Good Engineering Practices Under ASTM E2500

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)

Introduction
1.1 Purpose
1.2 Scope
1.3 Definitions
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
References
Appendices

Risk Assessments as part of Design and Verification

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.

Conducting A Hazard and Operability Study (HAZOP)

A Hazard and Operability Study (HAZOP) is a structured and systematic examination of a complex planned or existing process or operation to identify and evaluate problems that may represent risks to product, personnel or equipment. The primary goal of a HAZOP is to ensure that risks are managed effectively by identifying potential hazards and operability problems and developing appropriate mitigation strategies.

Why Use HAZOP?

Biotech facilities involve intricate processes that can be prone to various risks, including contamination, equipment failure, and process deviations. Implementing a HAZOP can:

Risk Identification and Mitigation: HAZOPs help identify potential hazards associated with biotech processes, such as contamination risks, equipment malfunctions, and deviations from standard operating procedures. By identifying these risks, facilities can implement mitigation strategies to prevent accidents and ensure safety.
Process Optimization: Through the systematic analysis of processes, HAZOPs can identify inefficiencies and areas for improvement, leading to optimized operations and enhanced productivity.

Part of a Continuum of Risk Tools

A HAZOP (Hazard and Operability) study differs from other risk assessment methods in a few key ways:

Systematic examination of process deviations: HAZOP uses a very structured approach of examining potential deviations from the intended design and operation of a process, using guidewords like “more”, “less”, “no”, “reverse”, etc. This systematic approach helps identify hazards that may be missed by other methods.
Focus on operability issues: The HAZOP examines operability problems that could impact process efficiency or product quality.
Node-by-node analysis: The process is broken down into nodes or sections that are analyzed individually, allowing for very thorough examination.
Qualitative analysis: Unlike quantitative risk assessment methods, HAZOP is primarily qualitative, focusing on identifying potential hazards rather than quantifying risk levels. HAZOPs do not typically assign numerical scores or rankings to risks.
Consideration of causes and consequences: For each deviation, the team examines possible causes, consequences, and existing safeguards before recommending additional actions.
Applicable to complex processes: The structured approach makes HAZOP well-suited for analyzing complex processes with many variables and potential interactions.

Method	Description	Strengths	Limitations
HAZOP (Hazard and Operability Study)	Systematic examination of process/operation to identify potential hazards and operability problems	– Very thorough and structured approach – Examines deviations from design intent – Team-based	– Time consuming – Primarily qualitative
FMEA (Failure Mode and Effects Analysis)	Systematic method to identify potential failure modes and their effects	– Quantitative risk prioritization – Proactive approach – Can be used on products and processes	– Does not consider combinations of failures – Can be subjective
HACCP (Hazard Analysis and Critical Control Points)	Systematic approach to food safety hazards	– Focus on prevention – Identifies critical control points	– Requires prerequisite programs in place
PHA (Preliminary Hazard Analysis)	Early stage hazard identification technique	– Can be used early in design process – Relatively quick to perform – Identifies major hazards	– Not very detailed – Qualitative only – May miss some hazards
Bow-Tie Analysis	Combines fault tree and event tree analysis	– Visual representation of risk pathways – Shows preventive and mitigative controls – Good communication tool	– Does not show detailed failure logic – Can oversimplify complex scenarios – Time consuming for multiple hazards

Key differences:

HAZOP focuses on deviations from design intent, while FMEA looks at potential failure modes
HACCP is specific to identify hazards and is commonly used in food safety, while the others are more general risk assessment tools
PHA is used early in design, while the others are typically used on existing systems
Bow-Tie provides a visual risk pathway, while the others use more tabular formats
FMEA and HAZOP tend to be the most thorough and time-intensive methods

The choice of method depends on the specific application, stage of design, and level of detail required. Often a combination of methods may be used.

