As October rolls around I am focusing on 3 things: finalizing a budget; organization design and talent management; and a 2025 metrics plan. One can expect those three things to be the focus of a lot of my blog posts in October.
Go and read my post on Metrics plans. Like many aspects of a quality management system we don’t spend nearly enough time planning for metrics.
So over the next month I’m going to develop the strategy for a metrics plan to ensure the optimal performance, safety, and compliance of our biotech manufacturing facility, with a focus on:
Facility and utility systems efficiency
Equipment reliability and performance
Effective commissioning, qualification, and validation processes
Robust quality risk management
Stringent contamination control measures
Following the recommended structure of a metrics plan, here is the plan:
Rationale and Desired Outcomes
Implementing this metrics plan will enable us to:
Improve overall facility performance and product quality
Reduce downtime and maintenance costs
Ensure regulatory compliance
Minimize contamination risks
Optimize resource allocation
Metrics Framework
Our metrics framework will be based on the following key areas:
Facility and Utility Systems
Equipment Performance
Commissioning, Qualification, and Validation (CQV)
Quality Risk Management (QRM)
Contamination Control
Success Criteria
Success will be measured by:
Reduction in facility downtime
Improved equipment reliability
Faster CQV processes
Decreased number of quality incidents
Reduced contamination events
Implementation Plan
Steps, Timelines & Milestones
Develop detailed metrics for each key area (Month 1)
Implement data collection systems (Month 2)
Train personnel on metrics collection and analysis (Month 3)
Begin data collection and initial analysis (Month 4)
Review and refine metrics (Month 9)
Full implementation and ongoing analysis (Month 12 onwards)
This plan gets me ready to evaluate these metrics as part of governance in January of next year.
In October I will breakdown some metrics, explaining them and provide the rationale, and demonstrate how to collect. I’ll be striving to break these metrics into key performance indicators (KPI), key behavior indicators (KBI) and key risk indicators (KRI).
It is crucial for a Marketing Authorization Holder (MAH) to review and approve changes made by a Contract Development and Manufacturing Organization (CDMO) for several important reasons:
Regulatory Compliance
The Market Authorization Holder (MAH) – or the sponsor for pre-commercial GMP manufacturing – bears the primary responsibility for ensuring compliance with the marketing authorization and regulatory requirements throughout the product’s lifecycle. By reviewing and approving CDMO changes, the MAH can:
Ensure changes align with the approved marketing authorization
Verify that any variations to the marketing authorization are properly submitted to regulatory authorities
Maintain oversight of post-approval change management as required by regulations
Before I go any further on the topic I want you to go and read my post Classification of Changes for GMP/GDP. This post will build on that discussion.
I think it is better for the CDMO to put a lot of thought into this, and the MAH (the client) to evaluate and adapt. For all but the big players, the volume is going to be on the CDMO’s side. But if you are the client and your CDMO hasn’t taken this into account to the appropriate degree, you need to ensure appropriate steps taken. As such the rest of this post will be written from the CDMO’s side, but the same principles apply to the MAH (and should be included in the audit program).
Remember we have three goals:
Fulfill our contractual responsibilities
Help the MAH maintain appropriate control as the product owner
Ensure alignment between both parties on change implementation
The critical requirement here is ensuring the right changes get to the right client so they can be filled the right way. Returning to basics, we are approaching changes as:
Now it’s easy to apply this to product. Create and/or receive the design space and the control space. Everything that falls into a non-established condition does not get reported to the client at time of execution. If it is “Do and Report” is is in the APQR. If it is “Do and Record” they can see it during the audit.
Where a lot of CDMOs trip up here are facility and quality system changes. My recommendation here is the same, define a design space based on the CMC section of the Common Technical Document which basically boils down to:
The CMC (Chemistry, Manufacturing, and Controls) section of a regulatory dossier typically includes the following key facility-related information:
Manufacturing Facilities
Names and addresses of all manufacturing, testing, and storage facilities involved in production
Description of the manufacturing operations performed at each site
Floor plans and layouts of production areas
Details on utilities and support systems (HVAC, water, gases, etc.)
