Category: compliance

Building the FUSE(P) User Requirements in an ICH Q8, Q9 and Q10 World

“The specification for equipment, facilities, utilities or systems should be defined in a URS and/or a functional specification. The essential elements of quality need to be built in at this stage and any GMP risks mitigated to an acceptable level. The URS should be a point of reference throughout the validation life cycle.” – Annex 15, Section 3.2, Eudralex Volume 4

User Requirement Specifications serve as a cornerstone of quality in pharmaceutical manufacturing. They are not merely bureaucratic documents but vital tools that ensure the safety, efficacy, and quality of pharmaceutical products.

Defining the Essentials

A well-crafted URS outlines the critical requirements for facilities, equipment, utilities, systems and processes in a regulated environment. It captures the fundamental aspects and scope of users’ needs, ensuring that all stakeholders have a clear understanding of what is expected from the final product or system.

Crafting Good User Requirements

Building Quality from the Ground Up

The phrase “essential elements of quality need to be built in at this stage” emphasizes the proactive approach to quality assurance. By incorporating quality considerations from the outset, manufacturers can:

  • Minimize the risk of errors and defects
  • Reduce the need for costly corrections later in the process
  • Ensure compliance with Good Manufacturing Practice (GMP) standards

Mitigating GMP Risks

Risk management is a crucial aspect of pharmaceutical manufacturing. The URS plays a vital role in identifying and addressing potential GMP risks early in the development process. By doing so, manufacturers can:

  • Implement appropriate control measures
  • Design systems with built-in safeguards
  • Ensure that the final product meets regulatory requirements

The URS as a Living Document

One of the key points in the regulations is that the URS should be “a point of reference throughout the validation life cycle.” This underscores the dynamic nature of the URS and its ongoing importance.

Continuous Reference

Throughout the development, implementation, and operation of a system or equipment, the URS serves as:

  • A benchmark for assessing progress
  • A guide for making decisions
  • A tool for resolving disputes or clarifying requirements

Adapting to Change

As projects evolve, the URS may need to be updated to reflect new insights, technological advancements, or changing regulatory requirements. This flexibility ensures that the final product remains aligned with user needs and regulatory expectations.

Practical Implications

  1. Involve multidisciplinary teams in creating the URS, including representatives from quality assurance, engineering, production, and regulatory affairs.
  2. Conduct thorough risk assessments to identify potential GMP risks and incorporate mitigation strategies into the URS.
  3. Ensure clear, objectively stated requirements that are verifiable during testing and commissioning.
  4. Align the URS with company objectives and strategies to ensure long-term relevance and support.
  5. Implement robust version control and change management processes for the URS throughout the validation lifecycle.

Executing the Control Space from the Design Space

The User Requirements Specification (URS) is a mechanism for executing the control space, from the design space as outlined in ICH Q8. To understand that, let’s discuss the path from a Quality Target Product Profile (QTPP) to Critical Quality Attributes (CQAs) to Critical Process Parameters (CPPs) with Proven Acceptable Ranges (PARs), which is a crucial journey in pharmaceutical development using Quality by Design (QbD) principles. This systematic approach ensures that the final product meets the desired quality standards and user needs.

It is important to remember that this is usually a set of user requirements specifications, respecting the system boundaries.

From QTPP to CQAs

The journey begins with defining the Quality Target Product Profile (QTPP). The QTPP is a comprehensive summary of the quality characteristics that a drug product should possess to ensure its safety, efficacy, and overall quality. It serves as the foundation for product development and includes considerations such as:

  • Dosage strength
  • Delivery system
  • Dosage form
  • Container system
  • Purity
  • Stability
  • Sterility

Once the QTPP is established, the next step is to identify the Critical Quality Attributes (CQAs). CQAs are physical, chemical, biological, or microbiological properties that should be within appropriate limits to ensure the desired product quality. These attributes are derived from the QTPP and are critical to the safety and efficacy of the product.

