Some Recent Psychological Safety Articles from HBR

“When a Team Member Speaks Up — and It Doesn’t Go Well” by Megan Reitz
and Amy C. Edmondson addresses the critical issue of speaking up in organizations and the potential negative outcomes that can occur. Great stuff, well worth the read, and particularly relevant to the themes of a just, conducive, and quality culture where open communication and diverse perspectives are core values.

“Research: “New Hires’ Psychological Safety Erodes Quickly” by Amy C. Edmondson, Derrick P. Bransby, and Michaela J. Kerrissey confirms what I’ve long suspected about a deadly trough in psychological safety. I’ve certainly felt it myself. Going to be thinking about this for a long while.

I’m Not Lazy, I am Just Overwhelmed

I get it. When searching for a job, it’s easy to find the realities of that search depressing and direct criticism at hiring managers (or the recruiter, and it is almost never the recruiter) for slow hiring processes or seeming unresponsive to candidates. However, the reality is that most hiring managers, like myself, are not lazy – we are overwhelmed.

The Many Hats of a Hiring Manager

Hiring managers typically juggle multiple responsibilities beyond just recruiting:

We are managing our current team and ongoing projects. So many projects and remember we are all putting in too many hours as individual contributors.
Participating in strategic planning
Attending meetings and handling administrative tasks
Staying on top of industry trends and developments

On top of these day-to-day duties, hiring managers must also navigate the complex and time-consuming process of bringing on new team members. And too often, it is easy to get pulled away from hiring as critical issues happen.

The Time-Intensive Nature of Hiring

Recruiting quality candidates is far more involved than many realize:

Writing detailed job descriptions
Reviewing resumes and applications (often hundreds per role). Don’t underestimate the allure of just stopping after a certain point, picking your tops, and advancing them.
Conducting initial phone screenings. Which means coordinating at least two calendars.
Coordinating and participating in multiple rounds of interviews
Evaluating candidates and making hiring decisions
Negotiating offers and onboarding new hires

Studies show the average time to hire is 36 days, with hiring managers spending significant time on each step. For specialized or senior roles, the process can take even longer. In quality i’d love to take only 36 days, or 90.

Competing Priorities

While hiring is crucial, it often competes with other urgent business priorities. Managers must balance recruitment efforts with hitting targets, serving internal and external clients, and keeping current projects on track.

Apologies

Looking for a job sucks for everyone. The searcher hates it; the hiring manager hates the process; HR is just trying to keep things happening. Technology gets introduced, and frankly, it makes it more challenging. But we hiring managers aren’t lazy – we are dedicated professionals trying to balance competing priorities in a high-pressure environment.

Extractables and Leachables (E&L)

An effective program for managing extractables and leachables (E&L) in biotech involves a comprehensive approach that ensures product safety and compliance with regulatory standards. As single-use technologies have become more prevalent in biopharmaceutical manufacturing, leachables from bags, tubing, and other plastic components have become an area of concern. This has led to more rigorous supplier qualification and leachables risk assessment for single-use systems.

Extractables are chemical compounds that can be extracted from materials (like single-use systems, packaging, or manufacturing equipment) under exaggerated conditions such as elevated temperature, extended contact time, or use of strong solvents. They represent a “worst-case” scenario of chemicals potentially migrating into a drug product. Extractables are specific to the tested material and are independent of the drug product.

Leachables are chemical compounds that actually migrate from materials into the drug product under normal conditions of use or storage. They are specific to the combination of the material and the particular drug substance or product, representing the contaminants that may be present in the final drug formulation. Leachables are typically a subset of extractables that migrate under real-world conditions.

The accumulation of extractables and leachabes in a process fluid is governed by thermodynamics (the extent to which the materials would migrate) and kinetic (the rate at which would migrate) factors, as well as the amount of time during which such migration will occur. Higher temperatures increase the migration rate of leachables from the bulk of plastic to the surface in contact with the process stream or formulation.

Key points

Extractables studies are performed on materials using exaggerated conditions.
Leachables studies are performed on the actual drug product under normal conditions.
Extractables represent potential contaminants, while leachables are actual contaminants.
Both are critical for assessing product safety and quality in biotech manufacturing.

Proper evaluation of extractables and leachables is essential for regulatory compliance and ensuring patient safety in biopharmaceutical products.

Program Objectives

Safety Assurance: Ensure that any chemicals leached from materials into the product do not pose a risk to patient safety.
Regulatory Compliance: Meet all relevant regulatory requirements and guidelines.
Quality Control: Maintain the integrity and quality of the biopharmaceutical product.