Instructions for Conducting a HAZOP

Preparation

Assemble a multidisciplinary team comprising appropriate experts
Define the scope of the HAZOP study, including the specific processes or operations to be analyzed.
Gather and review all relevant documentation, such as process flow diagrams, piping and instrumentation diagrams, and standard operating procedures.

Execution

Divide the Process into Nodes: Break down the process into manageable sections or nodes. Each node typically represents a specific part of the process, such as a piece of equipment or a process step.
Identify Deviations: For each node, guidewords are applied to identify potential deviations from the intended design or operation. Common guidewords include:
- No: Complete absence of a process parameter (e.g., no flow).
- More: Quantitative increase (e.g., more pressure).
- Less: Quantitative decrease (e.g., less temperature).
- As well as: Presence of additional elements (e.g., contamination).
- Part of: Partial completion of an action (e.g., partial mixing).
- Reverse: Logical opposite of the intended action (e.g., reverse flow).
Analyze Causes and Consequences: Determine the possible causes of each deviation and analyze the potential consequences on safety, environment, and operations. This involves considering various factors such as equipment failure, human error, environmental conditions, or procedural issues that could lead to the deviation.
- Use of Experience and Knowledge: The team relies on their collective experience and knowledge of the process, equipment, and industry standards to hypothesize potential causes. This may include reviewing historical data, previous incidents, and near misses.
Recommend Actions: Develop recommendations for mitigating identified risks, such as changes to the process, additional controls, or procedural modifications.

Documentation and Follow-Up

Document all findings, including identified hazards, potential consequences, and recommended actions.
Assign responsibilities for implementing recommendations and establish timelines for completion.
Conduct follow-up reviews to ensure that recommended actions have been implemented effectively and that the process remains safe and operable.

Review and Update

Regularly review and update the HAZOP study to account for changes in processes, equipment, or regulations.
Ensure continuous improvement by incorporating lessons learned from past incidents or near misses.
Iterative Process: The process is iterative, with the team revisiting and refining their analysis as more information becomes available or as the understanding of the process deepens.

Node	Guideword	Parameter	Deviation	Cause	Consequence	Safeguards	Recommendations	Actions
Specific section or equipment being analyzed	Guideword applied (e.g. No, More, Less, Reverse, etc.)	Process parameter being examined (e.g. Flow, Temperature, Pressure, etc.)	How the parameter deviates from design intent when guideword is applied	Possible reasons for the deviation	Potential results if deviation occurs	Existing measures to prevent or mitigate the deviation	Suggested additional measures to control the risk	Specific tasks assigned to implement recommendations

Inappropriate Uses of Quality Risk Management

Quality Risk Management (QRM) is a vital aspect of pharmaceutical and biotechnology manufacturing, aimed at ensuring product quality and safety. I write a lot about risk management because risk management is so central to what I do. However, inappropriate uses of QRM can lead to significant negative consequences and I think it is a fairly common refrain in my day that an intended use is not an appropriate use of risk management. Let us explore these inappropriate uses, their potential consequences, and provide some examples so folks know what to avoid.

1. Justifying Non-Compliance

Inappropriate Use: Using QRM to justify deviations from Good Practices (GxP) or regulatory standards.

Consequences: This can lead to regulatory non-compliance, resulting in action from regulatory bodies, such as warnings, fines, or even shutdowns. Everytime I read a Warning Letter I imagine that there was some poorly thought out risk assessment. Using risk management this way undermines the integrity of manufacturing processes and can compromise product safety and efficacy.

Example: A company might use risk assessments to justify not adhering to environmental controls, claiming the risk is minimal. This can lead to contamination issues, as seen in cases where inadequate environmental monitoring led to microbial contamination of products.

2. Substituting for Scientific Evidence

Inappropriate Use: Relying on QRM as a substitute for robust scientific data and empirical evidence.

Consequences: Decisions made without scientific backing can lead to ineffective risk mitigation strategies, resulting in product failures or recalls.

Example: A manufacturer might use QRM to decide on process parameters without sufficient scientific validation, leading to inconsistent product quality. For example the inadequate scientific evaluation of raw materials led to variability in cell culture media performance.

