Single-use systems (SUS) have become increasingly prevalent in biopharmaceutical manufacturing due to their flexibility, reduced contamination risk, and cost-effectiveness. The thing is, management of the life-cycle of single-use systems becomes critical and is an area organizations can truly screw up by cutting corners. To do it right requires careful collaboration between all stakeholders in the supply chain, from raw material suppliers to end users.
Design and Development
Apply Quality by Design (QbD) principles from the outset by focusing on process understanding and the design space to create controlled and consistent manufacturing processes that result in high-quality, efficacious products. This approach should be applied to SUS design.
ASTM E3051 “Standard guide for specification, design, verification, and application of SUS in pharmaceutical and biopharmaceutical manufacturing” provides an excellent framework for the design process.
Make sure to conduct thorough risk assessments, considering potential failure modes and effects throughout the SUS life-cycle.
Engage end-users early to understand their specific requirements and process constraints. A real mistake in organizations is not involving the end-users early enough. From the molecule steward to manufacturing these users are critical.
Raw Material and Component Selection
Carefully evaluate and qualify raw materials and components. Work closely with suppliers to understand material properties, extractables/leachables profiles, and manufacturing processes.
Develop comprehensive specifications for critical materials and components. ASTM E3244 is handy place to look for guidance on raw material qualification for SUS.
Manage the Supplier through Manufacturing and Assembly
Implementing robust supplier qualification and auditing programs and establish change control agreements with suppliers to be notified of any changes that could impact SUS performance or quality. It is important the supplier have a robust quality management system and that they apply Good Manufacturing Practices (GMP) through their facilities. Ensure they have in place appropriate controls to
Validate sterilization processes
Conduct routine bioburden and endotoxin testing
Design packaging to protect SUS during transportation and storage. Shipping methods need to protect against physical damage and temperature excursions
Establish appropriate storage conditions and shelf-life based on stability studies
Provide appropriate labeling and traceability
Have appropriate inventory controls. Ideally select suppliers who understand the importance of working with you for collaborative planning, forecasting and replenishment (CPFR)
Testing and Qualification
Develop a comprehensive testing strategy, including integrity testing and conduct extractables and leachables studies following industry guidelines. Evaluate the suppliers shipping and transportation studies to evaluate SUS robustness and determine if you need additional studies.
Implementation and Use
End users should have appropriate and comprehensive documentation and training to end users on proper handling, installation, and use of SUS. These procedures should include how to perform pre-use integrity testing at the point of use as well as how to perform thorough in-process and final inspections.
Consider implementing automated visual inspection systems and other appropriate monitoring.
Implement appropriate environmental monitoring programs in SUS manufacturing areas. While the dream of manufacturing outdoors is a good one, chances are we aren’t even close yet. Don’t short this layer of control.
Continuous Improvement
Ensure you have appropriate mechanisms in place to gather data on SUS performance and any issues encountered during use. Share relevant information across the supply chain to drive improvements.
Conduct periodic audits of suppliers and manufacturing facilities.
Stay updated on evolving regulatory guidance and industry best practices. There is still a lot changing in this space.
Maintaining process closure is crucial for ensuring product quality and safety in biotechnology manufacturing, especially when using single-use systems (SUS). This approach is an integral part of the contamination control strategy (CCS). To validate process closure in SUS-based biotech manufacturing, a comprehensive method is necessary, incorporating:
Risk assessment
Thorough testing
Ongoing monitoring
By employing risk analysis tools such as Hazard Analysis and Critical Control Points (HACCP) and Failure Mode and Effects Analysis (FMEA), manufacturers can identify potential weaknesses in their processes. Additionally, addressing all four layers of protection helps ensure process integrity and product safety. This risk-based approach to process closure validation is essential for maintaining the high standards required in biotechnology manufacturing, including meeting Annex 1.
Understanding Process Closure
Process closure refers to the isolation of the manufacturing process from the external environment to prevent contamination. In biotech, this is particularly crucial due to the sensitivity of biological products and the potential for microbial contamination.