Regulatory Requirements

Compliance with USP <661> Plastic Packaging Systems and Their Materials of Construction, and USP <381> Elastomeric Closure for Injection
Compliance with USP <87> Biological Reactivity, In Vitro and USP <88> Biological Reactivity, In Vivo
Compliance with European Pharmacopoeia (EP) requirements for materials used in containers, including EP General Chapter 3.1 Materials Used for the Manufacture of Containers and EP 3.2.9 Rubber Closures
Compliance with Japanese Pharmacopoeia (JP) chapter 7.03 Test for Rubber Closures for Aqueous Infusions
Compliance with EU Commission Decision 97/534/EC for Animal derived stearates
Adherence to ICH Q8, Q9, and Q10 guidelines for quality risk management
Leverage ISO 10993-1:2018 Biological evaluation of medical devices

Program Components

Design Space

The starting point should be a review of the supplier’s data. These studies should be performed on materials at the component level under standardized conditions of temperature time, surface, area, etc., so that the data is representative of intended use, including sterilization techniques. Using this data, the end-user can calculate the minimum amount of extractables based on surface area and other conditions. Consider the impact of dilution and clearance over the complete process through risk assessment and then complement with targeted studies.

These studies should be developed based on Quality-by-design principles described in ICH Q8 to gather all the attributes and parameters used to determine a design space. Scientific variables should be identified to set up the Design of Experiment (DoE) for the testing plan.

Risk Assessment

Material Selection: Evaluate materials used for their potential to release harmful substances.
Process Understanding: Understand the process conditions (e.g., temperature, pH, solvents) that might affect the leaching of chemicals.
Risk Prioritization: Prioritize materials and processes based on their risk of contributing harmful leachables. Consider factors like stage of manufacturing, contact time, and proximity to final product.

The risk assessment needs to be within the overall context of process performance and product safety and efficacy. It should not be a separate risk assessment. You will dive deeper with more specific risk questions, but the hazard identification starts at the process level. In evaluating risks the following factors should be considered:

Proximity of the process steps undergoing a change to the final product. Polymeric components in process steps closer to DS or DP will carry a higher risk rating than those in upstream process steps. For example, a bag or filter used for the final filtration of bulk drug substance (BDS) will have a much higher risk rating than components used in upstream process steps since there are no purification steps post-UF/DF.
Storage and processing conditions (e.g., duration of exposure, temperature, pressure, pH extremes, buffer extraction propensity)
The type of process fluid (e.g., purification buffer versus formulated drug substance, presence of solubilizing agents)
Construction materials
Potential adverse events, including synergistic and additive affects
Drug dose, mode, and frequency of administration
Therapeutic necessity

Your risk assessment will drive study design and should consider:

Analytical challenges

Detecting and quantifying trace levels of leachables, which are often present at extremely low concentrations
Developing analytical methods capable of detecting and quantifying a wide range of potential extractables/leachables
Interference from formulation components or degradation products

Determining appropriate extraction conditions:

Selecting solvents and conditions that adequately simulate or exaggerate real-world use conditions
Balancing the need for aggressive extraction (to identify potential leachables) with realistic use conditions

Toxicological assessment

Evaluating the safety impact of identified extractables/leachables, especially for novel compounds
Determining appropriate safety thresholds and analytical evaluation thresholds

Regulatory expectations

Meeting evolving regulatory requirements and expectations, which can vary between regions
Justifying the extent of E&L studies performed based on risk assessment

Unexpected interactions

Leachables causing unexpected effects, such as oxidation of preservatives or formation of protein-leachable adducts
Interactions between leachables and the drug product that were not predicted by extractables studies

Time and resource constraints

E&L studies can be time-consuming and resource-intensive, potentially impacting development timelines

Absorption issues

Adsorption or absorption of drug product components by single-use materials, potentially affecting product stability or efficacy

Stability considerations

Leachables appearing during stability studies that were not identified in initial extractables screening
Changes in leachables profile over time or under different storage conditions

Material variability

Inconsistencies in extractables/leachables profiles between different lots of materials or components

Biopharmaceutical-specific challenges

Potential impact of leachables on sensitive cell lines or biological processes
Interference of leachables with bioassays or analytical methods specific to biologics

Extractables Studies

Objective: Identify potential extractables from materials under exaggerated conditions.
Methodology:
- Use a range of solvents that mimic the process fluids.
- Apply exaggerated conditions such as elevated temperatures and extended contact times.
- Analyze the extracts using techniques like GC-MS, LC-MS, and ICP-MS.
Data Review: Compare supplier-provided extractable data with the intended use to determine the need for specific studies.

Leachables Studies

Objective: Identify and quantify leachables under actual process conditions.
Methodology:
- Conduct studies during the development stages and monitor during stability studies.
- Use appropriate solvent systems and conditions that mimic the actual process.
- Analyze the product for leachables using validated analytical methods.
Toxicological Assessment: Assess the toxicological impact of identified leachables to ensure they are within safe limits.

Migration Studies

Objective: Evaluate the migration of chemicals from materials into the product over time.
Methodology:
- Perform studies during the development phase.
- Monitor leachables during formal stability studies under normal and accelerated conditions.