Information on facility design features for contamination control and product protection
Equipment
List of major production and laboratory equipment
Equipment specifications and capacities
Cleaning and maintenance procedures for equipment
Environmental Controls
Description of clean room classifications and environmental monitoring programs
Air handling systems and controls
Water systems (purified water, water for injection) and controls
Material Flow
Personnel and material flow diagrams
Segregation of operations to prevent cross-contamination
Quality Control Laboratories
Description of QC lab facilities and equipment
Environmental controls in QC labs
Storage Areas
Description of storage facilities for raw materials, intermediates, and finished products
Storage conditions and controls (temperature, humidity, etc.)
There is a whole lot of wiggle room here in things that fall into “Do and Record.” By building this into your change control system you can delineate what goes to to the client and what doesn’t. I recommend sitting down with this list and deciding what types of changes fall into “Tell and Do” – what you ask permission from clients before doing; “Do and Report” – what goes in the APQR; and, “Do and Record” – what the client sees when they audit.
You know have good rules on what changes go to a client for prior approval and which ones do not. This gets codified in two places: the change control process and the quality/technical agreement.
Some other things to build into your change control process:
Documenting when a client requests a change, the reason and the impact on the platform. Remember you have other clients, and more and more CDMO’s are offering a platform, so there needs to be appropriate review and endorsement.
Think through how changes to facility (and other platform elements) are communicated and gated for multiple clients. Have a mechanism to manage client specific activities and to track first-product impacted for multiple products.
Have clear timelines and expectations on change communication and approval with the client in the quality/technical agreement. Hold each other accountable.
Have contingency plans. There will always be that one client who will be in shortage if you make that urgent change just when you want/need to.
Have a method for evaluating requested changes to the change plan by clients and making decisions around it. There will be that one client who doesn’t agree or wants something weird that disagrees with what all the other clients want.
Have rules in place to manage changes inactive for long periods or extensions specific for those changes that rise to client approval. These will have a different flow than internal changes.
I’ve used a bit of commercial headspace for this post, relying on the APQR. For clinical processes, product tends to fall into campaign-mindset, so “Do and Report” ends up being more a clinical campaign change report than an APQR.
Everyone probably feels like the above illustration sooner or later about their water system.
The Critical Role of Water in Pharmaceutical Manufacturing
In the pharmaceutical industry, we often joke that we’re primarily water companies that happen to make drugs on the side. This quip underscores a fundamental truth: water is a crucial component in drug manufacturing processes. Its purity and quality are paramount to ensuring the safety and efficacy of pharmaceutical products.
Why Water Quality Matters
Water is ubiquitous in pharmaceutical manufacturing, used in everything from cleaning equipment to serving as a key ingredient in many formulations. Given its importance, regulatory bodies like the FDA and EMA have established stringent Good Manufacturing Practice (GMP) guidelines for water systems in pharmaceutical facilities.
GMP Requirements for Water Systems
The GMPs mandate that water systems be meticulously designed, constructed, installed, commissioned, qualified, monitored, and maintained. The primary goal? Preventing microbiological contamination. This comprehensive approach encompasses several key areas:
System Design: Water systems must be engineered to minimize the risk of contamination.
Construction and Installation: Materials and methods used must meet high standards to ensure system integrity.
Commissioning and Qualification: Rigorous testing is required to verify that the system performs as intended.
Monitoring: Ongoing surveillance is necessary to detect any deviations from established parameters.
Maintenance: Regular upkeep is crucial to maintain system performance and prevent degradation.
Key Regulatory Requirements
Agency
Title
Year
URL
EMA
Guideline on the quality of water for pharmaceutical use
To meet these GMP requirements, pharmaceutical manufacturers must implement several specific measures:
Minimizing Particulates
Particulate matter in water can compromise product quality and potentially harm patients. Filtration systems and regular cleaning protocols are essential to keep particulate levels in check.
Controlling Microbial Contamination
Microorganisms can proliferate rapidly in water systems if left unchecked. Strategies to prevent this include:
Regular sanitization procedures
Maintaining appropriate water temperatures
Implementing effective water treatment technologies (e.g., UV light, ozonation)
Preventing Endotoxin Formation
Endotoxins, produced by certain bacteria, can be particularly problematic in pharmaceutical water systems. Measures to prevent endotoxin formation include:
Minimizing areas where water can stagnate
Ensuring complete drainage of pipes
Regular system flushing
The Ongoing Challenge
Maintaining water quality in pharmaceutical manufacturing is not a one-time effort but an ongoing process. It requires constant vigilance, regular testing, and a commitment to continuous improvement. As regulations evolve and our understanding of potential contaminants grows, so too must our approaches to water system management.
