Cleanroom Guidelines and Standards:
Part 2 PIC/S and ISO 14644
By Stefaan Vanhalle - R&D Manager
In this second installment of our five-part series on cleanroom guidelines & standards, we dive into the specifics of PIC/S and ISO 14644.
Introduction
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The Pharmaceutical Inspection Co-operation Scheme (PIC/S) is an international framework established to promote the development and harmonization of Good Manufacturing Practice (GMP) standards across the pharmaceutical industry. PIC/S fosters collaboration among regulatory authorities to ensures that medicinal products are consistently produced to the highest standards of quality, safety, and efficacy. Since its creation, PIC/S has been active in the development and promotion of harmonized GMP standards and guidance documents. The main instrument for harmonization has been the PIC/S GMP Guide. |
Originally, the latter derives from the WHO GMP Guide and has been further developed in order to comply with stringent manufacturing and health requirements, to cover new areas (e.g. biologicals) and to adapt to scientific and industrial technology (e.g. biotech). In 1989, the EU adopted its own GMP Guide (Eudralex Volume 4), which - in terms of GMP requirements - is equivalent to the PIC/S GMP Guide. Since that time, the EU and the PIC/S GMP Guides have been developed in parallel (both guides are practically identical). PIC/S GMP Guide PE009-17 encompasses a wide range of good manufacturing practices applicable to various types of pharmaceutical products, including both sterile and non-sterile medicinal products.
PIC/S GMP Guide PE009-17 Annex 1 provides specific guidance on the manufacturing of sterile medicinal products. Next to the guide to good manufacturing practice for medicinal products, PIC/S also published the PIC/S guide to good practices for the preparation of medicinal products in healthcare establishments (PE010-4). Belgium is the only country that has included the guide for the preparation of medicinal products in healthcare establishments in its national legislation. It will take effect in January 2026.
PIC/S GMP Guidelines Related to Cleanrooms:
PIC/S GMP guidelines (including both sterile and non-sterile medicinal products) offer comprehensive guidance on the design, classification, and operation of cleanrooms to safeguard pharmaceutical manufacturing processes from contamination risks. Key facets of PIC/S GMP guidelines related to cleanrooms include:
- Cleanroom Design and Classification:
PIC/S GMP Guidelines emphasize the critical role of cleanroom design in preventing contamination during pharmaceutical manufacturing. The guidelines align with international standards such as ISO 14644-1, providing a unified approach to cleanroom classification based on airborne particulate cleanliness. Specific requirements for air quality, layout, and construction materials are detailed to ensure optimal conditions for the production of medicinal products. - Monitoring and Control:
Rigorous monitoring and control mechanisms are outlined to uphold the integrity of cleanrooms. The guidelines specify parameters for continuous monitoring, including airborne particulate and microbial contamination, to promptly identify deviations from established limits. Real-time monitoring technologies are encouraged to enhance the responsiveness of pharmaceutical manufacturers to potential risks. - Personnel Practices:
PIC/S GMP Guidelines addresses the critical factor of personnel in maintaining cleanroom conditions. Stringent practices for personnel hygiene, gowning procedures, and training are highlighted to minimize the introduction of contaminants. The guidelines emphasize the importance of personnel behavior within cleanrooms to assure aseptic practices are consistently followed.
Comparison with GMP Annex 1 and Other Standards:
When comparing PIC/S GMP Annex 1 guidelines with GMP Annex 1 and other relevant standards, several distinctions and commonalities emerge:
Scope and Applicability:
GMP Annex 1 is a part of the European Union’s GMP regulations (Eudralex Volume 4) and is legally binding within the EU. GMP Annex 1 specifically targets sterile medicinal products, providing detailed guidelines for cleanroom design and operation within this context. PIC/S GMP guidelines, encompass a broader range of pharmaceutical manufacturing practices, making them applicable to various drug types. This broader scope positions PIC/S as a more versatile guide for global pharmaceutical manufacturing. PIC/S GMP guidelines serve as guidelines rather than legally binding regulations. PIC/S GMP Annex 1 specifically targets sterile medicinal products. One exception is the guide to good practices for the preparation of medicinal products in healthcare establishments (PE010-4). Belgium has included the guide for the preparation of medicinal products in healthcare establishments in its national legislation making it legally binding.
Global Alignment:
GMP Annex 1 is part of the European Medicines Agency's regulatory framework, primarily influencing European pharmaceutical manufacturing. In contrast, PIC/S GMP guidelines involve a global collaboration of regulatory authorities, contributing to a more internationally harmonized approach to GMP standards. PIC/S stands out for its efforts to align regulatory expectations and facilitate global consistency.
