Validation in Paperless and Digital Manufacturing Systems

The pharmaceutical sector is experiencing great change as it is evolving from an older, conventional method of manufacturing using paper means to a newer, modern method of manufacturing using digital or paperless means. This transformation is happening due to several reasons: improved efficiency, real-time access to data, improved compliance and reduction of errors caused by humans.

Digital transformation does not come without its responsibilities; one of these responsibilities is validation. Validation means to verify that electronic systems (i.e. computerized) are working as intended and that the data produced by the electronic system is valid under Good Manufacturing Practices (GMP).

Regulators such as the US FDA and the EU EMA require that any type of Computer Systems (such as computerized manufacturing systems) used throughout the pharmaceutical industry must be validated. Validation will ensure that the system has the ability to produce data with accuracy, reliability and compliant with Good Manufacturing Practices.

The purpose of this article is to provide a detailed summary of validation processes for the paperless and digital manufacturing systems, therefore, you will find valuable information on the following topics: Regulatory Expectations, Validation Approach and Best Practices.

What is a Digital or Paperless Manufacturing System?

A digital or paperless manufacturing system uses electronic methods of managing, recording and controlling the processes involved in the manufacture of goods. Rather than relying on traditional paperwork or written documentation, manufacturers are switching to electronic forms of communication and recordkeeping to improve the efficiency of their manufacturing processes. Examples of digital or paperless manufacturing systems are:

• Electronic Batch Records (EBR)
• Manufacturing Execution Systems (MES)
• Electronic Quality Management Systems (eQMS)
• Laboratory Information Management Systems (LIMS)
• Supervisory Control and Data Acquisition (SCADA)

There are many advantages to using digital or paperless manufacturing systems, including improved efficiency and the ability to monitor production activities in real-time.

Why Validation is Critical in Digital Systems

Validation of computerized systems ensures the consistent performance of the computerized system per the specifications for that system.
Reasons why Validation is Important:

• Validation supports the accuracy and reliability of data.
• It eliminates the opportunity for tampering with or losing data.
• Validation helps maintain a state of compliance with relevant regulatory requirements.
• Validation supports manufacturing quality and patient safety.

Failures to validate digital and paperless manufacturing systems can produce risk. For example, the production of incorrect data, unauthorized access to data or failure to operate correctly.

Regulatory Requirements for Validation of Digital Systems

Validation of computerized systems (that are automated) by pharmaceutical related industries must meet multiple regulatory requirements.

1. 21 CFR Part 11

It focuses on electronic records and electronic signatures.
Key aspects included:
- Secure access controls to users
- Audit trails
- Electronic signatures
- Data integrity

2. Good Manufacturing Practices

Per GMP requirements, all systems affecting product quality must be validated and controlled.

3. GAMP 5

Utilizes a risk-based method for safety and validation of computerized systems.
The five GAMP areas stressed within it include:
- Lifecycle method
- Risk management
- Supplier involvement

4. ICH Q9 Quality Risk Management

Supports a risk-based method of validating systems through quality risk management principles.

Types of Digital System Validation

1. Computer-Based Systems Validation (CBVS)

This validation verifies that a computerized system fulfills its intended use.
This validation consists of:
- Requirements documentation
- Testing of functionalities
- Documenting the aforementioned items

2. Software Validation

Validating the electronic application utilized for manufacturing and quality.

3. Infrastructure Qualification

Validating the infrastructure of hardware and IT system networks.
This includes:
- Servers
- Databases
- Network security

4. Data Integrity Validation

Validation of data integrity with ALCOA+ principles:
- Attributable
- Legible
- Contemporaneous
- Original
- Accurate

Lifecycle Approach to Validation

Validation should be conducted according to a lifecycle approach recommended in GAMP 5.

1. Planning Phase

- Define the scope of the new system
- Determine what regulations apply to the new system
- Identify potential risks associated with the new system
- Create validation plan

2. Design Phase

- Create User Requirements Specification (URS)
- Create Functional Specification (FS)
- Design System Architecture

3. Testing Phase

Testing is done to validate that the system works as intended.
Testing includes:
- Installation Qualification (IQ)
- Operational Qualification (OQ)
- Performance Qualification (PQ)

4. Implementation Phase

Implementing the system includes the following functions:
- Deploy the new system
- Train end users on how to use the product
- Provide users with documentation

5. Maintenance Phase

- Implement change control procedures
- Review the system on a periodic basis
- Upgrade the system as necessary

Key Validation Requirements for Digital Systems

1. User Access Control

A system must provide a user with:

• A unique user identification
• Password protection
• Role-based access

This protects against the unauthorized access of data.

