Drug production takes place in pharmaceutical manufacturing plants, which serve as the heart of drug production. They take raw materials and complex formulations and turn them into safe, effective and high-quality medicines for patients worldwide.
Pharmaceutical manufacturing facilities once designed to meet current Good Manufacturing Practices (GMP) standards (that were compliant with regulatory authorities) may no longer function in the most efficient way and be fully compliant with the current GMPs because regulatory authorities continue to change requirements over time and as technology has evolved since originally constructing the facility. Updating pharmaceutical manufacturing facilities is about more than just making them modernized facilities, it is about ensuring operational excellence, quality and safety of pharmaceutical products.
This article will discuss practical methods for updating pharmaceutical manufacturing facilities, including but not limited to layout optimization, equipment upgrades, upgrades in automation, data integrity and sustainability.
The comprehensive facility assessment should address:
1. Performance relative to current GMP guidelines - FDA, EU, WHO and Schedule M.
2. Inefficiencies in workflow resulting in increased downtime or potential for contamination.
3. Equipment performance data and calibration data.
4. Environmental control system data, HVAC, temperature and humidity.
5. Flow of individuals and materials through the facility.
Using a GMP audit checklist as a reference, or having a third party perform a complete Assessment will help to identify all of the areas requiring corrective and preventive action.
After you have determined the current condition of the facility, you will then be able to develop the Action Plans based on the type of risk and the impact that regulatory requirements will have on the products produced at your facility.
Materials: The movement of raw materials, intermediates and finished products must be continuous, following a single pathway of travel with no interchange of transferred materials.
Clean room layouts should conform to ISO 14644 cleanroom standard and Schedule M requirements and prevent contamination, promote preventive maintenance of clean rooms through ease of cleaning.
- Automated granulators (granulation), tablet presses (tablet making) & capsule fillers (capsule making) with greater accuracy.
- Use clean-in-place (CIP) systems & steam in-place (SIP) systems for validated cleaning.
- Use SCADA systems & PLC control systems to provide real time monitoring of production.
Automation will improve the consistency of products, reduce operator errors and strengthen the integrity of data.
- Upgrade to energy efficient (99%) air handling units (AHU) & filter them through HEPA & verified.
- Validate & monitor the temperature, pressure differentials and relative humidity.
- Ensure oil-free compressed air & properly sanitized water systems.
Reliable utilities are the foundation of all facility compliance and repeatable process.
Here are some key upgrades that can be made to EM systems:
- Upgrading EM systems to include real-time particle monitoring systems.
- Establishing a schedule of integrity testing for HEPA filters (DOP/PAO).
- Maintaining pressure differentials between clean zones.
- Increasing air changes per hour (ACPH) for sterile areas to comply with iso classification of cleanrooms.
- Utilizing microbiological monitoring devices such as (settled plates, air samplers, contact plates).
Creating a routine trend analysis of EM to prevent conditions of non-conformance. Construction of cleanroom surfaces to include smooth, non-porous surfaces and resilient to cleaning chemicals.
- Integrating electronic batch records into your QMS that is a digital form of documentation.
- Conducting regular internal audits that ensures the compliance of QMS with regulatory requirements.
- Updating standard operating procedures (SOPs) and providing training to employees on updation and data integrity.
- Using risk-based quality management (ICH Q9) to make improvements to processes.
A data-driven QMS not only improves compliance but allows for continual improvement with the implementation of corrective and preventive actions (CAPA), tracking of deviations and through the implementation of change control.
Some examples of modernizing using digital technology include:
A. Manufacturing Execution Systems (MES) – where both production and quality aspects of your manufacturing process are integrated.
B. SCADA – where real-time views are provided for Utilities and other important operating metrics.
C. Laboratory Information Management System (LIMS) – where sample tracking and testing processes have been automatically digitized.
D. Electronic Batch Record (EBR) – where all documentation related to manufacturing process can be traced and completed electronically.