3. Supporting Predetermined Conclusions

Inappropriate Use: Manipulating QRM to support conclusions that have already been decided.

Consequences: This biases the risk management process, potentially overlooking significant risks and leading to inadequate risk controls.

Example: In a biopharmaceutical facility, QRM might be used to support the continued use of outdated equipment, despite known risks of cross-contamination, leading to product recalls.

4. Rationalizing Workarounds

Inappropriate Use: Using QRM to justify workarounds that bypass standard procedures or controls.

Consequences: This can introduce new risks into the manufacturing process, potentially leading to product contamination or failure.

Example: A facility might use QRM to justify a temporary fix for a malfunctioning piece of equipment instead of addressing the root cause, leading to repeated equipment failures and production delays.

5. Ignoring Obvious Issues

Inappropriate Use: Conducting risk assessments instead of addressing clear and evident problems directly.

Consequences: This can delay necessary corrective actions, exacerbating the problem and potentially leading to regulatory actions.

Example: A company might conduct a lengthy risk assessment instead of immediately addressing a known contamination source, resulting in multiple batches being compromised.

Inappropriate uses of Quality Risk Management can have severe implications for product quality, regulatory compliance, and patient safety. It is crucial for organizations to apply QRM objectively, supported by scientific evidence, and aligned with regulatory standards to ensure its effectiveness in maintaining high-quality manufacturing processes.

Applying a Layers of Controls Analysis to Contamination Control

Layers of Controls Analysis (LOCA)

Layers of Controls Analysis (LOCA) provides a comprehensive framework for evaluating multiple layers of protection to reduce and manage operational risks. By examining both preventive and mitigative control measures simultaneously, LOCA allows organizations to gain a holistic view of their risk management strategy. This approach is particularly valuable in complex operational environments where multiple safeguards and protective systems are in place.

One of the key strengths of LOCA is its ability to identify gaps in protection. By systematically analyzing each layer of control, from basic process design to emergency response procedures, LOCA can reveal areas where additional safeguards may be necessary. This insight is crucial for guiding decisions on implementing new risk reduction measures or enhancing existing ones. The analysis helps organizations prioritize their risk management efforts and allocate resources more effectively.

Furthermore, LOCA provides a structured way to document and justify risk reduction measures. This documentation is invaluable for regulatory compliance, internal audits, and continuous improvement initiatives. By clearly outlining the rationale behind each protective layer and its contribution to overall risk reduction, organizations can demonstrate due diligence in their safety and risk management practices.

Another significant advantage of LOCA is its promotion of a holistic view of risk control. Rather than evaluating individual safeguards in isolation, LOCA considers the cumulative effect of multiple protective layers. This approach recognizes that risk reduction is often achieved through the interaction of various control measures, ranging from engineered systems to administrative procedures and emergency response capabilities.

By building on other risk assessment techniques, such as Hazard and Operability (HAZOP) studies and Fault Tree Analysis, LOCA provides a more complete picture of protection systems. It allows organizations to assess the effectiveness of their entire risk management strategy, from prevention to mitigation, and ensures that risks are reduced to an acceptable level. This comprehensive approach is particularly valuable in high-hazard industries where the consequences of failures can be severe.

LOCA combines elements of two other methods – Layers of Protection Analysis (LOPA) and Layers of Mitigation Analysis (LOMA).

