Cleanrooms and GMP Design of Pharmaceutical Facilities
1. Current Good Manufacturing Practices (cGMP)
cGMP is a set of regulations published by the US Food and Drug Administration (FDA) that ensures pharmaceutical products are consistently produced and controlled according to quality standards.
Most national and international agencies regulating the pharmaceutical industry have similar regulations or guidelines based on cGMP principles.
Key Aspects Covered by cGMP Regulations:
- Organization and personnel qualifications and responsibilities
- Building and facilities design and maintenance
- Equipment validation, calibration and maintenance
- Control of components, containers and closures
- Production and process controls
- Packaging and labeling controls
- Laboratory controls and testing
- Records and reports management
- Returned and salvaged drug products handling
- Complaint handling procedures
2. Cleanroom Classification and Design
Cleanrooms provide controlled environments where airborne particulate contamination is limited to levels appropriate for contamination-sensitive activities.
Cleanroom Definition
A cleanroom can be defined through two perspectives:
- Control Perspective: A space where the number of airborne particles are measured and controlled, and where other environmental factors are controlled (humidity, temperature, pressure)
- Design Perspective: An enclosed space constructed in a way to minimise the introduction, generation and retention of particles
Key Definitions
- Particle: Solid or liquid object which, for purposes of classification of air cleanliness, falls within a threshold size in the range from 0.1 to 5μm
- Occupancy States:
- As-built: Installation is complete, all services functioning, no production equipment, materials, or personnel present
- At-rest: Equipment installed and operating in a manner agreed upon by customer and supplier, but with no personnel present
- Operational: The installation is functioning in the specified manner, with specified number of personnel present and working
3. ISO Cleanroom Classification System
The ISO classification system defines levels of airborne particulate cleanliness, representing maximum allowable concentrations (in particles per cubic metre of air) for considered sizes of particles.
ISO Classification Levels
There are 9 ISO classifications, from ISO 1 (cleanest) to ISO 9 (least clean).
Maximum permitted concentration formula:
Cn = 10N × (0.1/D)2.08
Cn = 10N × (0.1/D)2.08
Where:
Cn = Maximum permitted concentration of particles (particles/m³)
N = ISO classification number (1-9)
D = Particle size in μm
Cn = Maximum permitted concentration of particles (particles/m³)
N = ISO classification number (1-9)
D = Particle size in μm
ISO 14644-1:2015 Classification Table
| ISO Class Number | Maximum allowable concentrations (particles/m³) for particles equal to and greater than the considered size | |||||
|---|---|---|---|---|---|---|
| 0.1 μm | 0.2 μm | 0.3 μm | 0.5 μm | 1 μm | 5 μm | |
| ISO 1 | 10 | Not defined | ||||
| ISO 2 | 100 | 24 | 10 | Not defined | ||
| ISO 3 | 1,000 | 237 | 102 | 35 | Not defined | |
| ISO 4 | 10,000 | 2,370 | 1,020 | 352 | 83 | Not defined |
| ISO 5 | 100,000 | 23,700 | 10,200 | 3,520 | 832 | 29 |
| ISO 6 | 1,000,000 | 237,000 | 102,000 | 35,200 | 8,320 | 293 |
| ISO 7 | Not defined | Not defined | Not defined | 352,000 | 83,200 | 2,930 |
| ISO 8 | Not defined | Not defined | Not defined | 3,520,000 | 832,000 | 29,300 |
| ISO 9 | Not defined | Not defined | Not defined | 35,200,000 | 8,320,000 | 293,000 |
Source: ISO14644-1:2015 Table 1 (formerly Fed-Std-209E)
PIC/S Annex 1 Classification (for sterile products)
| Grade | Maximum permitted number of particles/m³ equal to or greater than the tabulated size | |
|---|---|---|
| At rest | In operation | |
| 0.5μm | 0.5μm | |
| A | 3,520 | 3,520 |
| B | 3,520 | 352,000 |
| C | 352,000 | 3,520,000 |
| D | 3,520,000 | Not defined |
Typical Applications by ISO Class
Typically, semiconductor, advanced engineering, optics, laser and electronics require an ISO 5 cleanroom along with pharmaceutical and medical device companies. The reasons that companies require these facilities vary from yield (money) to safety (regulation).
Air Changes Guidelines
- 240-480 changes/hr for Class A rooms (ISO 5)
- 60-90 changes/hr for Class B rooms (ISO 7)
- 20-40 changes/hr for Class C rooms (ISO 8)
These numbers are not regulations, just guidelines. They vary in different sources.
4. PIC/S Classification System for Sterile Products
The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) are international instruments between countries and pharmaceutical inspection authorities to improve cooperation in GMP between regulatory authorities and the pharmaceutical industry.
