Effective problem-solving is crucial for maintaining quality, making decisions, managing risks, and implementing changes. One visual brainstorming technique that can significantly enhance your work and should be in everyone’s tool box, is the How-How Diagram.
Understanding the How-How Diagram
The How-How Diagram is a structured approach to breaking down complex problems into manageable, actionable steps. It works by repeatedly asking “How?” to generate increasingly specific solutions. This method is particularly effective for collaborative problem-solving, as it encourages team members to think critically and creatively about potential solutions.
As similar structure as the Why-Why, many folks will find this tool comfortable to use.
Creating a How-How Diagram
Example template for a How-How diagram
Step 1: State the Problem
Begin by clearly defining the primary problem or need. Write this on a card or Post-It Note and place it on the left side of your workspace. Ensure that the problem is framed as a need to facilitate the “How?” question.
Step 2: Ask “How can this be done?”
Generate initial solutions by asking, “How can this be done?” Write each solution on a separate card and place them to the right of the problem statement.
Step 3: Identify Relationships
Some solutions may be alternatives, while others might need to occur together. Indicate these relationships by writing “and” or “or” between the cards.
Step 4: Repeat the Process
For each solution generated, ask “How?” again to break it down further. Continue this process, building a hierarchy of increasingly specific actions.
Step 5: Review and Refine
Once you’ve exhausted all possibilities, review the diagram. You may choose to draw connecting lines between related items, but it’s often best to leave this until the end to allow for easy rearrangement of cards.
Applying How-How Diagrams in CAPA Development
In CAPA processes, How-How Diagrams can be invaluable for:
Root Cause Analysis: Break down potential causes of issues to identify the true root cause.
Action Planning: Develop detailed, step-by-step corrective and preventive actions.
Implementation Strategy: Map out the specific steps needed to implement CAPA solutions effectively.
Enhancing Risk Management with How-How Diagrams
Risk management can benefit from How-How Diagrams in several ways:
Risk Identification: Systematically explore potential risks by asking “How could this go wrong?”
Mitigation Planning: Develop comprehensive risk mitigation strategies by breaking down each risk into manageable actions.
Contingency Planning: Create detailed contingency plans for identified risks.
Streamlining Change Control with How-How Diagrams
In change control processes, How-How Diagrams can:
Impact Analysis: Thoroughly explore the potential impacts of proposed changes.
Implementation Planning: Break down the change process into specific, actionable steps.
Communication Strategy: Develop a clear plan for communicating changes to all stakeholders.
Best Practices for Using How-How Diagrams
To maximize the effectiveness of How-How Diagrams:
Encourage Participation: Involve diverse team members to gain multiple perspectives.
Stay Focused: Keep the discussion centered on the main problem or goal.
Be Specific: Aim for concrete, actionable solutions rather than vague ideas.
Prioritize: Once the diagram is complete, identify the most critical or impactful actions.
Document: Capture the final diagram and use it as a reference for implementation and follow-up.
Conclusion
The How-How Diagram is a versatile and powerful tool for problem-solving by providing a structured approach to breaking down complex issues. It enables teams to develop comprehensive, actionable plans. Whether you’re addressing quality issues, managing risks, or implementing changes, the How-How Diagram can help you navigate the process with clarity and precision.
The FDA has published the 2024 Inspectional Observation Data Sets. I don’t think there are any surprise that on what the inspection observations data for fiscal year 2024 shows and what key GMP inspection themes emerge for drug manufacturers:
Quality Systems and Documentation
Inadequate Procedures and Documentation
Failure to establish or follow written procedures for various operations, including quality control, production, and process controls.
Lack of complete documentation for investigations, batch records, and laboratory testing.
Quality Control Unit Deficiencies
Inadequate responsibilities and authority of the quality control unit.
Failure to approve or reject components, products, procedures, or specifications.
Manufacturing and Process Controls
Equipment and Facility Issues
Inadequate design, maintenance, or cleaning of manufacturing equipment.
Deficiencies in facility maintenance, sanitation, and environmental controls.
Process Validation and Control
Lack of adequate process validation, especially for sterile drug products.
Insufficient control procedures to monitor and validate manufacturing processes.
Laboratory Controls
Inadequate Laboratory Practices
Failure to establish scientifically sound laboratory controls.
Deficiencies in test methods validation and stability testing programs.
Component Testing
Inadequate testing of drug components and reliance on supplier certificates without proper verification.
Sterile Drug Manufacturing
Aseptic Processing Deficiencies
Inadequate procedures and validation for sterile drug products.
Deficiencies in environmental monitoring and control systems for aseptic processing areas.
Training and Personnel
Inadequate Employee Training
Insufficient training of employees in GMP and specific job function.