Layers of Protection Analysis

To execute a Layers of Protection Analysis (LOPA), follow these key steps:

Define the hazardous scenario and consequences:

Clearly identify the hazardous event being analyzed
Determine the potential consequences if all protection layers fail

Identify initiating events:

List events that could trigger the hazardous scenario
Estimate the frequency of each initiating event

Identify Independent Protection Layers (IPLs):

Determine existing safeguards that can prevent the scenario
Evaluate if each safeguard qualifies as an IPL (independent, auditable, effective)
Estimate the Probability of Failure on Demand (PFD) for each IPL

Identify Conditional Modifiers:

Determine factors that impact scenario probability (e.g. occupancy, ignition probability)
Estimate probability for each modifier

Calculate scenario frequency:

Multiply initiating event frequency by PFDs of IPLs and conditional modifiers

Compare to risk tolerance criteria:

Determine if calculated frequency meets acceptable risk level
If not, identify need for additional IPLs

Document results:

Record all assumptions, data sources, and calculations
Summarize findings and recommendations

Review and validate:

Have results reviewed by subject matter experts
Validate key assumptions and data inputs

Key aspects for successful LOPA execution

Use a multidisciplinary team
Ensure independence between IPLs
Be conservative in estimates
Focus on prevention rather than mitigation
Consider human factors in IPL reliability
Use consistent data sources and methods

Layers of Mitigation Analysis

LOMA focuses on analyzing reactionary or mitigative measures, as opposed to preventive measures.

A LOCA as part of Contamination Control

A Layers of Controls Analysis (LOCA) can be effectively applied to contamination control in biotech manufacturing by systematically evaluating multiple layers of protection against contamination risks.

To determine potential hazards when conducting a Layer of Controls Analysis (LOCA) for contamination control in biotech, follow these steps:

Form a multidisciplinary team: Include members from manufacturing, quality control, microbiology, engineering, and environmental health & safety to gain diverse perspectives.
Review existing processes and procedures: Examine standard operating procedures, experimental protocols, and equipment manuals to identify potential risks associated with each step.
Consider different hazard types. Focus on categories like:
- Biological hazards (e.g., microorganisms, cell lines)
- Chemical hazards (e.g., toxic substances, flammable materials)
- Physical hazards (e.g., equipment-related risks)
- Radiological hazards (if applicable)
Analyze specific contamination hazard types for biotech settings:
- Mix-up: Materials used for the wrong product
- Mechanical transfer: Cross-contamination via personnel, supplies, or equipment
- Airborne transfer: Contaminant movement through air/HVAC systems
- Retention: Inadequate removal of materials from surfaces
- Proliferation: Potential growth of biological agents
Conduct a process analysis: Break down each laboratory activity into steps and identify potential hazards at each stage.
Consider human factors: Evaluate potential for human error, such as incorrect handling of materials or improper use of equipment.
Assess facility and equipment: Examine the layout, containment measures, and equipment condition for potential hazards.
Review past incidents and near-misses: Analyze previous safety incidents or close calls to identify recurring or potential hazards.
Consult relevant guidelines and regulations: Reference industry standards, biosafety guidelines, and regulatory requirements to ensure comprehensive hazard identification.
Use brainstorming techniques: Encourage team members to think creatively about potential hazards that may not be immediately obvious.
Evaluate hazards at different scales: Consider how hazards might change as processes scale up from research to production levels.

Facility Design and Engineering Controls
- Cleanroom design and classification
- HVAC systems with HEPA filtration
- Airlocks and pressure cascades
- Segregated manufacturing areas
Equipment and Process Design
- Closed processing systems
- Single-use technologies
- Sterilization and sanitization systems
- In-line filtration
Operational Controls
- Aseptic techniques and procedures
- Environmental monitoring programs
- Cleaning and disinfection protocols
- Personnel gowning and hygiene practices
Quality Control Measures
- In-process testing (e.g., bioburden, endotoxin)
- Final product sterility testing
- Environmental monitoring data review
- Batch record review
Organizational Controls
- Training programs
- Standard operating procedures (SOPs)
- Quality management systems
- Change control processes

Evaluate reliability and capability of each control:
- Review historical performance data for each control measure
- Assess the control’s ability to prevent or detect contamination
- Consider the control’s consistency in different operating conditions
Consider potential failure modes:
- Conduct a Failure Mode and Effects Analysis (FMEA) for each control
- Identify potential ways the control could fail or be compromised
- Assess the likelihood and impact of each failure mode
Evaluate human factors:
- Assess the complexity and potential for human error in each control
- Review training effectiveness and compliance with procedures
- Consider ergonomics and usability of equipment and systems
Analyze technology effectiveness:
- Evaluate the performance of automated systems and equipment
- Assess the reliability of monitoring and detection technologies
- Consider the integration of different technological controls