Types of Water
These water types are defined and regulated by pharmacopeias such as the United States Pharmacopeia (USP), European Pharmacopoeia (Ph. Eur.), and other regional standards. Pharmaceutical manufacturers must adhere to the specific requirements outlined in these references to ensure water quality and safety in drug production.
Potable Water
Potable water, also known as drinking water, may be used for some pharmaceuticals bt is more commonly used in cosmetics. It can also be used for cleanings walls and floors in non-asceptic areas.
Key points:
Must comply with EPA standards or comparable regulations in the EU/Japan
Can be used to manufacture drug substances (bulk drugs)
Not suitable for preparing USP dosage forms or laboratory reagents
Purified Water (PW)
Purified water is widely used in pharmaceutical manufacturing for non-sterile preparations.
Specifications (USP <1231>):
Conductivity: ≤1.3 μS/cm at 25°C
Total organic carbon (TOC): ≤500 ppb
Microbial limits: ≤100 CFU/mL
Applications:
Non-parenteral preparations
Cleaning equipment for non-parenteral products
Preparation of some bulk chemicals
Water for Injection (WFI)
Water for Injection is used for parenteral drug products and has stricter quality standards.
Specifications (USP <1231>):
Conductivity: ≤1.3 μS/cm at 25°C
TOC: ≤500 ppb
Bacterial endotoxins: <0.25 EU/mL
Microbial limits: ≤10 CFU/100 mL
Production methods:
Distillation
Reverse osmosis (allowed by Ph. Eur. since 2017)
Sterile Water for Injection (SWFI)
SWFI is WFI that has been sterilized for direct administration.
Characteristics:
Sterile
Non-pyrogenic
Packaged in single-dose containers
Highly Purified Water (HPW)
Previously included in the European Pharmacopoeia, but now discontinued.
Type of Water
Description
USP Reference
EP Reference
Potable Water
Meets drinking water standards, used for early stages of manufacturing
Not applicable
Not applicable
Purified Water (PW)
Used for non-sterile preparations, cleaning equipment
USP <1231>
Ph. Eur. 0008
Water for Injection (WFI)
Used for parenteral products, higher purity than PW
USP <1231>
Ph. Eur. 0169
Sterile Water for Injection (SWFI)
WFI that has been sterilized for direct administration
USP <1231>
Ph. Eur. 0169
Bacteriostatic Water for Injection
Contains bacteriostatic agents, for multiple-dose use
USP <1231>
Ph. Eur. 0169
Sterile Water for Irrigation
Packaged in single-dose containers larger than 1L
USP <1231>
Ph. Eur. 1116
Sterile Water for Inhalation
For use in inhalators, less stringent endotoxin levels
USP <1231>
Ph. Eur. 1116
Water for Hemodialysis
Specially treated for use in hemodialysis, produced on-site
USP <1231>
Not specified
Additional relevant USP chapters:
USP <645>: Water for Pharmaceutical Purposes – Microbial Attributes
USP <85>: Bacterial Endotoxins Test
Always refer to the most current versions of the pharmacopoeial monographs and regulatory guidelines for detailed information.
Good Water System Design
Hygienic and Sanitary Design
The cornerstone of any good water system is its hygienic and sanitary design. This principle encompasses several aspects:
Smooth, cleanable surfaces: All surfaces in contact with water should be smooth, non-porous, and easily cleanable to prevent biofilm formation.
Self-draining components: Pipes and tanks should be designed to drain completely, eliminating standing water that could harbor microorganisms.
Accessibility: All parts of the system should be easily accessible for inspection, cleaning, and maintenance.
Material Selection
Choosing the right materials is crucial for maintaining water quality and system integrity:
Corrosion resistance: Use materials that resist corrosion, such as stainless steel (316L grade for high-purity applications) or appropriate food-grade plastics.
Smooth internal finish: Crevices are places where corrosion happens, electropolishing improves the resistance of stainless steel to corrosion.
Leachate prevention: Select materials that do not leach harmful substances into the water, even under prolonged contact or elevated temperatures.
Non-adsorptive surfaces: Avoid materials that may adsorb contaminants, which could later be released back into the water.
Microbial Control
Preventing microbial growth is essential for water system safety:
Elimination of dead legs: Design piping to avoid areas where water can stagnate and microorganisms can proliferate.
