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.
As October rolls around I am focusing on 3 things: finalizing a budget; organization design and talent management; and a 2025 metrics plan. One can expect those three things to be the focus of a lot of my blog posts in October.
Go and read my post on Metrics plans. Like many aspects of a quality management system we don’t spend nearly enough time planning for metrics.
So over the next month I’m going to develop the strategy for a metrics plan to ensure the optimal performance, safety, and compliance of our biotech manufacturing facility, with a focus on:
Facility and utility systems efficiency
Equipment reliability and performance
Effective commissioning, qualification, and validation processes
Robust quality risk management
Stringent contamination control measures
Following the recommended structure of a metrics plan, here is the plan:
Rationale and Desired Outcomes
Implementing this metrics plan will enable us to:
Improve overall facility performance and product quality
Reduce downtime and maintenance costs
Ensure regulatory compliance
Minimize contamination risks
Optimize resource allocation
Metrics Framework
Our metrics framework will be based on the following key areas:
Facility and Utility Systems
Equipment Performance
Commissioning, Qualification, and Validation (CQV)
Quality Risk Management (QRM)
Contamination Control
Success Criteria
Success will be measured by:
Reduction in facility downtime
Improved equipment reliability
Faster CQV processes
Decreased number of quality incidents
Reduced contamination events
Implementation Plan
Steps, Timelines & Milestones
Develop detailed metrics for each key area (Month 1)
Implement data collection systems (Month 2)
Train personnel on metrics collection and analysis (Month 3)
Begin data collection and initial analysis (Month 4)
Review and refine metrics (Month 9)
Full implementation and ongoing analysis (Month 12 onwards)
This plan gets me ready to evaluate these metrics as part of governance in January of next year.
In October I will breakdown some metrics, explaining them and provide the rationale, and demonstrate how to collect. I’ll be striving to break these metrics into key performance indicators (KPI), key behavior indicators (KBI) and key risk indicators (KRI).
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.
I don’t like the term validation deviation, preferring to use discrepancy to cover the errors or failures that occur during qualification/validation, such as when the actual results of a test step in a protocol do not match the expected results. These discrepancies can arise for various reasons, including errors in the protocol, execution issues, or external factors.
I don’t like using the term deviation as I try to avoid terms becoming too overused in too many ways. By choosing discrepancy it serves to move them to a lower order of problem so they can be addressed holistically.
Validation discrepancies really get to the heart of deciding whether the given system/process is fit-for-purpose and fit-for-use. As such, they require being addressed in a timely and pragmatic way.
And, like anything else, having an effective procedure to manage is critical.
Validation discrepancies are a great example of building problem-solving into a process.
ASTM E2500, the Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment, is intended to “satisfy international regulatory expectations in ensuring that manufacturing systems and equipment are fit for the intended use and to satisfy requirements for design, installation, operation, and performance.”
The ASTM E2500 approach is a comprehensive framework for specification setting, design, and verification of pharmaceutical and biopharmaceutical manufacturing systems and equipment. It emphasizes a risk- and science-based methodology to ensure that systems are fit for their intended use, ultimately aiming to enhance product quality and patient safety.
Despite its 17-year history, it is fair to say it is not the best-implemented standard. There are still many unrealized opportunities and some major challenges. I don’t think a single organization I’ve been in has fully aligned, and ASTM E2500 can feel aspirational.
Key Principles
Risk Management: The approach integrates risk management principles from ICH Q8, Q9, and Q10, focusing on identifying and mitigating risks to product quality and patient safety throughout the lifecycle of the manufacturing system.
Good Engineering Practices (GEP): It incorporates GEP to ensure systems are correctly designed, installed, and operated.
Flexibility and Efficiency: It strives for a more flexible and efficient organization of verification activities that can be adapted to each project’s specific context.
Regulatory agencies expect drugmakers to persuade them that we know our processes and that our facilities, equipment, systems, utilities, and procedures have been established based on concrete data and a thorough risk assessment. The ASTM E2500 standard provides a means of demonstrating that all of these factors have been validated in consideration of carefully evaluated risks.
What the Standard Calls for
Four Main Steps
Requirements: Define the system’s needs and critical aspects. Subject Matter Experts (SMEs) play a crucial role in this phase by defining needs, identifying critical aspects, and developing the verification strategy.
Specification & Design: Develop detailed specifications and design the system to meet the requirements. This step involves thorough design reviews and risk assessments to ensure the system functions as intended.
Verification: Conduct verification activities to confirm that the system meets all specified requirements. This step replaces the traditional FAT/SAT/IQ/OQ/PQ sequence with a more streamlined verification process that can be tailored to the project’s needs.