Throughout this process it is important to apply the four layers of protection that form the foundation of a robust contamination control strategy:
Process: The inherent ability of the process to prevent or control contamination
Equipment: The design and functionality of equipment to maintain closure
Operating Procedures: The practices and protocols followed by personnel
Production Environment: The controlled environment surrounding the process
I was discussing this with some colleagues this week (preparing for some risk assessments) and I was reminded that we really should put the Patient in at the center, the zero. Truer words have never been spoken as the patient truly is our zeroth law, the fundamental principle of the GxPs.
Key Steps for Validating Process Closure
Risk Assessment
Start with a comprehensive risk assessment using tools such as HACCP (Hazard Analysis and Critical Control Points) and FMEA (Failure Mode and Effects Analysis). It is important to remember this is not a one or another, but a multi-tiered approach where you first determine the hazards through the HACCP and then drill down into failures through an FMEA.
HACCP Approach
In the HACCP we will apply a systematic, preventative approach to identify hazards in the process with the aim to produce a documented plan to control these scenarios.
a) Conduct a hazard analysis b) Identify Critical Control Points (CCPs) c) Establish critical limits d) Implement monitoring procedures e) Define corrective actions f) Establish verification procedures g) Maintain documentation and records
FMEA Considerations
In the FMEA we will look for ways the process fails, focusing on the SUS components. We will evaluate failures at each level of control (process, equipment, operating procedure and environment).
Identify potential failure modes in the SUS components
Assess the severity, occurrence, and detectability of each failure mode
Calculate Risk Priority Numbers (RPN) to prioritize risks
Verification
Utilizing these risk assessments, define the user requirements specification (URS) for the SUS, focusing on critical aspects that could impact product quality and patient safety. This should include:
Process requirements (e.g. working volumes, flow rates, pressure ranges)
Following the ASTM E2500 approach, when we conduct the design review of the proposed SUS configuration, to evaluate how well it meets the URS, we want to ensure we cover:
Overall system design and component selection
Materials of construction
Sterilization/sanitization approach
Integrity assurance measures
Sampling and monitoring capabilities
Automation and control strategy
Circle back to the HACCP and FMEA to ensure they appropriately cover critical aspects like:
Loss of sterility/integrity
Leachables/extractables introduction
Bioburden control failures
Cross-contamination risks
Process parameter deviations
These risk assessments will define critical control parameters and acceptance criteria based on the risk assessment. These will form the basis for verification testing. We will through our verification plan have an appropriate approach to:
Verify proper installation of SUS components
Check integrity of connections and seals
Confirm correct placement of sensors and monitoring devices
Document as-built system configuration
Test system integrity under various operating conditions
Perform leak tests on connections and seals
Validate sterilization processes for SUS components
Verify functionality of critical sensors and control
Run simulated production cycles
Monitor for contamination using sensitive detection methods
Verify maintenance of sterility throughout the process
Assess product quality attributes
The verification strategy will leverage a variety of supplier documentation and internal testing.
Closure Analysis Risk Assessment (CLARA)
Acceptance and release will be to perform a detailed CLARA to:
Identify all potential points of contamination ingress
Assess the effectiveness of closure mechanisms
Evaluate the robustness of aseptic connections
Determine the impact of manual interventions on system closure
On Going Use
Coming out of our HACCP we will have a monitoring and verification plan, this will include some important aspects based on our CCPs.
Integrity Testing
Implement routine integrity testing protocols for SUS components
Utilize methods such as pressure decay tests or helium leak detection
Establish acceptance criteria for integrity tests
Environmental Monitoring
Develop a comprehensive environmental monitoring program
Include viable and non-viable particle monitoring
Establish alert and action limits for environmental contaminants
Establish a robust change control process for any modifications to the SUS or process
Regularly review and update risk assessments based on new data or changes
Implement a continuous improvement program to enhance process closure
Leveraging the Four Layers of Protection
Throughout the validation process, ensure that each layer of protection is addressed:
Process:
Optimize process parameters to minimize contamination risks
Implement in-process controls to detect deviations
Equipment:
Validate the design and functionality of SUS components
Ensure proper integration of SUS with existing equipment
Operating Procedures:
Develop and validate aseptic techniques for SUS handling
Implement procedures for system assembly and disassembly
Production Environment:
Qualify the cleanroom environment
Validate HVAC systems and air filtration
Remember that validation is an ongoing process. Regular reviews, updates to risk assessments, and incorporation of new technologies and best practices are essential for maintaining a state of control in biotech manufacturing using single-use systems.
