Understanding Clean Room Grades and GMP Classification

In cleanroom manufacturing, even microscopic contamination can mean failed compliance, product recalls and operational setbacks. For senior production and operations managers seeking a contract manufacturer, understanding cleanroom classifications isn’t just about compliance – it’s about ensuring efficiency, risk mitigation and seamless integration into your supply chain. Whether for sterile assembly or precision moulding, aligning with a manufacturing and cleanroom partner who meets ISO 14644 and GMP standards can make the difference between a smooth production run and costly disruptions. In this blog, we cover the key cleanroom classifications, how they impact medical device manufacturing, and what they mean for your production processes.

Introduction to Clean Rooms

Definition and Purpose of Clean Rooms

A cleanroom is a controlled environment where parameters such as airborne particles and air pressure are regulated to minimise contamination. These rooms are essential in industries like pharmaceuticals, biotechnology and medical device manufacturing, where even microscopic contaminants can compromise product quality and safety.

Industries Requiring Clean Rooms

Numerous sectors rely on the use of cleanrooms, including:

• Pharmaceuticals: Ensuring sterile conditions for drug production;

• Biotechnology: Preventing contamination in biological research and production;

• Medical Device Manufacturing: Maintaining high standards for devices that come into contact with patients;

• Electronics: Protecting sensitive components from particulate interference;

• Aerospace: Controlling environmental factors during the assembly of precision instruments.

Overview of Clean Room Classification Systems

Cleanrooms are classified based on the concentration and size of particles permissible per cubic metre of air. Two predominant classification systems are the ISO 14644 standards and Good Manufacturing Practice (GMP) guidelines. Both the clean room classifications under ISO 14644 and clean room GMP classifications define cleanliness levels to ensure products meet strict regulatory requirements.

ISO 14644 Clean Room Standards

The International Organisation for Standardisation (ISO) developed the ISO 14644 series to standardise cleanroom classifications globally. These standards define cleanroom grades by the number of particles per cubic metre of air, with classifications ranging from ISO Class 1 (the cleanest) to ISO Class 9 (the least clean). For instance, an ISO Class 5 cleanroom permits up to 3,520 particles of 0.5 micrometers or larger per cubic meter.

ISO Classes of air cleanliness by particle concentration

(a) All concentrations in the table are cumulative, e.g. for ISO Class 5, the 10 200 particles shown at 0,3 µm include all particles equal to and greater than this size.

(b) These concentrations will lead to large air sample volumes for classification. Sequential sampling procedure may be applied.

(c) Concentration limits are not applicable in this region of the table due to very high particle concentration.

(d) Sampling and statistical limitations for particles in low concentrations make classification inappropriate.

(e) Sample collection imitations for both particles in low concentrations and sizes greater than 1 µm make classification at this particle size inappropriate, due to potential particle losses in the sampling system.

(f) In order to specify this particle size in association with ISO Class 5, the macroparticle descriptor M may be adapted and used in conjunction with at least one other particle size.

Source: BS EN ISO 14644-1:2015

GMP Guidelines for Clean Room Design

Good Manufacturing Practice (GMP) guidelines, particularly those outlined by the European Union (EU), provide a framework for ensuring that products are consistently produced and controlled according to quality standards. The EU GMP cleanroom classification defines four clean room grades (A, B, C, D), each with specific contamination limits intended for different stages of pharmaceutical production.

Detailed Breakdown of GMP Clean Room Grades

Understanding the distinctions between GMP cleanroom grades is vital for compliance and optimising the design of the manufacturing facility.

Grade A: High-Risk Operations

Grade A, the highest of the cleanroom grades, ensures environments are designated for high-risk operations, such as:

• Filling zones

• Stopper bowls

• Open ampoules and vials

• Aseptic connections

These areas require unidirectional airflow systems to maintain a laminar flow of air (i.e. air moving in smooth, parallel layers with minimal mixing), ensuring minimal particle contamination. The particle concentration must not exceed 3,520 particles (≥0.5µm) per cubic metre.