Acceptance & Release: Finalize the verification process and release the system for operational use. This step includes the final review and approval of all verification activities and documentation.
Four Cross-Functional Processes
Good Engineering Practices (GEP): Ensure all engineering activities adhere to industry standards and best practices.
Quality Risk Management: Continuously assess and manage risks to product quality and patient safety throughout the project.
Design Review: Regularly reviews the system design to ensure it meets all requirements and addresses identified risks.
Change Management: Implement a structured process for managing system changes to ensure that all modifications are appropriately evaluated and documented.
Applications and Benefits
Applicability: The ASTM E2500 approach can be applied to new and existing manufacturing systems, including laboratory, information, and medical device manufacturing systems.
Lifecycle Coverage: It applies throughout the manufacturing system’s lifecycle, from concept to retirement.
Regulatory Compliance: The approach is designed to conform with FDA, EU, and other international regulations, ensuring that systems are qualified and meet all regulatory expectations.
Efficiency and Cost Management: By focusing on critical aspects and leveraging risk management tools, the ASTM E2500 approach can streamline project execution, reduce time to market, and optimize resource utilization.
The ASTM E2500 approach provides a structured, risk-based framework for specifying, designing, and verifying pharmaceutical and biopharmaceutical manufacturing systems. It emphasizes flexibility, efficiency, and regulatory compliance, making it a valuable tool for ensuring product quality and patient safety.
What Makes it Different?
ASTM E2500
The more traditional approach
Testing Approach
It emphasizes a risk-based approach, focusing on identifying and managing risks to product quality and patient safety throughout the manufacturing system’s lifecycle. This approach allows for flexibility in organizing verification activities based on the specific context and critical aspects of the system.
Typically follows a prescriptive sequence of tests (FAT, SAT, IQ, OQ, PQ) as outlined in guidelines like EU GMP Annex 15. This method is more rigid and less adaptable to the specific needs and risks of each project.
Verification vs Qualification
The term “verification” encompasses all testing activities, which can be organized more freely and rationally to optimize efficiency. Verification activities are tailored to the project’s needs and focus on critical aspects.
Follows a structured qualification process (Installation Qualification, Operational Qualification, Performance Qualification) with predefined steps and documentation requirements.
Role of Subject Matter Experts
SMEs play a crucial role from the start of the project, contributing to the definition of needs, identification of critical aspects, system design review, and development of the verification strategy. They are involved throughout the project lifecycle.
SMEs are typically involved at specific points in the project lifecycle, primarily during the qualification phases, and may not have as continuous a role as in the ASTM E2500 approach.
Integration of Good Engineering Practices
Offers greater flexibility in organizing verification activities, allowing for a more efficient and streamlined process. This can lead to reduced time to market and optimized resource utilization.
While GEP is also important, the focus is more on the qualification steps rather than integrating GEP throughout the entire project lifecycle.
Change Management
It emphasizes early and continuous change management, starting from the supplier’s site, to avoid test duplication and ensure that changes are properly evaluated and documented.
It emphasizes early and continuous change management, starting from the supplier’s site, to avoid test duplication and ensure that changes are properly evaluated and documented.
Documentation
Documentation is focused on risk management and verification activities, ensuring compliance with international regulations (FDA, EU, ICH Q8, Q9, Q10). The approach is designed to meet regulatory expectations while allowing for flexibility in documentation.
quires extensive documentation for each qualification step, which can be more cumbersome and less adaptable to specific project needs.
Opinion
I’m watching to see what the upcoming update to Annex 15 will do to address the difficulties some see between an ATSM E2500 approach and the European regulations. I also hope we will see an update to ISPE Baseline® Guide Volume 5: Commissioning and Qualification to align an approach.
ISPE Baseline® Guide Volume 5
ATSM E2500
Design inputs Impact assessment Design Qualification Commissioning Multiple trial runs to get things right IQ, OQ, PQ, and acceptance criteria GEP Scope and QA Scope overlapped Focused on Documentation Deliverables Change Management
Design inputs Design Review Risk Mitigation Critical Control Parameters define Acceptance Criteria Verification Testing Performance Testing GEP Scope and QA Scope have a clear boundary Process, Product Quality and Patient Safety Quality by Design, Design Space, and Continuous Improvement
To be honest I don’t think ATSM E2500, ISPE Guide 5, or anything else has the balance just right. And your program ends up being a triangulation between these and the regulations. And don’t even bring in trying to align GAMP5 or USP <1058> or…or…or…
And yes, I do consider this part of my 3-year plan. I look forward to the challenges of a culture shift, increased SME involvement, formalization of GEPs (and teaching engineers how to write), effective change management, timely risk assessments, and comprehensive implementation planning.
Investigations of a Dog 