Connected to the Contamination Control Strategy
Closed systems are a key element of the overall contamination control strategy with closed processing and closed systems now accepted as the most effective contamination control risk mitigation strategy. I might not be able to manufacture in the woods yet, but darn if I won’t keep trying.
They serve as a primary barrier to prevent contamination from the manufacturing environment by helping to mitigate the risk of contamination by isolating the product from the surrounding environment. Closed systems are the key protective measure to prevent contamination from the manufacturing environment and cross-contamination from neighboring operations.
The risk assessments leveraged during the implementation of closed systems are a crucial part of developing an effective CCS and will communicate the (ideally) robust methods used to protect products from environmental contamination and cross-contamination. This is tied into the facility design, environmental controls, risk assessments, and overall manufacturing strategies, which are the key components of a comprehensive CCS.
ASTM E2500 recognizes that Good Engineering Practices (GEP) are essential for pharmaceutical companies to ensure the consistent and reliable design, delivery, and operation of engineered systems in a manner suitable for their intended purpose.
Key Elements of Good Engineering Practices
Risk Management: Applying systematic processes to identify, assess, and control risks throughout the lifecycle of engineered systems. This includes quality risk management focused on product quality and patient safety.
Cost Management: Estimating, budgeting, monitoring and controlling costs for engineering projects and operations. This helps ensure projects deliver value and stay within budget constraints.
Organization and Control: Establishing clear organizational structures, roles and responsibilities for engineering activities. Implementing monitoring and control mechanisms to track performance.
Innovation and Continual Improvement: Fostering a culture of innovation and continuous improvement in engineering processes and systems.
Lifecycle Management: Applying consistent processes for change management, issue management, and document control throughout a system’s lifecycle from design to decommissioning.
Project Management: Following structured approaches for planning, executing and controlling engineering projects.
Design Practices: Applying systematic processes for requirements definition, design development, review and qualification.
Operational Support: Implementing asset management, calibration, maintenance and other practices to support systems during routine operations.
Key Steps for Implementation
Develop and document GEP policies, procedures and standards tailored to the company’s needs
Establish an Engineering Quality Process (EQP) to link GEP to the overall Pharmaceutical Quality System
Provide training on GEP principles and procedures to engineering staff
Implement risk-based approaches to focus efforts on critical systems and processes
Use structured project management methodologies for capital projects
Apply change control and issue management processes consistently
Maintain engineering documentation systems with appropriate controls
Conduct periodic audits and reviews of GEP implementation
Foster a culture of quality and continuous improvement in engineering
Ensure appropriate interfaces between engineering and quality/regulatory functions
The key is to develop a systematic, risk-based approach to GEP that is appropriate for the company’s size, products and operations. When properly implemented, GEP provides a foundation for regulatory compliance, operational efficiency and product quality in pharmaceutical manufacturing.
Invest in a Living, Breathing Engineering Quality Process (EQP)
The EQP establishes the formal connection between GEP and the Pharmaceutical Quality System it resides within, serving as the boundary between Quality oversight and engineering activities, particularly for implementing Quality Risk Management (QRM) based integrated Commissioning and Qualification (C&Q).
It should also provide an interface between engineering activities and other systems like business operations, health/safety/environment, or other site quality systems.
