Batch and the Batch Record

Inevitably, in biotech, with our manufacturing processes such as cell culture, fermentation, and purification, we ask the question (especially with continuous manufacturing), “Just what is a batch anyway.” Luckily for us, the ISA S88.01 provides a standard, with models and terminology, to give us a structured framework to define, control, and automate batch processes effectively

ISA S88.01 (ANSI/ISA-88) standardizes batch control terminology by providing a consistent set of models and terminology for describing all the aspects of batch processing. This standardization helps improve communication between all parties involved in batch control, including users, vendors, and engineers.

Models and Terminology: ISA S88.01 defines a set of models and terminology to describe batch control’s physical and procedural aspects. This includes the physical model, which outlines the hierarchical structure of equipment, and the procedural control model, which details the sequence of operations and phases involved in batch processing.
Physical Model: The physical model begins at the enterprise level and includes sites, areas, process cells, units, equipment, and control modules. This hierarchical structure ensures that all physical components involved in batch processing are consistently described.
Procedural Control Model: This model consists of recipe procedures, unit procedures, operations, and phases. Each level in this hierarchy represents a different level of detail in the batch process, from high-level procedures to specific actions performed by equipment.
Recipe Types and Contents: ISA S88.01 standardizes the types of recipes (general, site, master, and control) and their contents, which include the header, formula, equipment requirements, procedure, and other necessary information. This ensures recipes are consistently structured and understood across different systems and organizations.
State Definitions: The standard defines various states that units or phases can transition through during their operation, such as idle, running, held, paused, aborted, and completed. These states provide a standardized framework for interaction between recipe phases and control system equipment.
Data Structures and Guidelines: ISA S88.01 provides guidelines for data structures and batch control languages, simplifying programming, configuration tasks, and communication between system components. This helps ensure that data is consistently managed and communicated within the batch control system.

The Batch Record

Batch records are the primary documentation that captures the real-time performance of production records. Batch records are crucial to confirming that all expected and required actions have been completed within parameters to produce a product that meets specifications and complies with quality standards.

The Master Batch Record (MBR) is the version-controlled documentation necessary to trace the complete cycle of manufacture of a batch of product, from the dispensing of materials through all processing, testing, and subsequent packaging to the dispatch for sale or supply of the finished product. This documentation includes quality control, quality assurance, and environmental data relevant to the intended manufacturing.

The MBR may be segmented on intended manufacturing and testing stages, each part controlled separately.

The Production Batch Record (PBR) is issued for manufacturing one (or more) batches from the MBR and is compiled during manufacturing.

The MBR and PBR may be controlled in the document management system, within a manufacturing execution system (MES)/electronic batch record (EBR) platform, or some hybrid. Parts may also be found within the LIMS, data historian, and other electronic systems. A critical part of building the MBR is ensuring the correct connections between it and data in specific electronic platforms.

	Electronic System	Description
Master Production Record	Master Recipe	Contains product name or designation, recipe designation or version, formulas, equipment requirements or classes, sequence of activities, procedures, normalized bill of materials (quantity per unit volume to produce)
	Work Instructions	Additional detailed instructions – may include electronic SOPs or SOP references
	Critical Process Parameters	Required Process Parameters that are to be checked or monitored or are to be downloaded to other systems such as automation
Production Batch Record	Control Recipe	A Master Recipe dispatched or otherwise made available in manufacturing-related areas for Execution. Includes Master Recipe information with the addition of schedule, specific quantity to make, actual target bill of materials quantities, and other data for the batch and production instance
	Electronic Production Record	A store of data and information created by systems or entered by personnel during execution of Control Recipes May be located in one or more systems or databases Data may or may not be stored in human readable format
	Production Report	Data and information in human-readable format, presented either in electronic or paper format for activities such as review, disposition, investigation, audit, and analysis.

Comparison of the MBR and PBR Paper to Electronic

The Validation Discrepancy

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.

