affect product quality and performance. Therefore, appropriate evaluation and management are necessary when 4M changes occur.

It should be noted that while changes to the human element (Man), such as operators, are not direct targets of 4M change in medical device regulations, appropriate education, training, and competency evaluation are required from a GMP (Good Manufacturing Practice) perspective. This is particularly important for special processes such as sterilization. Special processes refer to processes that can only be performed through sampling inspection because they involve destructive testing. In such processes, operator skills and training directly impact product quality.

Relationship Between Design Changes and Manufacturing Changes

In medical device regulations, the term “design change” is commonly used in the context of change management. This is an interesting characteristic. Many regulatory “design changes” actually refer to changes in the manufacturing process, or “manufacturing changes.”

The primary purpose of making design changes is often to modify manufacturing methods. For example, when changing a product’s material, it technically constitutes a change to design specifications, but the purpose is often manufacturing-related reasons such as manufacturing process optimization, cost reduction, or supply stabilization.

Importantly, in medical device regulations, except for changes to the human element (Man), changes to Machine, Material, Method, and Measurement must be managed by the design department. In other words, 4M change requests are typically submitted by the manufacturing department to the design department, reviewed and approved by the design department, subjected to a design review, and then implemented at the manufacturing site.

Thus, in the medical device industry, design and manufacturing are closely related, and 4M change management should be understood as a concept that encompasses both. It is important to understand that much of the content treated as design changes in applications and notifications to regulatory authorities corresponds to manufacturing changes from a 4M perspective.

Legal Basis and Regulatory Requirements for 4M Change Management

4M change management for medical devices is not merely a voluntary corporate initiative but is based on strict requirements from regulatory authorities in each country.

FDA Transition to QMSR (Effective February 2026)

On February 2, 2024, the U.S. Food and Drug Administration (FDA) amended the Quality System Regulation (21 CFR Part 820) and established the new Quality Management System Regulation (QMSR). This amended regulation will take effect on February 2, 2026. The QMSR significantly revises the content of the previous QSR (Quality System Regulation) by incorporating ISO 13485:2016 by reference.

Under the previous QSR, Design Controls were explicitly specified in Section 820.30, with design change control detailed in 820.30(i). Manufacturing process changes were specified in 820.70(b), and document change control was specified in 820.40(b), with reapproval by the original approver mandated.

After the transition to QMSR, these requirements will be integrated into Clause 7.3 (Design and Development) of ISO 13485:2016. Specifically, design change control will be governed by Section 7.3.9 “Control of design and development changes” of ISO 13485:2016. However, it is important to note that while FDA incorporates ISO 13485:2016 by reference, it also specifies additional requirements in 21 CFR Part 820, so it is not completely identical to ISO 13485:2016.

The major changes associated with the QMSR transition are as follows:

Item	QSR (Until February 1, 2026)	QMSR (From February 2, 2026)
Basic Structure	Completed within 21 CFR Part 820	Incorporates ISO 13485:2016 by reference + FDA additional requirements
Design Control Provisions	Detailed provisions in 820.30	Applies ISO 13485:2016 Clause 7.3
Design Change Control	820.30(i)	ISO 13485:2016 7.3.9 + FDA additional requirements
Manufacturing Process Changes	820.70(b)	ISO 13485:2016 7.5 + FDA additional requirements
Design History File	Explicitly specified in 820.30(j)	ISO 13485:2016 7.3.10 (Design and development files)

Importantly, the transition to QMSR does not fundamentally change the basic concepts and requirements of design control. FDA takes the position that QSR and ISO 13485:2016 are “substantially similar,” and QMSR aims to promote international harmonization. Therefore, for companies that have been properly implementing design control and 4M change management, the transition to QMSR should not pose a significant burden.