PIC/S Grade Definitions
Grade A: The local zone for high risk operations (filling zone, open ampoules and vials, making aseptic connections). Provided by a LAF work station with a homogeneous air speed in a range of 0.36 - 0.54 m/s (guidance value).
Grade B: For aseptic preparation and filling, this is the background environment for the grade A zone.
Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products.
PIC/S Requirements for Clean Areas
- Entry through airlocks for personnel and/or for equipment and materials
- Air supplied must pass through filters of appropriate efficiency
- Various operations (component preparation, product preparation and filling) should be in separate areas within the clean area
Terminally Sterilized Products Requirements
- Preparation of components and most products should be done in at least a Grade D environment
- Where the product is at a high or unusual risk of microbial contamination: Grade C
- Filling of products for terminal sterilization: Grade C
- Where the product is at unusual risk of contamination from the environment: Grade A with Grade C background
- Preparation and filling of ointments, creams, suspensions and emulsions should be in Grade C before terminal sterilization
Aseptic Preparation Requirements
- Components after washing: Grade D
- Handling of sterile starting materials, unless subjected to sterilization or filtration: Grade A with Grade B background
- Otherwise: Grade C
- Handling and filling of aseptically prepared products: Grade A
- Transfer of partially closed containers, as used in freeze drying: either in a Grade A environment with grade B background or in sealed transfer trays in a grade B environment
5. GMP Requirements for Pharmaceutical Facility Design
Key GMP Building Requirements
- Building shall be of suitable size, location and construction
- Building shall be easily cleanable and maintainable
- Building shall be designed to prevent equipment and material mix-ups and contamination
- Separate areas shall be provided for different operations
- Adequate control of air pressure, microorganisms, dust, humidity and temperature as appropriate
- Written procedures required for cleaning and sanitation
Process and Facility Design Principles
Facility design and layout must satisfy:
- Process requirements
- Personnel flows
- Material flows (raw materials and products)
- Equipment layout requirements
- Operational access requirements
- Maintenance access requirements
Facility should be designed around process needs!
Planning and Design Considerations
- A project plan shall be developed to define requirements of products, processes and scope of installation
- A process equipment list shall be compiled with critical requirements for each piece
- Diversity factors shall be defined, considering peak and average demand for each utility and environmental control system
- A contamination control concept shall be developed for each zone of an installation
Zoning Concept
For economic, technical and operational reasons, clean zones are often enclosed or surrounded by further zones of lower cleanliness. The zones with the highest cleanliness demands is reduced to the minimum size. Movement of material and personnel between adjacent clean zones gives rise to the risk of contamination transfer, requiring careful management of material and personnel flow.
Personnel and Material Flows
Personnel flows considered:
- Manufacturing personnel
- Maintenance personnel
- Quality control personnel
Material flows considered:
- Raw materials
- Finished goods
- Waste
- Product (In-process, Intermediate & Final)
- Equipment: Clean and dirty components, Portable equipment, Product containers
Process Flow Diagrams (PFDs)
PFDs are graphical representations of the manufacturing process based on manufacturing instructions. They are reference tools that support manufacturing and assist engineers and constructors with developing facilities and equipment design requirements.
There are no universal standards for PFDs. Each company uses its own methodology and symbology.
All PFDs contain at a minimum the following basic information:
- Material balance and material streams based on formulation and batch size
- Graphical representation of the major steps in the manufacturing process
- Identification of the equipment used in the manufacturing process
6. Cleanroom Features and Construction Materials
Cleanroom Design Features
- Walls and floors designed for easy cleaning, resistant to wear and cleaning chemicals
- Coved floor and wall corners to prevent particle accumulation
- Minimized horizontal piping, ducts, equipment surfaces where dust can accumulate
- Lighting supplied by sealed fixtures, often incorporated into ceiling HEPA filter modules
Typical Cleanroom Finishes
- Epoxy terrazzo floors
- Epoxy painted walls
- Suspended drywall or plaster ceiling, painted for easy cleaning
Clean rooms can be built at the site or purchased as modules from a vendor.