Grade B: Background for Grade A

Serving as the background environment for Grade A zones, Grade B areas support activities like aseptic preparation and filling. While slightly less stringent than Grade A, these areas still demand rigorous control, with particle limits matching those of Grade A when at rest (i.e. when all utilities and equipment are installed but not operating, and with no personnel present in the room). In operation, Grade B clean rooms permit up to 352,000 particles (≥0.5 micrometers) per cubic metre.

Grade C: Clean Areas for Less Critical Processes

Grade C cleanrooms are allocated for less critical stages in the manufacturing and sterilisation process, such as the preparation of solutions to be filtered. The acceptable particle count is higher than in Grades A and B, reflecting the reduced risk associated with these operations.

Grade D: General Clean Areas

Grade D areas are suitable for processes with a lower risk of product contamination, including handling components after washing. While still controlled, these environments have the highest permissible particle counts among GMP classifications.

EU GMP Cleanroom Classification (in Operation):

For Grade D, where in-operation limits are not predetermined, manufacturers are advised to establish limits based on a risk assessment and data analysis.

Comparing ISO and GMP Clean Room Classifications

Key Differences and Similarities

While both ISO and GMP classification systems aim to control contamination, they differ in focus and application:

• ISO Standards: Provide a universal classification based solely on particle concentration, applicable across various industries.

• GMP Guidelines: Offer a risk-based approach tailored to pharmaceutical manufacturing, encompassing both particle counts and operational protocols.

In simple terms, there is a rough equivalence between the two systems:

• Grade A: Equivalent to ISO Class 5

• Grade B: Equivalent to ISO Class 5 at rest and ISO Class 7 in operation

• Grade C: Equivalent to ISO Class 7 at rest and ISO Class 8 in operation

• Grade D: Equivalent to ISO Class 8

Application in Various Industries

While ISO classifications are used across multiple sectors, GMP grades are specifically designed for the pharmaceutical industry to ensure product safety and efficacy. Medical device manufacturers often adhere to ISO standards but may also implement GMP guidelines when producing combination products or devices requiring sterile conditions.

At Meridian Medical, we exemplify this commitment by operating six purpose-built ISO Class 7 cleanroom manufacturing facilities, totalling 852m², dedicated to the assembly and packaging of both sterile and non-sterile disposable medical devices. Additionally, our 300m² Class 8 cleanroom houses an advanced injection moulding facility that operates 24 hours a day, five days a week. This infrastructure ensures that we meet and exceed the stringent cleanliness and quality standards required for diverse medical device manufacturing needs.

Maintaining Compliance with Clean Room Standards

Ensuring compliance with clean room classification and maintaining the appropriate clean room grades is critical to operational success in medical device manufacturing.

Monitoring and Control Processes

Regular environmental monitoring is essential to detect and address potential contamination sources promptly. This includes:

• Airborne Particle Monitoring: Using particle counters to continuously measure and record air cleanliness

• Surface Sampling: Assessing surfaces for microbial contamination using swab sampling, contact plates or surface rinsing

• Personnel Monitoring: Evaluating the cleanliness of operators through garment sampling.

Regular Audits and Inspections

Scheduled audits and inspections help verify that cleanroom operations comply with established standards. These assessments may be conducted by internal teams or external regulatory bodies and typically involve:

• Reviewing Documentation: Ensuring that all standard operating procedures (SOPs), cleaning logs and maintenance records are up-to-date and accurately reflect current practices

• Evaluating Personnel Practices: Observing staff to confirm they are adhering to gowning protocols, hygiene standards and proper cleanroom behaviours, thereby minimising contamination risks

• Inspecting Environmental Controls: Assessing the functionality and maintenance of HVAC (Heating, Ventilation & Air Conditioning) systems, HEPA (High-Efficiency Particulate Air) filters and pressure differentials to maintain the required cleanroom conditions

• Identifying Areas for Improvement: Highlighting deficiencies or deviations from protocols and recommending corrective actions to enhance cleanroom performance and compliance.

Innovations in Contamination Control

Modern cleanrooms are increasingly integrating automated systems to minimise human intervention, thereby reducing the potential for contamination. Robotic systems with sealed components and non-particle shedding materials, as well as automated workflows handle sensitive processes with precision, ensuring consistent quality and hygiene. Additionally, the adoption of advanced particle counters and real-time environmental monitoring tools allows for immediate detection and prompt responses to any deviations from protocol or contamination events.