However, companies need to prepare for the effective date of February 2, 2026, by:

Conducting comparative analysis between existing QMS documents and ISO 13485:2016 requirements
Confirming that records created before QMSR implementation meet QMSR requirements
Updating procedures and forms as needed
Implementing training for responsible personnel

Requirements of ISO 13485:2016

ISO 13485:2016, the International Organization for Standardization (ISO) quality management system standard for medical devices, specifies design change control in Section 7.3.9 “Control of design and development changes” with the following elements:

Identification and documentation of changes
Evaluation of the impact of changes on function, performance, usability, safety, and regulatory requirements
Review, verification, validation (as appropriate), and approval of changes before implementation
Evaluation of the impact on existing component parts, products in process, or already delivered
Evaluation of the impact on risk management inputs and outputs
Evaluation of the impact on other product realization processes
Maintaining records of changes, reviews, and necessary actions

ISO 13485:2016 Clause 7.3.9 will also apply under FDA’s QMSR from February 2026 onward, further increasing its importance.

Status of Domestic Regulations in Japan

In Japan, the Ministerial Ordinance on Standards for Manufacturing Control and Quality Control of Medical Devices and In Vitro Diagnostic Reagents (QMS Ordinance) applies. The QMS Ordinance was revised in 2021, and the transitional period ended in March 2024. The current QMS Ordinance has been revised to improve consistency with ISO 13485:2016.

In the QMS Ordinance, design change control is specified in Article 36. Additionally, Article 55-3 specifies the obligation for marketing authorization holders to promptly report significant changes.

The Pharmaceuticals and Medical Devices Agency (PMDA) guidelines also clearly state that changes to 4M elements are treated as “design changes.” In the Japanese regulatory system, conformity with the QMS Ordinance is required at the time of approval application or change application, and conformity assessment is conducted.

The structure of the QMS Ordinance is as follows:

Chapter	Content	Relationship to ISO 13485:2016
Chapter 1 General Provisions	Scope of application, definitions, responsibilities of marketing authorization holders	Includes Japan-specific requirements
Chapter 2 Basic Requirements	General quality management system	Largely corresponds to ISO 13485:2016
Chapter 3 Additional Requirements	Requirements transferred from GQP Ordinance, etc.	Japan-specific requirements
Chapters 4-6	Additional requirements for special medical devices, etc.	Japan-specific requirements

Regarding design change control, Article 36 of the QMS Ordinance corresponds to Section 7.3.9 of ISO 13485:2016.

Organizational Structure for 4M Change Management

Appropriate organizational structure is essential for 4M change management in medical device manufacturing. The relationship between the design department and manufacturing department, and the role of the quality assurance department that oversees them, is particularly important.

Roles of Design and Manufacturing Departments

In medical device regulations, 4M change management (except for Man) is conducted through the following process:

Proposal of Change: In many cases, the manufacturing department proposes changes for purposes such as manufacturing process improvement, efficiency enhancement, cost reduction, or supply stabilization. Improvement proposals may also come from the quality assurance department or based on the CAPA (Corrective Action and Preventive Action) process.
Submission of Change Request: The manufacturing or quality assurance department submits a change request to the design department. The change request form includes the reason for the change, purpose, scope, and anticipated impacts.
Review by Design Department: The design department evaluates the impact of the proposed change on product design specifications, performance, safety, and effectiveness. This evaluation includes risk assessment (based on ISO 14971).
Design Review: The proposed change is evaluated through a formal design review process. Representatives from relevant departments such as design, manufacturing, quality assurance, and regulatory affairs participate in the design review.
Approval of Change: If the change is approved, the design department issues an Engineering Change Order (ECO). It is also determined whether the change requires notification to or approval application from regulatory authorities.
Implementation of Change: The manufacturing department implements the change based on the change instructions from the design department. Prior to implementation, process validation, equipment qualification (IQ/OQ/PQ), operator training, etc., are conducted as needed.
Verification After Change: The design and quality assurance departments cooperate to confirm that the product and process after the change meet requirements. Verification includes product inspection, process parameter monitoring, stability testing, etc.
Confirmation of Effectiveness and Follow-up: After implementing the change, the effectiveness of the change is monitored over a certain period to confirm that intended improvements are achieved and no unexpected adverse effects have occurred.

This system ensures that even changes related to the manufacturing process are appropriately managed within the framework of design control.