Automation will support compliance with FDA regulation 21 CFR Part 11. It includes electronic signatures, audit trails and secure storage for data.
a. Good documentation practices (GDP)
b. Cleanroom gowning and behavior
c. Equipment operating and cleaning
d. Control of contamination
e. Deviation and CAPA handling.
Periodic requalification programs and comprehensive training records must be established for personnel.
The hygiene control actions like proper gowning, handwashing and restricted access to the critical area are important in maintaining the hygiene in the facility.
Validated cleaning procedures will replace manual cleaning for:
- Automate repeatable cleaning processes by using cleaning in place and sterilization in place systems.
- Ultrasonic cleaning machines for small parts and tools.
- Use of rotary sanitizers like quaternary ammonium, alcohol, hydrogen peroxide to reduce the chances of developing resistance to microbial agents.
Validation of cleaning processes must be performed according to Good Manufacturing Practice (GMP) as per manufacturer's recommendation and established industry standards to demonstrate effective cleaning including removal of all residues, detergents and microorganisms.
Following are some ways to improve sustainability:
- Install energy recovery systems into HVAC systems.
- Use LED light bulbs equipped with occupancy sensors.
- Recycle purified water used for non-critical cleaning processes.
- Optimize airflow to reduce HVAC system load.
- Apply green building design principles to all new projects.
Sustainably manufactured goods build brand image and save cost for the manufacturer.
- Validation includes validation of equipment qualification (IQ, OQ and PQ), process validation and cleaning validation.
- Calibration involves routine calibration of your instruments for accuracy and traceability purposes.
- Requalifying HVAC, utilities and equipment that are critical to production should occur on a regular basis.
Your validation and calibration records will be one of the first documents reviewed during an inspection by the FDA or WHO.
To improve and strengthen documentation in your company, you should:
- Implement electronic data management systems.
- Utilize templates with controlled document numbers and version control.
- Document all activities at the time they occur.
- Audit trails must be able identify the person who performed, reviewed and approved each step of the process.
All paper and electronic data must meet the requirements of ALCOA+ that includes Attributable, Legible, Contemporary, Original, Accurate, Complete, Consistent, Enduring and Accessible.
Each department should embrace the mindset of quality first. This will improve the ability to sustain improvements over time.
- Encourage open lines of communication between the production and quality teams.
- Develop a system that maintains a root cause analysis for every aberration.
- Establish a process for verifying CAPA effectiveness.
- Conduct regular review of continuous improvement by management.
By implementing continuous improvement, a company progresses from being in compliance to being recognized as a world class organization. Continuous improvement of the pharmaceutical manufacturing facility is an ongoing process, not simply a one-time effort.
Specifically, focusing on the facility layout, environmental control, automated process and sustainable practices helps attain consistent quality and be prepared for audits from any country's regulatory agencies.
Ultimately, the more effective the manufacturing facility, the more effective the drugs. Patients will have more confidence in the drugs manufactured at this facility and it should be the ultimate goal of any pharmaceutical manufacturer.
Pharmaceutical manufacturing facilities once designed to meet current Good Manufacturing Practices (GMP) standards (that were compliant with regulatory authorities) may no longer function in the most efficient way and be fully compliant with the current GMPs because regulatory authorities continue to change requirements over time and as technology has evolved since originally constructing the facility. Updating pharmaceutical manufacturing facilities is about more than just making them modernized facilities, it is about ensuring operational excellence, quality and safety of pharmaceutical products.
1. Review the Current Condition of the Facility
You need to first identify what the facility currently has for improvement.The comprehensive facility assessment should address:
1. Performance relative to current GMP guidelines - FDA, EU, WHO and Schedule M.
2. Inefficiencies in workflow resulting in increased downtime or potential for contamination.
3. Equipment performance data and calibration data.
4. Environmental control system data, HVAC, temperature and humidity.
5. Flow of individuals and materials through the facility.
Using a GMP audit checklist as a reference, or having a third party perform a complete Assessment will help to identify all of the areas requiring corrective and preventive action.
After you have determined the current condition of the facility, you will then be able to develop the Action Plans based on the type of risk and the impact that regulatory requirements will have on the products produced at your facility.