Absorption Studies

Objective: Assess the potential for adsorption or absorption of product components.
Methodology:
- Conduct studies if stability issues are observed during hold time studies.
- Evaluate the impact on product stability and quality.

Stability Studies

Objective: Ensure the stability of the product in contact with materials.
Methodology:
- Conduct real-time and accelerated stability studies.
- Monitor product quality attributes such as potency, purity, and safety.

Implementation and Validation

Supplier Qualification

Supplier Evaluation: Assess suppliers’ ability to provide materials that meet E&L requirements.
Documentation Review: Ensure suppliers provide comprehensive extractables data and compliance certificates.

In-House Testing

Validation: Validate the findings from supplier data with in-house testing.
Protocol Development: Develop protocols for E&L testing specific to the product and process conditions.
Acceptance Criteria: Establish acceptance criteria based on regulatory guidelines and risk assessments.

Toxicological Assessment and Risk Mitigation

Assess the toxicological impact of identified leachables to ensure they are within safe limits. Perform Risk Mitigation to:

Implement appropriate controls based on risk assessment results
Consider factors like materials selection, process parameters, and analytical testing
Develop strategies to minimize leachables impact on product quality and safety

Continuous Monitoring

Routine Testing: Implement routine testing of leachables during production.
Change Management: Re-evaluate E&L profiles when there are changes in materials, suppliers, or processes.

Training and Education

Staff Training

Awareness: Train staff on the importance of E&L studies and their impact on product safety.
Technical Training: Provide technical training on conducting E&L studies and interpreting results.

Supplier Collaboration

Engagement: Work closely with suppliers to ensure they understand and meet E&L requirements.
Feedback: Provide feedback to suppliers based on study results to improve material quality.

Conclusion

A robust E&L program in biotech is essential for ensuring product safety, regulatory compliance, and maintaining high-quality standards. By implementing a comprehensive approach that includes risk assessment, thorough testing, supplier qualification, continuous monitoring, and staff training, biotech companies can effectively manage the risks associated with extractables and leachables.

Should Have, Could Have, and Would Have

Avoiding the Word Should in GxP Documents

Generally, it’s best to avoid using “should” in a GxP document (e.g., SOP, plan, report, etc.). The word “should” can come across as non-committal or indicate a preference rather than a firm intention or goal.

GxP Documents are meant to be clear, concise, and direct. A more definitive language and active voice are preferred.

When writing about your goals and plans, it’s better to use more confident and assertive language rather than tentative words like “should.”

If you need to express a goal or aspiration that isn’t mandatory, consider rephrasing it more directly or using alternative constructions that show commitment and motivation.

Focus on using active voice and present tense verbs to describe your experiences, goals, and reasons for applying to the program.

Remember that a GxP Document, like a plan or SOP, is your opportunity to demonstrate your clarity of purpose and commitment. Using more decisive language can help convey this.

In summary, while “should” might be appropriate in some contexts, it’s generally best to avoid it in a GxP document in favor of more direct and confident language that propels into action.

Modals of Lost Opportunity

The term “modals of lost opportunity” refers to the modal verbs should have, could have, and would have. These modals express regret or hypothetical scenarios about past events that did not occur. They allow speakers to reflect on what might have been different if specific actions had been taken. They can be used in business and technical writing to express regret, hypothetical scenarios, and constructive feedback. But they should be used very carefully in GxP writing.

Should have indicates that a different action was recommended or expected in the past. It often implies a sense of regret or criticism about what was done or not done.

Example: “I should have left my house earlier.” This implies that leaving earlier would have been the better choice, possibly to avoid being late.

Could have is used to talk about possibilities or abilities that existed in the past but were not realized. It often reflects on missed opportunities or potential outcomes that did not happen.

Example: “If I had gone to college, I could have gotten a better job.” This suggests that attending college was a possibility that could have led to a better job, but it did not happen.

Would have is used to imagine a specific result that would have occurred if a different action had been taken. It often expresses a more certain outcome compared to “could have.”

Example: “If we had arrived earlier, we would have caught our flight.” This indicates that arriving earlier would have definitely resulted in catching the flight.

Usage in Sentences

Should Have: “You should have completed your training.” This implies that training was the recommended action that was not taken.
Could Have: “She could have won the race if she hadn’t fallen.” This suggests that winning was a possible outcome if not for the fall.
Would Have: “I would have called you, but I didn’t know your number.” This indicates a definite action that would have occurred if the number was known.

Transparency at the FDA

Leveling Up Agency Disclosures

I fully agree with this excellent post and its closing line “The public should therefore not need to request such materials from the agency, but should have easy, online access to them at any time.”

All 483s, complete response letters (CRL), and other FDA decisions should be easily accessible. This would be a net positive gain for our profession. I know I’ve reached out to my congress critters about this as the FDA is going through budgeting (and Congress continues to not fund the agency enough).