Main Responsibilities of Each Department

Main Responsibilities of Design Department:

Conducting change impact assessment (using methods such as FMEA: Failure Mode and Effects Analysis)
Conducting risk assessment (based on ISO 14971)
Developing verification and validation plans
Updating design specifications, drawings, procedures, etc.
Determining regulatory responses (such as determining the need for FDA 510(k), partial change approval applications, etc.)
Hosting design reviews and creating records
Updating Design History File (DHF)

Main Responsibilities of Manufacturing Department:

Creating and submitting change proposal documents
Creating change implementation plans
Implementing operator education and training
Conducting process validation
Conducting temporary process control after change implementation (such as implementing Statistical Process Control: SPC)
Updating manufacturing procedures and work instructions
Updating Device Master Record (DMR)
Reflecting change content in lot records (DHR: Device History Record)

Main Responsibilities of Quality Assurance Department:

Evaluating the validity of change requests
Participating in and approving risk assessments
Participating in design reviews
Determining the need for and implementing notifications/applications to regulatory authorities
Monitoring and improving the change management process
Confirming effectiveness after change implementation
Conducting audits and reviews
Coordinating with the CAPA process

Documentation and Traceability

In 4M change management, ensuring documentation and traceability is extremely important. Major documents include:

Change Management Documents:

Change Request Form: Request form from manufacturing to design department
Change Impact Assessment: Record of evaluation of impact of change on products and processes
Risk Assessment Records: Records of risk analysis and evaluation based on ISO 14971
Design Review Records: Minutes and decisions regarding change evaluation
Engineering Change Order (ECO): Instruction document from design to manufacturing department
Verification and Validation Protocols and Reports
Training Records

Major Documents Related to Product Realization:

Design History File (DHF): All records of design and development, including records of design changes. Corresponds to Section 7.3.10 “Design and development files” of ISO 13485:2016.
Device Master Record (DMR): Master document describing manufacturing process details. Corresponds to Section 4.2.3 “Medical device file” of ISO 13485:2016.
Device History Record (DHR): Manufacturing history record for each lot or each product manufactured.

By appropriately managing these documents, the entire process from the reason for the change, evaluation, approval, to implementation can be made traceable. Traceability is particularly important for the following purposes:

Responding to regulatory authority inspections
Responding to customer audits
Root cause investigation when product nonconformities occur
Identifying target lots when recalls occur
Data analysis for continuous improvement

Process of 4M Change Management

4M change management in medical device manufacturing is generally conducted through the following process. It should be noted that this process is often operated within the framework of regulatory “design changes.”

1. Application and Proposal of Change

Typically, the manufacturing department recognizes the need for a change and makes a change request to the design department. Changes may also be proposed from the quality assurance department or the CAPA process. At this stage, the following information is documented:

Purpose and reason for the change
Scope and detailed content of the change
Products, processes, and documents affected
Anticipated benefits and risks
Urgency and priority
Proposer and date

In many cases, even changes aimed at manufacturing process improvement are processed as design change requests.

2. Evaluation of Change

The design department, in cooperation with the quality assurance department, evaluates the impact of the change on product quality, safety, and effectiveness. Specifically, evaluation is conducted from the following perspectives:

Risk Analysis:

Conducting risk assessment based on ISO 14971
Conducting or updating FMEA (Failure Mode and Effects Analysis)
Conducting hazard analysis
Evaluating risk acceptability

Determination of Need for Validation:

Need for design verification
Need for design validation
Need for process validation
Need for cleaning validation (if applicable)
Need for sterilization validation (if applicable)

Impact on Regulatory Requirements:

Need to submit FDA 510(k) (for products for the U.S. market)
Need for partial change approval application (for products for the Japanese market)
Impact on CE conformity (for products for the European market)
Need for notifications to other regulatory authorities

Impact on Customers:

Need for customer notification
Need for customer approval
Need for labeling changes
Impact on usage methods

Impact on Design and Manufacturing:

Need for changes to design specifications
Need for changes to drawings
Need for changes to manufacturing procedures
Need for changes to inspection procedures
Need for equipment changes or additions
Need for supplier changes

Cost and Implementation Schedule:

Cost estimate for change implementation
Implementation schedule and expected completion date
Impact on inventory and transition plan

3. Design Review and Approval of Change

Based on the evaluation results, a decision is made on whether to implement the change through a formal design review process. In the design review, the following matters are deliberated:

Validity and necessity of the change
Validity of risk assessment results
Validity of verification and validation plans
Appropriateness of regulatory response
Feasibility of implementation plan
Appropriateness of resource allocation

If the change is approved as a result of the design review, the design department issues an Engineering Change Order (ECO) to the manufacturing department. Additionally, the quality assurance department makes a final confirmation of the need for notification to regulatory authorities and initiates notification procedures as needed.