2. Improving Facility Layout for Compliance and Efficiency
Cross-contamination and suboptimal workflow efficiencies in cleanrooms are commonly caused by poor layout design. To enhance cleanliness and workflow efficiency through better layout, cleanroom layouts must be restructured to direct the flow of both people and products (materials) without any backtracking.A. Unidirectional Flow
People: Gowning and gowning transfer will occur at separate entry points from the exit points of all cleanrooms. Air lock access between areas must also occur to separate clean areas from unclean areas.Materials: The movement of raw materials, intermediates and finished products must be continuous, following a single pathway of travel with no interchange of transferred materials.
B. Assignment of Dedicated Areas
Areas for dispensing, compounding, granulation and packaging must be separated.C. Space Optimization
Ensure adequate use of all available space without mess. Assigning dedicated area to reduce the chances of cross-contamination and helps in maintaining a clean workspace.Clean room layouts should conform to ISO 14644 cleanroom standard and Schedule M requirements and prevent contamination, promote preventive maintenance of clean rooms through ease of cleaning.
3. Upgrading Equipment & Utilities
A. Equipment Modernization
Purchase GMP compliant-automated equipment which will eliminate the need for manual handling. For example:- Automated granulators (granulation), tablet presses (tablet making) & capsule fillers (capsule making) with greater accuracy.
- Use clean-in-place (CIP) systems & steam in-place (SIP) systems for validated cleaning.
- Use SCADA systems & PLC control systems to provide real time monitoring of production.
Automation will improve the consistency of products, reduce operator errors and strengthen the integrity of data.
B. Utility Systems
The critical utilities are HVAC, purified water systems, WFI and compressed air systems. The critical utilities must be validated, monitored and maintained.- Upgrade to energy efficient (99%) air handling units (AHU) & filter them through HEPA & verified.
- Validate & monitor the temperature, pressure differentials and relative humidity.
- Ensure oil-free compressed air & properly sanitized water systems.
Reliable utilities are the foundation of all facility compliance and repeatable process.
4. Improve Environmental Monitoring & Cleanroom Controls
The primary focus of Good Manufacturing Practices (GMP) compliance is to control contamination and the best way to achieve this is to improve environmental monitoring (EM) systems to protect the integrity of the cleanroom.Here are some key upgrades that can be made to EM systems:
- Upgrading EM systems to include real-time particle monitoring systems.
- Establishing a schedule of integrity testing for HEPA filters (DOP/PAO).
- Maintaining pressure differentials between clean zones.
- Increasing air changes per hour (ACPH) for sterile areas to comply with iso classification of cleanrooms.
- Utilizing microbiological monitoring devices such as (settled plates, air samplers, contact plates).
Creating a routine trend analysis of EM to prevent conditions of non-conformance. Construction of cleanroom surfaces to include smooth, non-porous surfaces and resilient to cleaning chemicals.
5. Improve Quality Management SystemMS
The quality management system (QMS) of your business will make sure everything produced by your business is monitored and controlled. You can improve the effectiveness of your QMS by:- Integrating electronic batch records into your QMS that is a digital form of documentation.
- Conducting regular internal audits that ensures the compliance of QMS with regulatory requirements.
- Updating standard operating procedures (SOPs) and providing training to employees on updation and data integrity.
- Using risk-based quality management (ICH Q9) to make improvements to processes.
A data-driven QMS not only improves compliance but allows for continual improvement with the implementation of corrective and preventive actions (CAPA), tracking of deviations and through the implementation of change control.
6. Create Digital and Automated Processes
A lot of pharmaceutical companies are using automated processes as part of the digital transformation to help reduce the number of times people need to perform their jobs manually, remove the chances of mistakes by people and enhance the integrity of data.Some examples of modernizing using digital technology include:
A. Manufacturing Execution Systems (MES) – where both production and quality aspects of your manufacturing process are integrated.
B. SCADA – where real-time views are provided for Utilities and other important operating metrics.
C. Laboratory Information Management System (LIMS) – where sample tracking and testing processes have been automatically digitized.