From CQAs to CPPs

With the CQAs identified, the focus shifts to determining the Critical Process Parameters (CPPs). CPPs are process variables that have a direct impact on the CQAs. These parameters must be monitored and controlled to ensure that the product consistently meets the desired quality standards. Examples of CPPs include:

  • Temperature
  • pH
  • Cooling rate
  • Rotation speed

The relationship between CQAs and CPPs is established through risk assessment, experimentation, and data analysis. This step often involves Design of Experiments (DoE) to understand how changes in CPPs affect the CQAs. This is Process Characterization.

Establishing PARs

For each CPP, a Proven Acceptable Range (PAR) is determined. The PAR represents the operating range within which the CPP can vary while still ensuring that the CQAs meet the required specifications. PARs are established through rigorous testing and validation processes, often utilizing statistical tools and models.

Build the Requirements for the CPPs

The CPPs with PARs are process parameters that can affect critical quality attributes of the product and must be controlled within predetermined ranges. These are translated into user requirements. Many will specifically label these as Product User Requirements (PUR) to denote they are linked to the overall product capability. This helps to guide risk assessments and develop an overall verification approach.

Most of Us End Up on the Less than Happy Path

This approach is the happy path that aligns nicely with the FDA’s Process Validation Model.

This can quickly break down in the real world. Most of us go into CDMOs with already qualified equipment. We have platforms on which we’ve qualified our equipment, too. We don’t know the CPPs until just before PPQ.

This makes the user requirements even more important as living documents. Yes, we’ve qualified our equipment for these large ranges. Now that we have the CPPs, we update the user requirements for the Product User Requirements, perform an overall assessment of the gaps, and, with a risk-based approach, do additional verification activations either before or as part of Process Performance Qualification (PPQ).

FUSE and FUSE(P) – Definitions

I’ve been utilizing a few acronyms in a lazy way, and it is important to define them moving forward.

The acronyms FUSE stands for Facility Utility System Equipment; and FUSE(P) adds Process. This framework is used to describe and manage critical components of systems in facilities, particularly in industrial and pharmaceutical manufacturing settings. Here’s a breakdown of its elements:

Facility

This refers to the physical infrastructure where manufacturing or processing takes place. It includes buildings, production areas, and support spaces designed to house equipment and facilitate operations.

Utility Systems

Utilities are critical systems and services that support pharmaceutical and biotech manufacturing production processes. They are essential for maintaining product quality, safety, and regulatory compliance. The mechanical, electrical, and plumbing systems that support facility operations. Key utility systems include:

  • Heating, Ventilation, and Air Conditioning (HVAC)
  • Electrical distribution
  • Water systems (purified, process, and domestic)
  • Compressed air and gas systems
  • Waste management systems

System

In this context, a system refers to the integrated collection of equipment, components, and structures that work together to perform a specific function.

Equipment

This encompasses the individual machines, devices, and components used in the facility, manufacturing processes, quality control and elsewhere. Examples include mixing tanks, filling machines, packaging equipment, and quality control instruments

Process

This element refers to the manufacturing or production processes that the facility and its utility systems support. It includes:

  • Production workflows
  • Environmental control
  • Cleaning
  • Computer systems for managing manufacturing and operational processes:

The FUSE(P) framework emphasizes the interconnected nature of these elements and their collective impact on product quality, safety, and operational efficiency. It guides the design, implementation, and management of facility utility systems to ensure they meet Good Manufacturing Practice (GMP) standards and support reliable production processes.

Viral Risk Management

While rare, viral contamination events can have severe consequences, potentially impacting product quality, patient safety, and company reputation. And while a consent decree is a good way to grow your skills, I tend to prefer to avoid causing one to happen.

Luckily, regulatory bodies have provided comprehensive guidelines, with ICH Q5A(R2) being a cornerstone document. Let’s explore the best practices for viral risk management in biotech, drawing from ICH Q5A and other relevant guidances.

The Three Pillars of Viral Safety

ICH Q5A outlines three complementary approaches to control potential viral contamination:

  1. Selection and testing of cell lines and raw materials
  2. Assessment of viral clearance capacity in production processes
  3. Testing of the product at appropriate stages for contaminating viruses

These pillars form the foundation of a robust viral safety strategy.