Based on the information provided in the document, here is a suggested table of contents for an Engineering Quality Process (EQP):
Table of Contents – Engineering Quality Process (EQP)
Application and Context 2.1 Relationship to Pharmaceutical Quality System (PQS) 2.2 Relationship to Good Engineering Practice (GEP) 2.3 Interface with Quality Risk Management (QRM)
EQP Elements 3.1 Policies and Procedures for the Asset Lifecycle and GEPs 3.2 Risk Assessment 3.3 Change Management 3.4 Document Control 3.5 Training 3.6 Auditing
Deliverables 4.1 GEP Documentation 4.2 Risk Assessments 4.3 Change Records 4.4 Training Records 4.5 Audit Reports
Roles and Responsibilities 5.1 Engineering 5.2 Quality 5.3 Operations 5.4 Other Stakeholders
EQP Implementation 6.1 Establishing the EQP 6.2 Maintaining the EQP 6.3 Continuous Improvement
Facility design and manufacturing processes are complex, multi-stage operations, fraught with difficulty. Ensuring the facility meets Good Manufacturing Practice (GMP) standards and other regulatory requirements is a major challenge. The complex regulations around biomanufacturing facilities require careful planning and documentation from the earliest design stages.
Which is why consensus standards like ASTM E2500 exist.
Central to these approaches are risk assessment, to which there are three primary components:
An understanding of the uncertainties in the design (which includes materials, processing, equipment, personnel, environment, detection systems, feedback control)
An identification of the hazards and failure mechanisms
An estimation of the risks associated with each hazard and failure
Folks often get tied up on what tool to use. Frankly, this is a phase approach. We start with a PHA for design, an FMEA for verification and a HACCP/Layers of Control Analysis for Acceptance. Throughout we use a bow-tie for communication.
Aspect
Bow-Tie
PHA (Preliminary Hazard Analysis)
FMEA (Failure Mode and Effects Analysis)
HACCP (Hazard Analysis and Critical Control Points)
Primary Focus
Visualizing risk pathways
Early hazard identification
Potential failure modes
Systematically identify, evaluate, and control hazards that could compromise product safety
Timing in Process
Any stage
Early development
Any stage, often design
Throughout production
Approach
Combines causes and consequences
Top-down
Bottom-up
Systematic prevention
Complexity
Moderate
Low to moderate
High
Moderate
Visual Representation
Central event with causes and consequences
Tabular format
Tabular format
Flow diagram with CCPs
Risk Quantification
Can include, not required
Basic risk estimation
Risk Priority Number (RPN)
Not typically quantified
Regulatory Alignment
Less common in pharma
Aligns with ISO 14971
Widely accepted in pharma
Less common in pharma
Critical Points
Identifies barriers
Does not specify
Identifies critical failure modes
Identifies Critical Control Points (CCPs)
Scope
Specific hazardous event
System-level hazards
Component or process-level failures
Process-specific hazards
Team Requirements
Cross-functional
Less detailed knowledge needed
Detailed system knowledge
Food safety expertise
Ongoing Management
Can be used for monitoring
Often updated periodically
Regularly updated
Continuous monitoring of CCPs
Output
Visual risk scenario
List of hazards and initial risk levels
Prioritized list of failure modes
HACCP plan with CCPs
Typical Use in Pharma
Risk communication
Early risk identification
Detailed risk analysis
Product Safety/Contamination Control
At BOSCON this year I’ll be talking about this fascinating detail, perhaps too much detail.
Everyone probably feels like the above illustration sooner or later about their water system.
The Critical Role of Water in Pharmaceutical Manufacturing
In the pharmaceutical industry, we often joke that we’re primarily water companies that happen to make drugs on the side. This quip underscores a fundamental truth: water is a crucial component in drug manufacturing processes. Its purity and quality are paramount to ensuring the safety and efficacy of pharmaceutical products.
Why Water Quality Matters
Water is ubiquitous in pharmaceutical manufacturing, used in everything from cleaning equipment to serving as a key ingredient in many formulations. Given its importance, regulatory bodies like the FDA and EMA have established stringent Good Manufacturing Practice (GMP) guidelines for water systems in pharmaceutical facilities.
GMP Requirements for Water Systems
The GMPs mandate that water systems be meticulously designed, constructed, installed, commissioned, qualified, monitored, and maintained. The primary goal? Preventing microbiological contamination. This comprehensive approach encompasses several key areas:
System Design: Water systems must be engineered to minimize the risk of contamination.