2. Audit Trails

Audit trails are the records of an event:

• Data is created or changed in an electronic format
• A user has the ability to interact with a system
• An administrator alters the system

The audit trail must be secured and not altered in any way.

3. Electronic Signatures

The electronic signature must:

• Be unique to each person signing it
• Have the same legal meaning as a written signature
• Be secure and auditable.

Electronic signatures improve the accountability of the digital system users.

4. Data Backup and Recovery

The system must comply with:

• Regular data backups
• Disaster recovery plans
• Data recovery processes

This will assure the integrity and availability of the data.

5. System Security

The system must include:

• Firewalls
• Encryption
• Antivirus

These methods may protect the system from cyber-attacks.

Challenges in Validating Digital Systems

There are a number of challenges associated with the validation of digital systems:

• Complex architecture of systems
• Interfacing with multiple systems
• Frequent software changes
• Cybersecurity threats
• High volumes of data

The structured and risk-based approach is required when addressing the above-mentioned digital system challenges.

Best Practices for Validating Systems

1. Use a Risk Based Approach

Focus validation resources on those systems that are critical to product quality.

2. Task Cross-Functional Teams with Validation Efforts

It includes:
- Quality Assurance
- Information Technology (IT)
- Production
- Validation Experts

3. Make Sure Documentation is Complete

Documentation must include:
- Validation Plans
- Test Protocols
- Validation Reports
- Change Control Records

4. Train Employees

Educate users on:
- How to use your system as it was intended
- What your system requires for compliance
- The importance of providing integrity of data

5. Review the System on a Regular Basis

Regularly reviewing your system will provide:
- Continued compliance with your company's system
- Identification of any gaps in the system
- Opportunities for improvement in the company’s systems

Benefits of Paperless Manufacturing Systems

1) Improved Productivity

- Faster entry and collection of data
- Less paper document storage and retrieval

2) Improved Data Integrity

- Reduced potential for error through manual handling
- Assured ability to trace data

3) Real-Time Monitoring

- Instant access to process data
- Ability to quickly respond to changing situations

4) Compliance with Regulations

- Simplified audit preparation
- Improved accuracy of documents

Future Trends in Digital Validation

Some examples of future technology are:

• Validation of Cloud-based systems
• Artificial Intelligence will be used in validation
• Process for validating continuously
• Automation of testing and validation methods

These advancements will continue to create increased efficiencies and greater compliance.

For pharmaceutical companies today, this involves validation of their computerized systems used for manufacturing, as well as for the manufacturing processes themselves.

As the pharmaceutical industry shifts to a more digital environment, there are increasing challenges to verify the reliability of digital systems, to maintain the integrity of data contained in those systems and to meet all regulatory requirements.

By using a Life Cycle approach, following risk-based methodologies and conforming to standards such as 21 CFR Part 11 and GAMP 5, companies will successfully validate the digital systems they use for manufacturing.

A validated digital system accomplishes more than just meeting compliance; it will also contribute to greater efficiency, more accurate and complete records and improved quality of products produced by manufacturers. Thus, the digital systems that manufacturers use to produce their products have become the "cornerstone" of modern pharmaceutical manufacturing.

Frequently Asked Questions (FAQs) on Digital Manufacturing Systems

Q1. What is the meaning of validation in digital manufacturing systems?

Answer: Validation refers to the process of making sure that the computer controlled manufacturing systems operate according to their intended purpose and meet any applicable regulatory compliance requirements.

Q2. What is Computer System Validation (CSV)?

Answer: CSV indicates the validation of the computerized software and supporting systems that are employed within the systems that support actual pharmaceutical activities.

Q3. What is 21 CFR Part 11?

Answer: This regulation defines standards for electronic records & signatures when used together as part of electronic systems.

Q4. Why is data integrity important?

Answer: Integrity of data is the assurance that your information is reliable, trustworthy and contains all data necessary for a reasonable researcher would need to complete their submitted work.

Q5. What does GAMP 5 mean?

Answer: GAMP 5 is a guideline that provides a framework for validating systems.

Q6. What is an audit trail?

Answer: Audit trails are records that track every transaction made within an electronic format.

Q7. What does lifecycle validation mean?

Answer: Lifecycle validation consists of all steps in the process of executing a new computer-based system, from planning through design through maintenance through to decommissioning.

Q8. What are the benefits of using a paperless system?

Answer: A paperless solution will allow for significant improvement in overall efficiencies and quality & accuracy of information or data collected.

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