4. Implementation of Change

The manufacturing department implements the actual change according to the change instructions from the design department. Depending on the type and scale of the change, the following activities are conducted:

Process Validation:

Installation Qualification (IQ)
Operational Qualification (OQ)
Performance Qualification (PQ)
Process validation (during initial production or continuous process verification)

Equipment Qualification:

For new equipment introduction: Conducting IQ/OQ/PQ
For changes to existing equipment: Conducting necessary qualifications based on impact assessment

Operator Training:

Implementing education and training on change content
Disseminating revised procedure content
Confirming understanding and creating training records

Transition Management:

Managing inventory of old specification products and new specification products
Identification by lot number or serial number
Ensuring traceability

Temporary Intensified Control:

Increasing inspection frequency immediately after change implementation
Strict monitoring of process parameters
Implementing Statistical Process Control (SPC)
100% inspection of initial production lot (as needed)

5. Verification After Change

The design and quality assurance departments cooperate to confirm that the product and process after the change meet requirements. Specifically, the following verifications are conducted:

Product Inspection:

Confirming conformity to design specifications
Conducting functional tests
Conducting performance tests
Conducting safety tests (as needed)

Process Confirmation:

Monitoring and recording process parameters
Calculating and evaluating process capability indices (Cp, Cpk)
Analyzing Statistical Process Control (SPC) data
Monitoring nonconformity rates

Long-term Evaluation:

Conducting stability testing (as needed)
Conducting durability testing (as needed)
Monitoring changes over time

Field Feedback:

Monitoring complaint data
Analyzing nonconformity reports
Evaluating post-market safety information

6. Documentation and Recording of Change

The content, evaluation results, implementation status, and verification results of the change are appropriately documented and recorded. The following documents are updated or created:

Update of Design Documents:

Design History File (DHF): Adding detailed records of design changes
Revision of design specifications
Revision of drawings
Update of risk management files

Update of Manufacturing Documents:

Device Master Record (DMR): Reflecting changes in manufacturing process
Revision of manufacturing procedures
Revision of work instructions
Revision of inspection procedures

Other Records:

Change management records: Records of the entire process from change request to implementation and verification
Design review minutes
Verification and validation reports
Training records
Records of notifications and approval applications to regulatory authorities

These records are important for future audits, inspections, or investigations when problems occur. Records must be retained for the retention period specified in 21 CFR Part 820 or QMSR (from February 2026), ISO 13485:2016, and QMS Ordinance.

7. Confirmation of Effectiveness and Continuous Improvement

After implementing the change, the effectiveness of the change is monitored over a certain period and linked to continuous improvement.

Measuring Effectiveness:

Evaluating whether the purpose of the change was achieved
Monitoring Key Performance Indicators (KPIs)
Confirming improvement in quality indicators
Confirming cost reduction effects (if applicable)

Monitoring Unexpected Impacts:

Presence or absence of impact on other processes
Presence or absence of new problems
Feedback from customers

Continuous Improvement:

Evaluating the effectiveness of the change management process itself
Documenting and sharing lessons learned
Applying to similar changes
Establishing best practices

Special Considerations in 4M Change Management

Supplier Change Management

When changing suppliers of raw materials or components, or when an existing supplier changes its manufacturing method, special attention is required.

Requirements for Supplier Changes:

Evaluation and approval of new suppliers
Equivalence evaluation of supplied materials and parts
Review of receiving inspection criteria
Strict inspection of initial lots
Ensuring supply chain traceability

Change Notifications from Suppliers: When a supplier changes its own manufacturing method, it has an obligation to notify the customer, the medical device manufacturer. Upon receiving this notification, the medical device manufacturer must conduct an impact assessment according to its own 4M change management process.