Cell Line and Raw Material Control

  • Thoroughly document the origin and history of cell lines
  • Implement comprehensive testing programs for cell banks, including master and working cell banks
  • Carefully assess and control animal-derived raw materials
  • Consider using chemically-defined or animal-free raw materials where possible
  • Implement stringent change control and quality agreements with raw material suppliers

Viral Clearance Capacity

  • Design manufacturing processes with multiple orthogonal viral clearance steps
  • Validate the effectiveness of viral clearance steps using model viruses
  • Aim for a cumulative viral reduction factor of at least 4 log10 per the USP guidelines
  • Consider both dedicated viral inactivation steps (e.g., low pH treatment) and removal steps (e.g., nanofiltration)
  • For continuous manufacturing, assess the impact of process dynamics on viral clearance

In-Process and Final Product Testing

  • Develop a comprehensive testing strategy for in-process materials and final product
  • Utilize state-of-the-art detection methods, including PCR and next-generation sequencing (NGS)
  • Consider replacing traditional in vivo assays with molecular methods where appropriate
  • Implement a testing program that covers a broad spectrum of potential viral contaminants

Risk-Based Approach

The revised ICH Q5A(R2) emphasizes a risk-based approach to viral safety. This involves:

  • Conducting thorough risk assessments of the entire manufacturing process
  • Identifying critical control points for viral contamination
  • Implementing appropriate mitigation strategies based on risk levels
  • Continuously monitoring and updating the risk assessment as new information becomes available

Prior knowledge, including “in-house” experience, plays a crucial role in viral risk assessment and management for biopharmaceutical manufacturing. Here’s how it can be effectively utilized:

Leveraging Historical Data

  • Review past viral contamination events or near-misses within the organization
  • Analyze trends in raw material quality and supplier performance
  • Evaluate the effectiveness of previous risk mitigation strategies

Process Design and Optimization

  • Apply lessons learned from previous manufacturing campaigns to improve process robustness
  • Use historical data to identify critical control points for viral contamination
  • Optimize viral clearance steps based on past validation studies

Cell Line Susceptibility

  • Use accumulated data on cell line susceptibility to various viruses to inform risk assessments
  • Apply knowledge of cell line behavior under different conditions to enhance contamination detection

Risk Assessment Approach

The risk assessment process should take a holistic approach, focusing on:

  • Raw material sourcing and testing
    • Identifying high-risk materials, especially animal-derived components
    • Assessing chemically-undefined components like hydrolysates and peptones
    • Evaluating materials produced or stored in non-controlled environments
  • Cell substrate selection and characterization
    • Documenting the derivation and source history of the cell line
    • Testing cell banks extensively for adventitious agents
    • Assessing the cell line’s susceptibility to various viruses
  • Process design for viral clearance
    • Designing manufacturing processes with multiple orthogonal viral clearance steps
  • Facility design and operations
    • Implementing robust cleaning and sanitization procedures
    • Ensuring proper facility layout and air handling systems to prevent contamination spread
  • Personnel training and practices
    • Training on proper gowning procedures and personal protective equipment (PPE) usage
    • Policies on illness reporting and exclusion of sick employees from critical areas

Preparedness and Response

While prevention is key, being prepared for a potential contamination event is crucial:

  • Develop a comprehensive viral contamination response plan[6]
  • Regularly practice and update the response plan through mock drills
  • Establish clear communication channels and decision-making processes
  • Prepare strategies for containment, decontamination, and facility restart

Continuous Improvement

Viral risk management is an ongoing process:

  • Stay updated on emerging technologies and regulatory guidance
  • Participate in industry forums and share best practices
  • Invest in employee training and awareness programs
  • Continuously evaluate and improve viral safety strategies

By implementing these best practices and adhering to regulatory guidances like ICH Q5A, we can strive to significantly mitigate the risk of viral contamination. While no approach can guarantee absolute safety, a comprehensive, risk-based strategy that leverages cutting-edge technologies and emphasizes preparedness will go a long way in protecting patients, products, and the industry as a whole.