D. Electronic Batch Record (EBR) – where all documentation related to manufacturing process can be traced and completed electronically.
Automation will support compliance with FDA regulation 21 CFR Part 11. It includes electronic signatures, audit trails and secure storage for data.
7. Training and Personnel Hygiene
A highly advanced facility without skilled disciplined personnel will fail. Setting up regular training and competency assessments, so personnel know what is expected per GMP and what the hygiene practices are. Training should include:a. Good documentation practices (GDP)
b. Cleanroom gowning and behavior
c. Equipment operating and cleaning
d. Control of contamination
e. Deviation and CAPA handling.
Periodic requalification programs and comprehensive training records must be established for personnel.
The hygiene control actions like proper gowning, handwashing and restricted access to the critical area are important in maintaining the hygiene in the facility.
8. Enhance Cleaning and Sanitation Processes
A company with an improved facility also has better cleaning and sanitization practices.Validated cleaning procedures will replace manual cleaning for:
- Automate repeatable cleaning processes by using cleaning in place and sterilization in place systems.
- Ultrasonic cleaning machines for small parts and tools.
- Use of rotary sanitizers like quaternary ammonium, alcohol, hydrogen peroxide to reduce the chances of developing resistance to microbial agents.
Validation of cleaning processes must be performed according to Good Manufacturing Practice (GMP) as per manufacturer's recommendation and established industry standards to demonstrate effective cleaning including removal of all residues, detergents and microorganisms.
9. Implement Energy-Efficient Sustainable Methods
Sustainability is one of the most critical issues of the world these days. By operating plants as energy-efficient, companies are able to lower their operations costs and demonstrate their corporate responsibility.Following are some ways to improve sustainability:
- Install energy recovery systems into HVAC systems.
- Use LED light bulbs equipped with occupancy sensors.
- Recycle purified water used for non-critical cleaning processes.
- Optimize airflow to reduce HVAC system load.
- Apply green building design principles to all new projects.
Sustainably manufactured goods build brand image and save cost for the manufacturer.
10. Strengthen Validation and Calibration Programs
Routine validation and calibration keep all systems and equipment in a state of control.- Validation includes validation of equipment qualification (IQ, OQ and PQ), process validation and cleaning validation.
- Calibration involves routine calibration of your instruments for accuracy and traceability purposes.
- Requalifying HVAC, utilities and equipment that are critical to production should occur on a regular basis.
Your validation and calibration records will be one of the first documents reviewed during an inspection by the FDA or WHO.
11. Enhance Documentation & Data Accuracy
Inadequate documentation is a very common finding during regulatory inspections.To improve and strengthen documentation in your company, you should:
- Implement electronic data management systems.
- Utilize templates with controlled document numbers and version control.
- Document all activities at the time they occur.
- Audit trails must be able identify the person who performed, reviewed and approved each step of the process.
All paper and electronic data must meet the requirements of ALCOA+ that includes Attributable, Legible, Contemporary, Original, Accurate, Complete, Consistent, Enduring and Accessible.
12. Developing a Culture of Continuous Improvement
As important as any physical change in facility is developing a culture of continuous improvement.Each department should embrace the mindset of quality first. This will improve the ability to sustain improvements over time.
- Encourage open lines of communication between the production and quality teams.
- Develop a system that maintains a root cause analysis for every aberration.
- Establish a process for verifying CAPA effectiveness.
- Conduct regular review of continuous improvement by management.
By implementing continuous improvement, a company progresses from being in compliance to being recognized as a world class organization. Continuous improvement of the pharmaceutical manufacturing facility is an ongoing process, not simply a one-time effort.
Specifically, focusing on the facility layout, environmental control, automated process and sustainable practices helps attain consistent quality and be prepared for audits from any country's regulatory agencies.
Ultimately, the more effective the manufacturing facility, the more effective the drugs. Patients will have more confidence in the drugs manufactured at this facility and it should be the ultimate goal of any pharmaceutical manufacturer.
No comments:
Post a Comment
Please don't spam. Comments having links would not be published.