Planning and Designing a Pharmaceutical Manufacturing Facility | Key Steps, Layouts and Compliance Essentials

The design of the manufacturing facility plays a large role in determining how efficiently products can be manufactured and the way in which the company will be able to meet all global regulatory requirements and quality standards. A successful facility design can help ensure product and patient safety as well as effective contamination control, operational effectiveness and long term scalability.

In addition to being a major capital investment, constructing or renovating a facility will also require balancing multiple engineering principles with GMP compliance; environmental control and overall costs associated with operations. There are many different types of products to be manufactured such as oral solid dosage forms, injectable products and biologicals so proper planning is essential to understanding the processes involved, product types to be produced and expected regulatory requirements.

The following guide details the specific steps, considerations and design principles necessary for developing a GMP compliant pharmaceutical manufacturing facility from start to qualification.

1. Project Scope and Objectives

Every successful facility project starts with a clear understanding of why you are building a facility and the purpose of your project. Identifying the type of product(s), how much is going to be manufactured, which regulatory markets you plan to sell your products in and the process characteristics of the finished product is essential in defining the project scope.

For example: A project that manufactures mature products through a contract manufacturer is likely to have a different project scope than a project that manufactures an unapproved product for pilot testing purposes; likewise, the project scope for a project that manufactures sterile products needs to include requirements to adhere to both current good manufacturing practices (cGMP) and the respective regulatory agencies’ requirements where the product is intended for sale.

2. Regulatory and GMP Requirements

To properly design your facility within the regulatory framework set forth, it is important to have a general understanding of the many international guidelines established and the specific requirements related to each, including those associated with cGMP manufacturing under 21 CFR Parts 210 and 211 issued by the FDA; sterile product manufacturing according to EU GMP Annex 1; world health organization (WHO) TRS 1019 Annex 2; ISO 14644 series for cleanroom class and air cleanliness and Schedule M for Indian domestic products.

The design intent of your facility should be to ensure that the flow of materials, personnel and processes is controlled; therefore minimizing the risk of cross contamination, contamination and mix-ups throughout the entire process. The expectation of the FDA and other regulatory authorities is that the facility will support compliance with current good manufacturing practice (cGMP) and not compensate for design errors through procedural controls.

3. Site Selection and Location Considerations

The proper choice of a site determines how well your organization performs, and how well local and regional regulations are met, therefore impacting your overall effectiveness. You should evaluate several factors, including:

• Proximity to utility sources.
• Local environmental characteristics (temperature and moisture), potential for flooding and seismic activity.
• Ease of access to incoming materials and outgoing products, potential disruption to shipping routes by local traffic patterns, etc.
• Zoning requirements for both industrial use and environmental protection within each community where you are considering establishing business facilities, ultimately, the potential for growing your operation with minimal disruption to ongoing operations.

Establishing feasibility for any new facility should include a thorough evaluation of the site prior to beginning actual facility design.

4. Facility Layout and Zoning Philosophy

The design of a Pharma facility is critical for the effective flow of products and staff through the facility. It will determine the efficiency of your Facility's workflow, its ability to control contamination and its ability to meet the regulatory requirements.
Key layout philosophies include:

A. Unidirectional Flow

The movement of materials and personnel through a Facility should be one-way. All material should be moved from the lowest classification area to the highest classification area without crossing/crossing between clean and dirty material flows.

B. Functional Segregation

There should be distinct areas designated for all functions in the Facility. Material receipt, Manufacturing, Packaging and Storage.

C. Zoning

Cleanliness zones should be designated for each of the four zones. For example, in sterile manufacturing, A (critical) through D (support) zones should have predetermined pressure differentials to prevent backflow.

D. Logical Work Flow

Layouts must facilitate efficient movement of materials and personnel while also minimizing backtracking and congestion.
Typical areas within a facility:

• Warehouse (raw materials and finished goods)
• Dispensing area
• Manufacturing area (granulation, compression, coating, etc.)
• Packaging hall
• Quality Control Laboratories
• Utility and Engineering areas
• Change Rooms and Airlocks

Tip: Design using process flow diagrams (PFDs) and personnel and Material Flow Mapping tools to identify the points of intersection and potential contamination risks early in the design process.

5. Cleanroom Design and Classification

The cleanroom design for sterile and critical activities is the cornerstone of contamination control.
Essential elements of cleanroom design:

• Air cleanliness classification is defined using ISO 14644-1 standards for ISO 5 to ISO 9 classes.
• Air changes per hour are typically between 20 and 600 for the various grades of cleanroom classes.
• HEPA filters must provide at least 99.97% particle capture efficiency for particles greater than 0.3 µm in diameter.
• Air pressure within cleanrooms must be positive relative to adjoining spaces with a pressure differential of 10 - 15 Pa.
• The temperature of cleanrooms must be maintained between 20 °C - 22 °C and room humidity between 40% - 60%.