FDA Inspections – GAO Report

The GAO has published a report on FDA’s Inspections that found a 36% decrease compared to fiscal year 2019 in the number of inspections, partly due to reduced investigator capacity. A piece of information that should surprise noone.

The report highlights a concerning trend in the FDA’s drug inspection workforce. From November 2021 to June 2024, the vacancy rate among investigators who inspect foreign and domestic manufacturers increased from 9% to 16%.

I think we’ve all seen the impact of this. It’s worth spending a little time reading the report.

ISO 8061 Adoption in Pharma

How widespread is adoption of ISO 8601, the standard for date and time formats? Is your company aligned?

I see ISO 8601 widely used in scientific fields, software development, and more and more international correspondence. Yet, I think its fair to say the adoption in pharma has been lacking. So I am really curious, has your organization fully or partially adopted it? If so, how did it go?

Date Format

The basic principle of ISO 8601 for dates is to represent them in a descending order of significance:

  • Complete date: YYYY-MM-DD (extended format) or YYYYMMDD (basic format)
    Example: 2022-09-27 or 20220927
  • Year and month: YYYY-MM
    Example: 2022-09
  • Year only: YYYY
    Example: 2022

Time Format

ISO 8601 defines the following time format:

  • Basic format: Thhmmss
  • Extended format: Thh:mm:ss

Where:

  • T is the time designator
  • hh represents hours (00-24)
  • mm represents minutes (00-59)
  • ss represents seconds (00-60, where 60 is used for leap seconds)

Example: T134730 or T13:47:30 represents 1:47:30 PM

Combined Date and Time

ISO 8601 allows combining date and time representations:

  • YYYY-MM-DDThh:mm:ss or YYYYMMDDThhmmss

Example: 2022-09-26T07:58:30 represents September 26, 2022, at 7:58:30 AM

Time Zone Designators

The standard also specifies how to represent time zones:

  • Z: Represents UTC (Coordinated Universal Time)
  • ±hh:mm or ±hhmm: Represents the offset from UTC

Example: 2022-09-07T15:50+00:00 or 2022-09-07T15:50Z represents 3:50 PM UTC on September 7, 2022.

Key Features

  1. The standard uses the Gregorian calendar.
  2. It employs a 24-hour clock system.
  3. All elements are represented by a fixed number of digits, zero-padded if necessary.
  4. The standard allows for reduced precision by omitting certain elements.
  5. It can represent dates, times, time intervals, and recurring time intervals

Government and Official Use

Many countries have officially adopted ISO 8601 as their recommended or mandated date format for government and official use. For example:

  • The UK government has mandated the use of ISO 8601 for IT systems, APIs, and machine-to-machine communication.
  • Canada’s government and Standards Council officially recommend ISO 8601 for all-numeric dates.
  • Australia recommends ISO 8601 as the short date format for government publications.

The European Union has adopted ISO 8601 as the European Standard EN 28601, making it valid in all EU countries.

Has anyone seen Health Canada or an EMA (and/or national competent authority) push back at a time/date not in ISO 8061 format? I think there has been a lot of push back in health care around adoption, for example the NHS in the UK uses 01-JAN-2017 for medicine labels even though the UK has adopted ISO 8061.

I find it fascinating that the eCTD specification does not mandate a specific date format for metadata or content within submissions, allowing flexibility for regional requirements. Yet we have seen many health authorities that have implemented eCTD do recommend or require the use of ISO 8601 date formats in certain contexts:

  • The US FDA guidance on eCTD recommends using ISO 8601 format (YYYY-MM-DD) for dates in the submission.
  • The EU guidance on eCTD also recommends ISO 8601 format for dates in certain metadata fields.

The eCTD XML backbone uses the W3C XML Schema date and dateTime datatypes, which are based on ISO 8601 formats. While not explicitly requiring ISO 8601, the eCTD specification does emphasize the importance of consistent and unambiguous date representations, which aligns with the goals of ISO 8601. It really makes me wonder when this decision will start rippling through other parts of the industry.

I’d love your thoughts.