Temperature control: Maintain temperatures outside the optimal range for microbial growth (typically below 20°C or above 50°C).
Regular sanitization: Incorporate features that allow for effective and frequent sanitization of the entire system.
System Integrity
Ensuring the system remains sealed and leak-free is critical:
Proper sealing: Use appropriate gaskets and seals compatible with the system’s operating conditions.
Pressure testing: Implement regular pressure tests to identify and address potential leaks promptly.
Quality connections: Utilize sanitary fittings and connections designed for hygienic applications.
Cleaning and Sanitization Compatibility
The system must withstand regular cleaning and sanitization:
Chemical resistance: Choose materials and components that can tolerate cleaning and sanitizing agents without degradation.
Thermal stability: Ensure all parts can withstand thermal sanitization processes if applicable.
CIP/SIP design: Incorporate Clean-in-Place (CIP) or Steam-in-Place (SIP) features for efficient and thorough cleaning.
Capacity and Performance
Meeting output requirements while maintaining quality is crucial:
Proper sizing: Design the system to meet peak demand without compromising water quality or flow rates.
Redundancy: Consider incorporating redundant components for critical parts to ensure continuous operation.
Efficiency: Optimize the system layout to minimize pressure drops and energy consumption.
Monitoring and Control
Implement robust monitoring systems to ensure water quality:
Sampling points: Strategically place sampling ports throughout the system for regular quality checks.
Instrumentation: Install appropriate instruments to monitor critical parameters such as flow rate, pressure, temperature, and conductivity.
Control systems: Implement automated control systems to maintain consistent water quality and system performance.
Regulatory Compliance
Ensure the system design meets all relevant regulatory requirements:
Material compliance: Use only materials approved for contact with water in your specific application.
Documentation: Maintain detailed documentation of system design, materials, and operating procedures.
Validation: Conduct thorough system qualification to demonstrate consistent performance and quality.
By adhering to these principles, you can design a water system that not only meets your capacity requirements but also ensures the highest standards of safety and quality. Remember, good water system design is an ongoing process that requires regular review and updates to maintain its effectiveness over time.
In the world of pharmaceutical manufacturing, cleanroom classifications play a crucial role in ensuring product quality and patient safety. However, a significant hurdle in the global harmonization of regulations has been a pain in our sides for a long time, that highlights the persistent differences between major regulatory bodies, including the FDA, EMA, and others, despite efforts to align through organizations like the World Health Organization (WHO) and the Pharmaceutical Inspection Co-operation Scheme (PIC/S).
The Current Landscape
United States Approach
In the United States, cleanroom classifications are primarily governed by two key documents:
The FDA’s “Sterile Drug Products Produced by Aseptic Processing” guidance
ISO 14644-1 standard for cleanroom classifications
The ISO 14644-1 standard is particularly noteworthy as it’s a general standard applicable across various industries utilizing cleanrooms, not just pharmaceuticals.
European Union Approach
The European Union takes a different stance, employing a grading system outlined in the EU GMP guide:
Grades A through D are used for normal cleanroom operation
ISO 14644 is still utilized, but primarily for validation purposes
World Health Organization Alignment
The World Health Organization (WHO) aligns with the European approach, adopting the same A to D grading system in its GMP guidelines.
The Implications of Disharmony
This lack of harmonization in cleanroom classifications presents several challenges:
Regulatory Complexity: Companies operating globally must navigate different classification systems, potentially leading to confusion and increased compliance costs.
Technology Transfer Issues: Transferring manufacturing processes between regions becomes more complicated when cleanroom requirements differ.
Inspection Inconsistencies: Differences in classification systems can lead to varying interpretations during inspections by different regulatory bodies.
The Missed Opportunity in Annex 1
The recent update to Annex 1, a key document in GMP regulations, could have been a prime opportunity to address this disharmony. However, despite involvement from WHO and PIC/S (and through them the FDA), the update failed to bring about the hoped-for alignment in cleanroom classifications.
Moving Forward
As the pharmaceutical industry continues to globalize, the need for harmonized regulations continues to be central. I would love to see future efforts towards harmonization here that would:
Prioritize alignment on fundamental technical specifications like cleanroom classifications
Consider the practical implications for manufacturers operating across multiple jurisdictions
While the journey towards full regulatory harmonization may be long and challenging, addressing key discrepancies like cleanroom classifications would represent a significant step forward for the global pharmaceutical industry.
Investigations of a Dog 