Use of Pronouns

Proper pronoun use is a small but significant step towards building a more inclusive, respectful, and equitable workplace. It helps create a culture where all individuals feel seen, heard, and valued, which is essential for fostering a positive and productive work environment.

Practical Steps to Ensure the Use of Preferred Pronouns at Work

1. Lead by Example

Include Pronouns in Signatures: Encourage employees to add their pronouns to email signatures, LinkedIn profiles, and other digital communication channels.
Introduce with Pronouns: Leaders and managers should model the behavior by introducing themselves with their pronouns in meetings and communications.

2. Use Gender-Neutral Language

Address Groups Inclusively: Use terms like “team,” “folks,” or “everyone” instead of gendered terms like “ladies and gentlemen”.
Inclusive Terms: Replace gender-specific terms such as “maternity leave” with “parental leave” and use “partner” or “spouse” instead of “husband” or “wife”.

3. Provide Education and Training

Regular Training Sessions: Conduct mandatory training on using correct pronouns and inclusive language.
Continuous Learning: Offer ongoing education opportunities rather than one-time sessions to ensure the practice becomes ingrained in the company culture.

4. Create a Supportive Environment

Encourage Voluntary Disclosure: While promoting pronoun sharing, ensure it remains voluntary to avoid pressuring employees who may not be ready to disclose their gender identity.
Normalize Pronoun Sharing: Make sharing pronouns a regular part of introductions and communications to normalize the practice.

5. Address Mistakes Appropriately

Correct and Apologize: If someone uses the wrong pronoun, they should correct themselves, apologize, and try to use the proper pronoun in the future.
Practice Pronouns: Encourage employees to practice using correct pronouns to prevent mistakes and create a more inclusive environment.

6. Implement Policies and Consequences

Anti-Discrimination Policies: Ensure that company policies explicitly prohibit discrimination based on gender identity and expression, including intentional misgendering.
Consequences for Misgendering: Include intentional misgendering and deadnaming in the formal definition of harassment and outline clear consequences for such behavior.

7. Visible Support from Leadership

Senior Leadership Engagement: Ensure senior leaders actively support and participate in pronoun initiatives to demonstrate the company’s commitment to inclusivity.

The Mistake I See in Most Quality Risk Management SOPs

I have a little trick when reviewing a Quality Risk Management SOP. I go to the process/procedure map section, and if I see only the illustration from ICH Q9, I know I am looking at an organization that hasn’t actually thought about risk management.

A risk management process needs more than the methodology behind individual risk management (assess, control, review). It needs to include the following:

Risk Plan: How do you manage risk management holistically? Which systems/processes have living risk assessments? What are your planned reviews? What significant initiatives around quality risk management are included?
Risk Register: How do you manage your entire portfolio of risks? Link to quality management review.
Selection of tools, and even more importantly, development of tools.
Mechanisms and tools for risk treatment
Improvement strategy for the quality risk management program. How do we know if the program is working as intended?
How to define, select, and train risk owners
How to engage the appropriate stakeholders in the risk process

Too many quality risk management SOPs do not read like process or procedure. They read like a regurgitation of ICH Q9 or the ISO31000 documents. Neither is a good thing. You must go deeper and create an executable process to govern the system.

Building a Part 11/Annex 11 Course

I have realized I need to build a Part 11 and Annex 11 course. I’ve evaluated some external offerings and decided they really lack that applicability layer, which I am going to focus on.

Here are my draft learning objectives.