Quantify risk reduction:
- Assign risk reduction factors to each layer based on its effectiveness
- Use a consistent scale (e.g., 1-10) to rate each control’s risk reduction capability
- Calculate the cumulative risk reduction across all layers
Assess interdependencies between layers:
- Identify any controls that rely on or affect other controls
- Evaluate how failures in one layer might impact the effectiveness of others
- Consider potential common mode failures across multiple layers
Review control performance metrics:
- Analyze trends in environmental monitoring data
- Examine out-of-specification results and their root causes
- Assess the frequency and severity of contamination events

Determine acceptable risk levels:
- Define your organization’s risk tolerance for contamination events
- Compare current risk levels against these thresholds
Identify gaps:
- Highlight areas where current controls fall short of required protection
- Note processes or areas with insufficient redundancy
Propose improvements:
- Suggest enhancements to existing controls
- Recommend new control measures to address identified gaps
Prioritize actions:
- Rank proposed improvements based on risk reduction potential and feasibility
- Consider cost-benefit analysis for major changes
Seek expert input:
- Consult with subject matter experts on proposed improvements
- Consider third-party assessments for critical areas
Plan for implementation:
- Develop action plans for addressing identified gaps
- Assign responsibilities and timelines for improvements

Document and review:

Create a comprehensive LOCA document
Regularly review and update the analysis. This is a living risk assessment.
Incorporate lessons learned from any contamination events

Implement continuous monitoring and review:
- Establish key performance indicators (KPIs)
- Conduct regular audits and inspections
- Review environmental monitoring data trends
Develop a holistic CCS document:
- Describe overall contamination control approach
- Detail how different controls work together
- Include risk assessments and rationales
Establish governance and oversight:
- Create a cross-functional CCS team
- Define roles and responsibilities
- Implement a regular review process
Integrate with quality systems:
- Align CCS with existing quality management processes
- Ensure change control procedures consider CCS impact
Provide comprehensive training:
- Train all personnel on CCS principles and practices
- Implement contamination control ambassador program

Implement regular review cycles:
- Schedule periodic reviews of the LOCA (e.g., annually or bi-annually)
- Involve a cross-functional team including quality, manufacturing, and engineering
Analyze trends and data:
- Review environmental monitoring data
- Examine out-of-specification results and their root causes
- Assess the frequency and severity of contamination events
Identify improvement opportunities:
- Use gap analysis to compare current controls against industry best practices
- Evaluate new technologies and methodologies for contamination control
- Consider feedback from contamination control ambassadors and staff
Prioritize improvements:
- Rank proposed enhancements based on risk reduction potential and feasibility
- Consider cost-benefit analysis for major changes
Implement changes:
- Update standard operating procedures (SOPs) as needed
- Provide training on new or modified control measures
- Validate changes to ensure effectiveness
Monitor and measure impact:
- Establish key performance indicators (KPIs) for each layer of control
- Track improvements in contamination rates and overall control effectiveness
Foster a culture of continuous improvement:
- Encourage proactive reporting of potential issues
- Recognize and reward staff contributions to contamination control
Stay updated on regulatory requirements:
- Regularly review and incorporate changes in regulations (e.g., EU GMP Annex 1)
- Attend industry conferences and workshops on contamination control
Integrate with overall quality systems:
- Ensure LOCA improvements align with the site’s Quality Management System
- Update the Contamination Control Strategy (CCS) document as needed
Leverage technology:
- Implement digital solutions for environmental monitoring and data analysis
- Consider advanced technologies like rapid microbial detection methods
Conduct periodic audits:
- Perform surprise audits to ensure adherence to protocols
- Use findings to further refine the LOCA and control measures