Utility Services and Ancillary Equipment
- Utility services should be designed and installed such that the cleanroom is not compromised by contamination
- Exposed piping, tubing and cable runs should be minimized
- Vacuum-cleaning equipment should be available
- Communication systems to reduce personnel movement
- Glazing: Avoid heat loss and solar gain, non-opening double glaze recommended
7. Solid Dosage Manufacturing Facility Design
Unit Operations in Solid Dosage Manufacturing
- Dispensing and Weighing
- Sifting and Classifying
- Milling
- Granulation
- Drying
- Blending
- Compression
- Encapsulation
- Coating
Dispensing Operations
Small Volume Dispensing: Down Flow Laminar Flow Hoods, Dedicated Rooms with Environmental Controls
Large Volume Dispensing: Silos, Super Sacks, Pneumatic Conveyance and Weigh Systems, Gravity Transfer and Weigh Systems
Other Design Considerations
- Storage and handling of materials in bulk containers (IBC), drums, bags, etc
- Material Handling Equipment
- Staging and Put Down Areas
- Wash Areas and Equipment Storage
- Pallet washers, IBC washers
Sifting and Classifying
Purpose: De-lumping of powders, Improve particle size distribution, Removal of oversized and undersized particles
Equipment: Vibratory screen sifters, Manual sieves
Milling
Used for: Particle size reduction, Changing particle shape, De-lumping
Granulation Methods
Wet Granulation (High Shear Granulation): High dispersion, Improved homogeneity, Good for small quantities of actives
Fluid Bed Granulation: Control of particle size, Suitable for materials that cannot withstand high shear, Granules dried in same machine
Drying
Purpose: Reduce moisture content of granules to 2-5%
Methods: Fluid Bed Dryers, Tray Dryers (ovens)
Blending
Purpose: Combine granulation with excipients and lubricants
- Excipient - typically lactose
- Lubricants - typically magnesium stearate added to improve flow properties
Convection mixing: Use of paddles or blades to achieve mixing (Ribbon blenders, Orbital screw blenders, planetary mixers, etc.)
Diffusion Blenders: Use of Tumbling Action (V Blenders, Cone Blenders, Bin Blenders)
Tablet Compression
Process: Blend (powder or granules) is filled into die cavities, Material is compressed into tablets
Encapsulation
Hard gelatin capsules filled with solids. Final blend must be uniform. Better for products with high API content. Filling done by volume, so constant bulk density is important.
Coating Types
- Film coating: Thin film (2 to 5 mils), Clear or with colorant
- Sugar coating: Heavy - may reach 50% of tablet weight
- Enteric coatings: Delay dissolution until the tablet reaches the intestinal tract
- Bead Coating: For time and sustained release products
Coatings can be Aqueous or Solvent Based.
Facility Layout Principles
- Provide short and logical routes for material and personnel flow
- Avoid cross-flows whenever possible
- Provide means of separation for quarantined, released and rejected materials
- Provide sufficient space for each operation, including staging, washing and other ancillary areas
- Help prevent cross-contamination
Layout of Mixing and Granulating Areas
- Easy movement of materials into separate processing rooms
- Minimize cross-contamination potential
- Air pressure in the corridor is higher than in the process rooms for product containment
8. Sterile Dosage Forms and Aseptic Processing
Vial Filling Process Steps
- Prep Bulk Product
- Filter Sterilize Bulk Product
- Wash & Sterilize Parts
- Prep Overseals
- Assembled Change Parts
- Wash Vials
- Depyrogenate Vials
- Fill Vials
- Check Weigh Vials
- Stopper Vials
- Overseal Vials
- Inspect Vials
- Package Vials
Background Environment: ISO 5 for critical areas, ISO 8 for supporting areas
Vial Filling Process Details
- Filling product into vials
- Checking vial weight: Manual (destructive) versus automated → cost impact
- Inserting vial stoppers: fully or partially (half way; used for freeze dried product)
- Over-sealing to secure the stopper
Vial Inspection
Every vial must undergo inspection, which can be manual or automatic. In-line inspection with the filling process results in less scratches and fewer rejected vials.
Environmental Requirements
The aseptic processing steps (where the product and product contact parts are exposed) are performed in a Class A / ISO5 environment. The other classes are used for areas with other activities depending on the potential impact on the process.
Contamination Control Strategy
All steps involving clean operators and materials must be separated from dirty operators and waste. This requires separate airlocks and corridors for the clean and dirty activities (unidirectional flows).
Even with all precautions (room pressurization, airflow, airlocks, garbing and treatment of materials), the ISO5 environment is under constant assault by the most contaminating object in the building - the operator.
To minimize the impact of the operator on the process, manufacturers are turning to new technologies - isolators or RABS (Restricted Access Barrier Systems).
Equipment Location Options
- Clean Room Environment (Traditional)
- Clean Room Environment & Restricted Access Barrier Systems (RABS)
- Aseptic Filling Isolator
9. Isolators and RABS Technology for Aseptic Processing
Isolators Definition
Isolators are sealed boxes around the process with access via gloves. They must be decontaminated using automated technology (VHP or H₂O₂) because the clean zone is very small.
Advantages of Isolators
- The operator is removed from the process, so less product risk
- Can be located in an ISO8 environment
- Reduced ISO5 area requirement
- Reduced requirements for sterile garb
- Fewer airlocks and material sanitization steps
- Material and people movement in the facility is simplified
- Cleaning and cleaning validation reduced
- Lower long term operation cost than traditional clean room facility
RABS (Restricted Access Barrier Systems)
Concept: To combine the advantages of an isolator with the flexibility of a clean room. In reality, RABS has not solved any of the perceived disadvantages of an isolator.
Isolators are the future of aseptic processing.