21 CFR Part 11 Learning Objectives

Understanding Regulatory Focus: Understand the current regulatory focus on data integrity and relevant regulatory observations.
FDA Requirements: Learn the detailed requirements within Part 11 for electronic records, electronic signatures, and open systems.
Implementation: Understand how to implement the principles of 21 CFR Part 11 in both computer hardware and software systems used in manufacturing, QA, regulatory, and process control.
Compliance: Learn to meet the 21 CFR Part 11 requirements, including the USFDA interpretation in the Scope and Application Guidance.
Risk Management: Apply the current industry risk-based good practice approach to compliant electronic records and signatures.
Practical Examples: Review practical examples covering the implementation of FDA requirements.
Data Integrity: Understand the need for data integrity throughout the system and data life cycles and how to maintain it.
Cloud Computing and Mobile Applications: Learn approaches to cloud computing and mobile applications in the GxP environment.

EMA Annex 11 Learning Objectives

General Guidance: Understand the general guidance on managing risks, personnel responsibilities, and working with third-party suppliers and service providers.
Validation: Learn best practices for validation and what should be included in validation documentation.
Operational Phase: During the operational phase, gain knowledge on data management, security, and risk minimization for computerized systems.
Electronic Signatures: Understand the requirements for electronic signatures and how they should be permanently linked to the respective record, including time and date.
Audit Trails: Learn about the implementation and review of audit trails to ensure data integrity.
Security Access: Understand the requirements for security access to protect electronic records and electronic signatures.
Data Governance: Evaluate the requirements for a robust data governance system.
Compliance with EU Regulations: Learn how to align with Annex 11 to ensure compliance with related EU regulations.

Course Outline: 21 CFR Part 11 and EMA Annex 11 for IT Professionals

Module 1: Introduction and Regulatory Overview

History and background of 21 CFR Part 11 and EMA Annex 11
Purpose and scope of the regulations
Applicability to electronic records and electronic signatures
Regulatory bodies and enforcement

Module 2: 21 CFR Part 11 Requirements

Subpart A: General Provisions
Definitions of key terms
Implementation and scope
Subpart B: Electronic Records
Controls for closed and open systems
Audit trails
Operational and device checks
Authority checks
Record retention and availability
Subpart C: Electronic Signatures
General requirements
Electronic signature components and controls
Identification codes and passwords

Module 3: EMA Annex 11 Requirements

General requirements
Risk management
Personnel roles and responsibilities
Suppliers and service providers
Project phase
User requirements and specifications
System design and development
System validation
Testing and release management
Operational phase
Data governance and integrity
Audit trails and change control
Periodic evaluations
Security measures
Electronic signatures
Business continuity planning

Module 4: PIC/S Data Integrity Requirements

Data Governance System
- Structure and control of the Quality Management System (QMS)
- Policies related to organizational values, quality, staff conduct, and ethics
Organizational Influences
- Roles and responsibilities for data integrity
- Training and awareness programs
General Data Integrity Principles
- ALCOA+ principles (Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring, and Available)
- Data lifecycle management
Specific Considerations for Computerized Systems
- Qualification and validation of computerized systems
- System security and access controls
- Audit trails and data review
- Management of hybrid systems
Outsourced Activities
- Data integrity considerations for third-party suppliers
- Contractual agreements and oversight
Regulatory Actions and Remediation
- Responding to data integrity issues
- Remediation strategies and corrective actions
Periodic System Evaluation
- Regular reviews and re-validation
- Risk-based approach to system updates and maintenance

Module 5: Compliance Strategies and Best Practices

Interpreting regulatory guidance documents
Conducting risk assessments
Our validation approach
Leveraging suppliers and third-party service providers
Implementing audit trails and electronic signatures
Data integrity and security controls
Change and configuration management
Training and documentation requirements

Module 6: Case Studies and Industry Examples

Review of FDA warning letters and 483 observations
Lessons learned from industry compliance initiatives
Practical examples of system validation and audits

Module 7: Future Trends and Developments

Regulatory updates and revisions
Impact of new technologies (AI, cloud, etc.)
Harmonization efforts between global regulations
Continuous compliance monitoring

The course will include interactive elements such as hands-on exercises, quizzes, and group discussions to reinforce the learning objectives. The course will provide practical insights for IT professionals by focusing on real-world examples from our company.