Future Trends in Clean Room Technology

Cleanroom technology is experiencing significant advancements, driven by the need for enhanced contamination control, operational efficiency and sustainability. Key trends shaping the future of cleanroom technology include:

• Sustainable Design: There’s a growing emphasis on energy-efficient cleanroom designs that reduce environmental impact without compromising performance. This includes the use of eco-friendly materials and systems that lower energy consumption.

• Modular Cleanrooms: The adoption of modular cleanroom systems offers flexibility and scalability, allowing for rapid deployment and reconfiguration to meet evolving industry needs.

• Advanced Filtration: Greater focus on energy-efficient HVAC designs, such as Variable Air Volume (VAV) systems and energy recovery ventilators, which adjust airflow based on real-time needs and capture waste energy for reuse. These innovations contribute to significant energy savings while maintaining stringent environmental controls.

These innovations and trends are poised to redefine cleanroom standards, ensuring that controlled environments meet the increasingly stringent requirements of various high-precision industries, including medical device manufacturing.

Maintaining Clean Room Standards for Optimal Performance

The Importance of Proper Clean Room Classification

Proper clean room classification is essential for maintaining controlled environments in industries like pharmaceuticals, biotechnology and electronics. Adhering to ISO and GMP standards ensures that contamination levels remain within acceptable limits, reducing the risk of biological contamination and ensuring compliance with regulatory requirements. By selecting the appropriate classification, manufacturers can optimise production processes, improve efficiency and uphold industry best practices.

Ensuring Product Quality and Safety

Maintaining a well-classified clean room directly impacts product quality and safety. Contamination can compromise sensitive manufacturing processes, leading to costly recalls or safety hazards. With proper air filtration, controlled workflows and strict adherence to cleanliness protocols, clean rooms protect both the integrity of products and the well-being of consumers. Investing in the right clean room standards safeguards quality and ensures regulatory compliance.

FAQs Cleanroom Grades

What are the grades of clean rooms?

Cleanrooms are classified based on the number of airborne particles per cubic meter, following ISO 14644-1 standards. The ISO classification ranges from ISO 1 (most stringent) to ISO 9 (least strict). In the pharmaceutical industry, EU GMP guidelines use Grades A to D, where Grade A is the most controlled. These classifications ensure environments meet required contamination control levels for sensitive manufacturing, such as pharmaceuticals and biotechnology.

What does class 100 and class 1000 clean room mean?

Class 100 and Class 1000 clean rooms follow the older US Federal Standard 209E, now replaced by ISO 14644-1. The class refers to the allowed amount of 0.5 microns or larger particles per cubic foot. A Class 100 room only allows a maximum of 100 particles (0.5 microns or larger) per cubic foot, while a Class 1000 room allows up to 1000 particles per cubic foot of the same size; essentially, a Class 100 cleanroom is ten times cleaner than a Class 1000 cleanroom.

What is a class B clean room?

A Class B cleanroom is defined under the EU GMP classification system for pharmaceutical manufacturing. It represents a high level of cleanliness, typically used for aseptic preparation in the background of critical Grade A environments. It must maintain stringent particle and microbial limits, with controlled air filtration, temperature and humidity. These rooms are crucial in sterile drug manufacturing, ensuring minimal contamination during processing and packaging.

What is a level 7 clean room?

A Level 7 clean room corresponds to ISO 7 in the ISO 14644-1 standard, allowing a maximum of 352,000 particles (≥0.5 microns) per cubic meter. It is commonly used in industries like medical device production and pharmaceutical compounding. With HEPA (High-Efficiency Particulate Air) filtration and controlled airflows, it ensures moderate contamination control while balancing operational costs. Personnel wear appropriate protective clothing to minimise particulate generation and maintain cleanliness, to ‘protect the products and process from human contamination’ as ISO 14644-5 states.

Partner with Meridian Medical

If your company is looking for a trusted partner to manufacture high-quality medical devices, Meridian Medical is ready to assist. With a proven track record and a commitment to excellence, Meridian Medical is your ideal contract manufacturing partner.

Contact us today to learn more about our services and how we can help bring your innovative medical devices to market. Get in touch by filling out our online form or contacting us on 01903 732344 or info@meridian-medical.com.