Emergency Changes

Even in emergency situations where there is no time to go through the normal change management process, the basic principles of change management apply.

Examples of Emergency Changes:

Use of alternative equipment due to sudden equipment failure
Use of alternative materials due to disruption in raw material supply
Emergency correction of safety-related issues

Management of Emergency Changes:

Pre-definition of approvers for emergency changes
Establishment of simplified approval process
Specification of provisional documentation methods
Completion of formal change management process after the fact
Verification of effectiveness and safety of emergency changes

Software Change Management

For medical devices that include software or manufacturing equipment, software changes are also subject to 4M change management.

Special Characteristics of Software Changes:

Compliance with IEC 62304 (Medical device software – Software lifecycle processes)
Importance of software version control
Need for regression testing
Impact assessment on cybersecurity
Confirmation of compatibility with legacy systems

Best Practices and Challenges in 4M Change Management

Best Practices

1. Proactive Change Management: Rather than making changes after problems occur, advance improvements predictively.

2. Risk-based Approach: Adjust the strictness of management according to the impact and magnitude of risk of the change.

3. Cross-functional Collaboration: Involve all relevant departments, including design, manufacturing, quality assurance, regulatory, and supply chain.

4. Digitalization and Digitization: Digitize the change management process to achieve paperless operations and efficiency. Utilize Quality Management System (QMS) software.

5. Data-driven Decision Making: Use statistical methods, trend analysis, and big data analysis to evaluate changes and make decisions based on data.

6. Continuous Training: Implement continuous education and training on change management processes and regulatory requirements.

Current Challenges and Future Prospects

Challenges:

Responding to increasingly complex regulatory requirements
Managing global supply chains
Balancing the complexity of change management processes with efficiency
Coexistence of digitalization and legacy systems
Securing and developing human resources

Future Prospects:

Change impact prediction and automation using AI/machine learning
Virtual verification using digital twin technology
Improved supply chain traceability through blockchain technology
Response to Industry 4.0 and Smart Manufacturing
Further progress in international regulatory harmonization (activities of IMDRF: International Medical Device Regulators Forum)

Conclusion

4M change management in medical device manufacturing is based on a strict process system founded on FDA QMSR (effective February 2026) and ISO 13485:2016. When changes occur in any of Machine, Material, Method, or Measurement, appropriate evaluation of their impact and implementation of necessary measures are required.

As an important point, while these changes are often treated as “design changes” in medical device regulations, it is important to understand that they are substantially aimed at changes in manufacturing processes. And 4M changes (except for Man) need to be managed primarily by the design department, implemented through a flow of change requests from the manufacturing department to the design department, review by the design department and design review, and change instructions from the design department to the manufacturing department.

The FDA QMSR implementation in February 2026 is an important milestone for the medical device industry. QMSR promotes international regulatory harmonization by incorporating ISO 13485:2016 by reference. Companies need to prepare for the transition to QMSR while confirming that their change management processes meet the requirements of ISO 13485:2016.

Through this collaboration system between the design and manufacturing departments, even changes in manufacturing processes are appropriately managed within the framework of design control, ensuring product quality and safety. Design changes and manufacturing changes should not be viewed as separate entities but as interrelated concepts.

Industry surveys report that companies implementing appropriate change management maintain product nonconformity rates below 0.05%. Future challenges include process optimization using AI/ML technology, virtual verification using digital twin technology, traceability improvement through blockchain technology, and promoting standardization toward international regulatory harmonization.

It should be noted that while the human element (Man) is not a direct target of 4M change in medical device regulations, the evolution of indirect quality assurance means such as appropriate education and training, competency evaluation, and the introduction of digital qualification certification systems under GMP requirements is expected. Particularly in special processes, operator competency directly affects product quality, so efforts to minimize the impact on manufacturing quality through continuous education, training, and competency management are essential.

The medical device industry bears the responsibility of providing products that directly relate to patient safety and health. 4M change management is an important means of fulfilling this responsibility and is a field that requires continuous improvement and evolution going forward.

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