Construction and Installation: Materials and methods used must meet high standards to ensure system integrity.
Commissioning and Qualification: Rigorous testing is required to verify that the system performs as intended.
Monitoring: Ongoing surveillance is necessary to detect any deviations from established parameters.
Maintenance: Regular upkeep is crucial to maintain system performance and prevent degradation.
Key Regulatory Requirements
Agency
Title
Year
URL
EMA
Guideline on the quality of water for pharmaceutical use
To meet these GMP requirements, pharmaceutical manufacturers must implement several specific measures:
Minimizing Particulates
Particulate matter in water can compromise product quality and potentially harm patients. Filtration systems and regular cleaning protocols are essential to keep particulate levels in check.
Controlling Microbial Contamination
Microorganisms can proliferate rapidly in water systems if left unchecked. Strategies to prevent this include:
Regular sanitization procedures
Maintaining appropriate water temperatures
Implementing effective water treatment technologies (e.g., UV light, ozonation)
Preventing Endotoxin Formation
Endotoxins, produced by certain bacteria, can be particularly problematic in pharmaceutical water systems. Measures to prevent endotoxin formation include:
Minimizing areas where water can stagnate
Ensuring complete drainage of pipes
Regular system flushing
The Ongoing Challenge
Maintaining water quality in pharmaceutical manufacturing is not a one-time effort but an ongoing process. It requires constant vigilance, regular testing, and a commitment to continuous improvement. As regulations evolve and our understanding of potential contaminants grows, so too must our approaches to water system management.
Types of Water
These water types are defined and regulated by pharmacopeias such as the United States Pharmacopeia (USP), European Pharmacopoeia (Ph. Eur.), and other regional standards. Pharmaceutical manufacturers must adhere to the specific requirements outlined in these references to ensure water quality and safety in drug production.
Potable Water
Potable water, also known as drinking water, may be used for some pharmaceuticals bt is more commonly used in cosmetics. It can also be used for cleanings walls and floors in non-asceptic areas.
Key points:
Must comply with EPA standards or comparable regulations in the EU/Japan
Can be used to manufacture drug substances (bulk drugs)
Not suitable for preparing USP dosage forms or laboratory reagents
Purified Water (PW)
Purified water is widely used in pharmaceutical manufacturing for non-sterile preparations.
Specifications (USP <1231>):
Conductivity: ≤1.3 μS/cm at 25°C
Total organic carbon (TOC): ≤500 ppb
Microbial limits: ≤100 CFU/mL
Applications:
Non-parenteral preparations
Cleaning equipment for non-parenteral products
Preparation of some bulk chemicals
Water for Injection (WFI)
Water for Injection is used for parenteral drug products and has stricter quality standards.
Specifications (USP <1231>):
Conductivity: ≤1.3 μS/cm at 25°C
TOC: ≤500 ppb
Bacterial endotoxins: <0.25 EU/mL
Microbial limits: ≤10 CFU/100 mL
Production methods:
Distillation
Reverse osmosis (allowed by Ph. Eur. since 2017)
Sterile Water for Injection (SWFI)
SWFI is WFI that has been sterilized for direct administration.
Characteristics:
Sterile
Non-pyrogenic
Packaged in single-dose containers
Highly Purified Water (HPW)
Previously included in the European Pharmacopoeia, but now discontinued.