Complaint Handling and Product Quality Reviews
Deficient Complaint Procedures
Inadequate procedures for handling product complaints.
Annual Product Quality Review
Failure to conduct adequate annual product quality reviews.
Equipment Related
Out of the 365 observations that mention equipment, 277 are from just 5 regulations. Let’s take a deeper look.
Reference Number
Short Description
Long Description
Frequency
21 CFR 211.63
Equipment Design, Size and Location
Equipment used in the manufacture, processing, packing or holding of drug products is not [of appropriate design] [of adequate size] [suitably located] to facilitate operations for its [intended use] [cleaning and maintenance]. Specifically, ***
85
21 CFR 211.67(a)
Cleaning / Sanitizing / Maintenance
Equipment and utensils are not [cleaned] [maintained] [sanitized] at appropriate intervals to prevent [malfunctions] [contamination] that would alter the safety, identity, strength, quality or purity of the drug product. Specifically, ***
76
21 CFR 211.67(b)
Written procedures not established/followed
Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product. Specifically, ***
60
21 CFR 211.68(a)
Calibration/Inspection/Checking not done
Routine [calibration] [inspection] [checking] of [automatic] [mechanical] [electronic] equipment is not performed according to a written program designed to assure proper performance. Specifically, ***
30
Improper design and qualification, improper cleaning, improper calibration and inspections. Yes these take work, but these are all areas that effort can improve.
In the world of creative problem-solving and idea generation, the Lotus Blossom technique stands out as a powerful and structured approach to brainstorming. Developed by Yasuo Matsumura, a Japanese management consultant, this method combines the free-flowing nature of traditional brainstorming with a systematic framework that encourages deeper exploration of ideas.
How It Works
The Lotus Blossom technique uses a visual diagram resembling a lotus flower, hence its name. Here’s a step-by-step breakdown of the process:
Start with a central idea or problem in the middle of a 3×3 grid.
Surround the central concept with eight related ideas or themes.
Take each of these eight ideas and make them the center of their own 3×3 grids.
Generate eight new ideas for each of these secondary grids.
Repeat the process until you have a fully bloomed “lotus” of ideas.
By the end of this process, you’ll have generated up to 64 ideas stemming from your original concept.
Benefits of the Lotus Blossom Technique
Structured Creativity: Unlike traditional brainstorming, which can sometimes feel chaotic, the Lotus Blossom method provides a clear structure for idea generation.
Depth and Breadth: This technique encourages both broad thinking and deep exploration of specific themes.
Visual Organization: The diagram format helps visualize connections between ideas and keeps the brainstorming process organized.
Flexibility: It can be used individually or in small groups, making it versatile for various settings.
Tips for Success
To make the most of the Lotus Blossom technique, consider these tips:
Embrace All Ideas: Don’t self-censor. Even seemingly unrelated or far-fetched ideas can spark innovation.
Time Management: Set time limits for each phase to maintain momentum and prevent overthinking.
Iterate and Refine: After completing the diagram, review and refine your ideas. Look for patterns or combinations that might lead to breakthrough solutions.
In the pharmaceutical industry, qualification and validation is a critical process to ensure the quality, safety, and efficacy of products. Over the years, several models have emerged to guide efforts for facilities, utilities, systems, equipment, and processes. This blog post will explore three prominent models: the 4Q model, the V-model, and the W-model. We’ll also discuss relevant regulatory guidelines and industry standards.
The 4Q Model
The 4Q model is a widely accepted approach to qualification in the pharmaceutical industry. It consists of four stages:
Design Qualification (DQ): This initial stage focuses on documenting that the design of facilities, systems, and equipment is suitable for the intended purpose. DQ should verify that the proposed design of facilities, systems, and equipment is suitable for the intended purpose. The requirements of the user requirements specification (URS) should be verified during DQ.
Installation Qualification (IQ): IQ verifies that the equipment or system has been properly installed according to specifications. IQ should include verification of the correct installation of components and instrumentation against engineering drawings and specifications — the pre-defined criteria.
Operational Qualification (OQ): This stage demonstrates that the equipment or system operates as intended across the expected operating ranges. OQ should ensure the system is operating as designed, confirming the upper and lower operating limits, and/or “worst case” conditions. Depending on the complexity of the equipment, OQ may be performed as a combined Installation/Operation Qualification (IOQ). The completion of a successful OQ should allow for the finalization of standard operating and cleaning procedures, operator training, and preventative maintenance requirements.
Performance Qualification (PQ): PQ confirms that the equipment or system consistently performs as expected under routine production conditions. PQ should normally follow the successful completion of IQ and OQ, though in some cases, it may be appropriate to perform PQ in conjunction with OQ or Process Validation. PQ should include tests using production materials, qualified substitutes, or simulated products proven to have equivalent behavior under normal operating conditions with worst-case batch sizes. The extent of PQ tests depends on the results from development and the frequency of sampling during PQ should be justified.
