Shipping Container Validation

Follow a systematic process to validate a shipping container by involving the traditional three main stages: Design Qualification (DQ), Operational Qualification (OQ), and Performance Qualification (PQ).

Design Qualification (DQ)

The DQ stage involves establishing that the shipping container design meets the user requirements and regulatory standards. Key steps include:

Define user requirement specifications (URS) for the container, including temperature range, duration of transport, and product-specific needs.
Review the container design specifications provided by the manufacturer.
Assess the container’s compatibility with the pharmaceutical product and its storage requirements.
Evaluate the container’s compliance with relevant regulatory guidelines and standards.

Operational Qualification (OQ)

OQ involves testing the container under controlled conditions to ensure it operates as intended. This stage includes:

Conducting empty container tests to verify basic functionality.
Testing temperature control systems and monitoring devices.
Evaluating the container’s ability to maintain required conditions under various environmental scenarios.
Assessing the ease of use and any potential operational issues.

Performance Qualification (PQ)

PQ is the most critical stage, involving real-world testing to ensure the container performs as required under actual shipping conditions. Steps include:

Develop a detailed PQ protocol that outlines test conditions, acceptance criteria, and data collection methods.
Conduct shipping trials using actual or simulated product loads.
Test the container under worst-case scenarios, including extreme temperature conditions and extended shipping durations.
Monitor and record temperature data throughout the shipping process.
Assess the impact of various handling conditions (e.g., vibration, shock) on container performance.
Evaluate the container’s performance across different shipping lanes and modes of transport.

Additional Considerations

Associated Materials and Equipment: Ensure all associated materials (e.g., coolants, packaging materials) and monitoring equipment are also qualified.
Re-qualification: For reusable containers, establish a process for periodic re-qualification to ensure ongoing performance.
Documentation: Maintain comprehensive documentation of all qualification stages, including test results, data analysis, and conclusions.
Risk Assessment: Conduct a risk assessment to identify potential failure modes and mitigation strategies.

Best Practices

Use a risk-based approach to determine the extent of testing required for each container type and shipping scenario.
Consider seasonal variations in ambient temperature profiles when designing qualification studies.
Utilize pre-qualified containers from reputable suppliers when possible to streamline the validation process.
Implement a robust change control process to manage any container or shipping process modifications post-validation.
Regularly review and update validation documentation to reflect any changes in regulatory requirements or shipping conditions.

Following this comprehensive approach, you can ensure that your shipping containers are properly validated for pharmaceutical transport, maintaining product quality and integrity throughout the supply chain. Validation is an ongoing process, and containers should be periodically reassessed to ensure continued compliance and performance.

What do I need a Toxicologist for in the GMPs

Working on a job description for a toxicologist. Here’s what I have so far: what am I missing on the GMP side (not the GCP, GVP, or GLP sides).

A toxicologist plays several important roles in GMP activities, including in cleaning validation and extractable/leachable (E&L) studies for pharmaceutical manufacturing:

For cleaning validation:

Establishing safety thresholds: Toxicologists help determine the Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE) limits for residual substances. These limits are crucial for setting acceptance criteria in cleaning validation.
Risk assessment: They evaluate the potential health risks associated with residual substances that may remain after cleaning processes.
Determining safety factors: Toxicologists apply appropriate safety factors when calculating acceptable residue limits, considering factors like route of administration and patient population.
Reviewing toxicological data: They analyze available toxicity data on active ingredients, excipients, and cleaning agents to inform safety assessments.

For extractable and leachable studies:

Toxicological evaluation: Toxicologists assess the potential health impacts of identified extractables and leachables from packaging materials or manufacturing equipment.
Setting thresholds: They help establish Safety Concern Thresholds (SCT) and Analytical Evaluation Thresholds (AET) for E&L studies.
Risk characterization: Toxicologists evaluate the toxicological significance of detected leachables in relation to patient exposure.
Providing expertise on regulatory guidelines: They ensure studies comply with regulatory expectations regarding toxicological risk assessment.
Interpreting study results: Toxicologists help interpret the significance of E&L findings in the context of patient safety.

Toxicologists provide critical expertise in assessing the potential health impacts of trace contaminants or leached substances. They also ensure that cleaning processes and packaging materials do not introduce unacceptable risks to patient safety. Their input is essential for developing scientifically sound and regulatorily compliant approaches to these critical pharmaceutical quality and safety aspects.

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.