Level of Detail:
GMP Annex 1 is highly detailed, offering specific requirements for aseptic processing of sterile medicinal products. PIC/S GMP guidelines (including both sterile and non-sterile medicinal products), while detailed, provide a broader perspective on pharmaceutical manufacturing, accommodating a diverse range of products. Manufacturers may find PIC/S guidelines to be more adaptable to different manufacturing contexts.
Alignment with ISO Standards:
Both PIC/S GMP Annex 1 and GMP Annex 1 align with ISO standards, particularly ISO 14644-1 for cleanroom classification. This alignment reinforces the global recognition and applicability of these guidelines.
In conclusion, PIC/S guidelines play a pivotal role in shaping global pharmaceutical manufacturing practices, offering a comprehensive and adaptable framework for quality assurance. While GMP Annex 1 provides detailed guidance specific to sterile medicinal products within the European context, PIC/S GMP guidelines offer a broader, globally harmonized perspective. The alignment with ISO standards further strengthens the credibility and applicability of both PIC/S GMP guidelines and GMP Annex 1 in the pursuit of maintaining the highest standards of pharmaceutical quality worldwide. Pharmaceutical manufacturers are encouraged to consider the nuances of each guideline to ensure compliance and contribute to the global standardization of pharmaceutical manufacturing practices.
Introduction to ISO 14644:
ISO 14644 stands as a cornerstone in the realm of contamination control, (in particular non viable particles) offering a exhaustive framework for cleanroom and controlled environment standards. Developed by the International Organization for Standardization (ISO), the ISO 14644 series addresses the critical need for uniformity in assessing and maintaining cleanrooms across diverse industries. Let’s dive into the key components of ISO 14644, including the classification of air cleanliness, particle monitoring and control, and the international recognition and adoption of these standards.
Classification of Air Cleanliness:
ISO 14644-1 serves as the foundation for cleanroom classification, providing a systematic approach to defining and categorizing the level of airborne particulate cleanliness. The classification is based on the maximum allowable particle counts per cubic meter at specified particle sizes. The standards define cleanroom classes from ISO Class 1 (the most stringent) to ISO Class 9 (the least stringent), with each class having specific limits for particles ≥0.1 micrometers.
Cleanroom Classes:
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Particle Size Limits: ISO 14644-1 establishes size-specific limits for particles, ensuring that the standards cover a broad range of contaminants. The limits become less stringent as the cleanroom class number increases. |
Adaptability and Applicability: ISO 14644 standards are designed to be adaptable to various industries, recognizing that different environments may have different requirements. This adaptability enhances the applicability of the standards across pharmaceuticals, healthcare, electronics, and other sectors where contamination control is crucial. |
Classification of Air Cleanliness:
Maintaining compliance with ISO 14644 standards requires robust particle monitoring and control measures. The standards outline guidelines for routine monitoring and validation processes to ensure the ongoing integrity of cleanrooms.
- Routine Monitoring:
Continuous monitoring of airborne particles is crucial for identifying deviations from specified cleanliness classes. ISO 14644 recommends using calibrated particle counters for routine monitoring, with the frequency and locations determined based on the criticality of the cleanroom and processes conducted within. - Validation Processes:
Prior to operation or after significant changes, validation processes are conducted to ensure compliance with cleanliness classes. This involves a thorough assessment of particle counts during various operational states, including both at-rest and in-operation conditions. - Contamination Control Strategies:
ISO 14644 emphasizes the importance of implementing control strategies to minimize the introduction and generation of particles. This includes measures such as air filtration, proper gowning procedures, and effective personnel training.
International Recognition and Adoption:
ISO 14644 standards have achieved widespread recognition and adoption on the global stage, contributing to the harmonization of contamination control practices across borders.
- Global Harmonization:
The international nature of ISO standards fosters harmonization, allowing industries worldwide to adhere to a common set of criteria for cleanroom performance. This global alignment facilitates consistency in manufacturing and quality assurance practices. - Regulatory Recognition:
ISO 14644 standards are recognized by regulatory bodies globally, with many countries incorporating these standards into their regulatory frameworks for industries such as pharmaceuticals and healthcare. Adherence to ISO 14644 often serves as evidence of compliance with regulatory requirements. - Industry Adoption:
Industries ranging from pharmaceuticals and biotechnology to electronics and aerospace have widely adopted ISO 14644 standards. This broad adoption reflects the universal recognition of the importance of maintaining controlled environments to ensure product quality and safety.
References
1) PIC/S guide to good manufacturing practice for medicinal products (PE 009-17 25/8/2023)
2) PIC/S guide to good practices for the preparation of medicinal products in healthcare establishments (PE 010-4, 1/3/2014).
3) ISO14644 Series (1-18)