The V-Model
The V-model, introduced by the International Society of Pharmaceutical Engineers (ISPE) in 1994, provides a visual representation of the qualification process:
The left arm of the “V” represents the planning and specification phases.
The bottom of the “V” represents the build and unit testing phases.
The right arm represents the execution and qualification phases.
This model emphasizes the relationship between each development stage and its corresponding testing phase, promoting a systematic approach to validation.
The W-Model
The W-model is an extension of the V-model that explicitly incorporates commissioning activities:
The first “V” represents the traditional V-model stages.
The center portion of the “W” represents commissioning activities.
The second “V” represents qualification activities.
This model provides more granularity to what is identified as “verification testing,” including both commissioning (e.g., FAT, SAT) and qualification testing (IQ, OQ, PQ).
User Requirements, Functional Specs, Design Specs, Commissioning, IQ, OQ, PQ
Focus
Sequential qualification stages
Linking development and testing phases
Integrating commissioning with qualification
Flexibility
Moderate
High
High
Emphasis on Commissioning
Limited
Limited
Explicit
Risk-based Approach
Can be incorporated
Can be incorporated
Inherently risk-based
Where Qualifcation Fits into the Regulatory Landscape and Industry Guidelines
WHO Guidelines
The World Health Organization (WHO) provides guidance on validation and qualification in its “WHO good manufacturing practices for pharmaceutical products: main principles”. While not explicitly endorsing a specific model, WHO emphasizes the importance of a systematic approach to validation.
EMA Guidelines
The European Medicines Agency (EMA) has published guidelines on process validation for the manufacture of biotechnology-derived active substances and data to be provided in regulatory submissions. These guidelines align with the principles of ICH Q8, Q9, and Q10, promoting a lifecycle approach to validation.
Annex 15 provides guidance on qualification and validation in pharmaceutical manufacturing. Regarding Design Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ) which is pretty much either the V or W model.
Annex 15 emphasizes a lifecycle approach to validation, considering all stages from initial development of the user requirements specification through to the end of use of the equipment, facility, utility, or system. The main stages of qualification and some suggested criteria are indicated as a “could” option, allowing for flexibility in approach.
Annex 15 provides a structured yet flexible approach to qualification, allowing pharmaceutical manufacturers to adapt their validation strategies to the complexity of their equipment and processes while maintaining compliance with regulatory requirements.
FDA Guidance
The U.S. Food and Drug Administration (FDA) issued its “Guidance for Industry: Process Validation: General Principles and Practices” in 2011. This guidance emphasizes a lifecycle approach to process validation, consisting of three stages: process design, process qualification, and continued process verification.
ASTM E2500, “Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment,” provides a risk-based approach to validation. It introduces the concept of “verification” as an alternative to traditional qualification steps, allowing for more flexible and efficient validation processes.
ISPE Guidelines
The International Society for Pharmaceutical Engineering (ISPE) has published several baseline guides and good practice guides that complement regulatory requirements. These include guides on commissioning and qualification, as well as on the implementation of ASTM E2500.
This guide offers practical guidance on implementing a science and risk-based approach to commissioning and qualification (C&Q). Key aspects include:
Applying Quality Risk Management to C&Q
Best practices for User Requirements Specification, Design Review, Design Qualification, and acceptance/release
Efficient use of change management to support C&Q
Good Engineering Practice documentation standards
The guide aims to simplify and improve the C&Q process by integrating concepts from regulatory guidances (EMA, FDA, ISO) and replacing certain aspects of previous approaches with Quality Risk Management and Good Engineering Practice concepts.
Conclusion
While the 4Q, V, and W models provide structured approaches to validation, the pharmaceutical industry is increasingly moving towards risk-based and science-driven methodologies. Regulatory agencies and industry organizations are promoting flexible approaches that focus on critical aspects of product quality and patient safety.
By leveraging guidelines such as ASTM E2500 and ISPE recommendations, pharmaceutical companies can develop efficient validation strategies that meet regulatory requirements while optimizing resources. The key is to understand the principles behind these models and guidelines and apply them in a way that best suits the specific needs of each facility, system, or process.
I think many of us have been discussing the blatant obstruction demonstrated in the December 2024 Warning Letter to Brands International Corporation, a drug manufacturer located in Ontario, Canada, citing it for limiting and delaying FDA’s inspection. Which it is important to remember congress has said is a big no-no.
I just want to stress that the Quality Manager there had a really bad day, week, month, year.
Good writeup of what to do around building your procedure for interviewing of employees during an inspection over at FDA Law blog.
Investigations of a Dog 