Type of Water
Description
USP Reference
EP Reference
Potable Water
Meets drinking water standards, used for early stages of manufacturing
Not applicable
Not applicable
Purified Water (PW)
Used for non-sterile preparations, cleaning equipment
USP <1231>
Ph. Eur. 0008
Water for Injection (WFI)
Used for parenteral products, higher purity than PW
USP <1231>
Ph. Eur. 0169
Sterile Water for Injection (SWFI)
WFI that has been sterilized for direct administration
USP <1231>
Ph. Eur. 0169
Bacteriostatic Water for Injection
Contains bacteriostatic agents, for multiple-dose use
USP <1231>
Ph. Eur. 0169
Sterile Water for Irrigation
Packaged in single-dose containers larger than 1L
USP <1231>
Ph. Eur. 1116
Sterile Water for Inhalation
For use in inhalators, less stringent endotoxin levels
USP <1231>
Ph. Eur. 1116
Water for Hemodialysis
Specially treated for use in hemodialysis, produced on-site
USP <1231>
Not specified
Additional relevant USP chapters:
USP <645>: Water for Pharmaceutical Purposes – Microbial Attributes
USP <85>: Bacterial Endotoxins Test
Always refer to the most current versions of the pharmacopoeial monographs and regulatory guidelines for detailed information.
Good Water System Design
Hygienic and Sanitary Design
The cornerstone of any good water system is its hygienic and sanitary design. This principle encompasses several aspects:
Smooth, cleanable surfaces: All surfaces in contact with water should be smooth, non-porous, and easily cleanable to prevent biofilm formation.
Self-draining components: Pipes and tanks should be designed to drain completely, eliminating standing water that could harbor microorganisms.
Accessibility: All parts of the system should be easily accessible for inspection, cleaning, and maintenance.
Material Selection
Choosing the right materials is crucial for maintaining water quality and system integrity:
Corrosion resistance: Use materials that resist corrosion, such as stainless steel (316L grade for high-purity applications) or appropriate food-grade plastics.
Smooth internal finish: Crevices are places where corrosion happens, electropolishing improves the resistance of stainless steel to corrosion.
Leachate prevention: Select materials that do not leach harmful substances into the water, even under prolonged contact or elevated temperatures.
Non-adsorptive surfaces: Avoid materials that may adsorb contaminants, which could later be released back into the water.
Microbial Control
Preventing microbial growth is essential for water system safety:
Elimination of dead legs: Design piping to avoid areas where water can stagnate and microorganisms can proliferate.
Temperature control: Maintain temperatures outside the optimal range for microbial growth (typically below 20°C or above 50°C).
Regular sanitization: Incorporate features that allow for effective and frequent sanitization of the entire system.
System Integrity
Ensuring the system remains sealed and leak-free is critical:
Proper sealing: Use appropriate gaskets and seals compatible with the system’s operating conditions.
Pressure testing: Implement regular pressure tests to identify and address potential leaks promptly.
Quality connections: Utilize sanitary fittings and connections designed for hygienic applications.
Cleaning and Sanitization Compatibility
The system must withstand regular cleaning and sanitization:
Chemical resistance: Choose materials and components that can tolerate cleaning and sanitizing agents without degradation.
Thermal stability: Ensure all parts can withstand thermal sanitization processes if applicable.
CIP/SIP design: Incorporate Clean-in-Place (CIP) or Steam-in-Place (SIP) features for efficient and thorough cleaning.
Capacity and Performance
Meeting output requirements while maintaining quality is crucial:
Proper sizing: Design the system to meet peak demand without compromising water quality or flow rates.
Redundancy: Consider incorporating redundant components for critical parts to ensure continuous operation.
Efficiency: Optimize the system layout to minimize pressure drops and energy consumption.
Monitoring and Control
Implement robust monitoring systems to ensure water quality:
Sampling points: Strategically place sampling ports throughout the system for regular quality checks.
Instrumentation: Install appropriate instruments to monitor critical parameters such as flow rate, pressure, temperature, and conductivity.
Control systems: Implement automated control systems to maintain consistent water quality and system performance.
Regulatory Compliance
Ensure the system design meets all relevant regulatory requirements:
Material compliance: Use only materials approved for contact with water in your specific application.
Documentation: Maintain detailed documentation of system design, materials, and operating procedures.
Validation: Conduct thorough system qualification to demonstrate consistent performance and quality.
By adhering to these principles, you can design a water system that not only meets your capacity requirements but also ensures the highest standards of safety and quality. Remember, good water system design is an ongoing process that requires regular review and updates to maintain its effectiveness over time.