Layout of a Cleanroom

• There are three different areas for gowning personnel, which should be kept clearly separated from one another.
• For personnel and material movements, each cleanroom's main entry and exit points must be equipped with air locks.
• All surfaces within a cleanroom must be smooth, non-porous, easily cleaned and chemically compatible with all cleanroom disinfectants (epoxy and PVC coated panels).

Air handling and process flow for sterile cleanrooms should be designed in a way that minimizes contamination risks by establishing unidirectional airflow, controlling access to the cleanroom environment and implementing validated methods for disinfecting and maintaining cleanroom environments.

6. HVAC System Design (Air Handling Units)

The HVAC system is one of the main support systems for the pharmaceutical plant because it provides clean air, maintains humidity, temperature and pressure, which helps to prevent contamination during the manufacturing process.

Primary Elements of Design

Dedicated Air Handling Unit (AHUs): Dedicated AHUs are utilized for all areas of the facility, including those with different cleanliness classes and product types.
Pressure hierarchy: A designated pressure hierarchy ensures that each zone maintains a higher pressure than the zone that surrounds it, this prevents the introduction of low-grade air into a high-grade area from either direction.
Stages of Filtration: There are three stages to the air filtration system - The Pre-filter, Fine filter and the High-Effective Particulate Air (HEPA) filter (Terminal)
Return Air Strategy: The return air strategy should minimize the amount of recirculated air between a high-grade and low-grade area.
Monitoring systems: Monitoring systems must include continuous monitoring of differential pressure, temperature and humidity.

When sterile manufacturing is taking place, consider implementing 100% Fresh Air System (100% FAS) to avoid contamination caused by recirculated air. Additionally, CIP and/or SIP should be implemented when necessary.

7. Material and Personnel Flow Design

The design of material and personnel flow is critical to preventing cross-contamination.
Material Flow: Define separate entry and exit points for raw materials and finished products; utilize MALs for the movement of materials into and out of clean zones; never cross material with waste.
Personnel Flow: Define separate entry and exit points for personnel; establish gowning rooms with defined clean and dirty zones; controlled access with biometric/keycard systems.

The layout should provide a pathway for all personnel and materials, which ensures that there is no intersection between personnel and materials within the critical areas of the manufacturing process.

8. Support Systems and Utilities

Pharmaceutical activities rely on a network of utility services that either directly or indirectly influence the level of quality within the product.

A. Purified Water (PW) and Water for Injection (WFI)

• PW and WFI are produced via a distillation or reverse osmosis source.
• They are contained within appropriate sanitary stainless-steel storage tanks (as per current Good Manufacturing Practice) and transported throughout the manufacturing facility using loop piping systems.
• They must be microbiologically and chemically tested on a regular basis.

B. Clean Steam

• Used for sterilization and cleaning in place maintenance.

C. Compressed Air and Nitrogen

• Compressed air and nitrogen are required to meet the pharmacopeial requirements found in ISO 8573-1 standard.
• Compressed air and nitrogen used in processes and as a protective blanket for storage tanks.

D. Waste Management Systems

• Chemical, biological and/or general waste must be separated from one another.
• Waste system design should include drainage systems equipped with traps designed to prevent any backflow from the waste drain systems.

E. HVAC Systems

• Systems that monitor and control temperature, pressure and energy efficiency must work together as a single integrated system.
• Before their use, all utility services must first receive an Installation Qualification, then an Operational Qualification and finally a Performance Qualification (as applicable).

9. Equipment Selection and Placement

The selection of, as well as the placement of, equipment, should be taken into account when evaluating the ease of use, cleaning and maintenance.
The following are criteria for selecting equipment:
1. Non-reactive and resistant to corrosion (for example: stainless steel type 316 L).
2. Suitable for the product and process being manufactured.
3. Capable of being incorporated in a cleaning-in-place and/or sterilizing-in-place system if required.

Adequate clearance must be provided for maintenance, repairs and movement of personnel around the equipment to ensure efficient operation.

The layout will support the flow of products through the processing equipment, thus eliminating the possibility of dead ends and eliminating hard to clean areas.

All equipment installed, calibrated and validated, shall be documented as part of an organisation’s GMP (Good Manufacturing Practices) compliance documentation.

10. Quality Control & Microbiology Labs

QC Laboratories play a vital role in any manufacturer’s operations, therefore they need to be developed to provide an accurate, safe and regulatory compliant environment.
When designing a QC Laboratory, consideration must be given to the following areas:
Segregation: You must implement separate laboratories for Chemistry, Microbiology and Instrumentation.
Ventilation: Each laboratory must have its own independent Air Handling unit if they use volatile chemicals.
Safety: Your laboratory must have proper safety measures/equipment in place – e.g.: Fumehoods, emergency showers and Emergency Eye Wash Stations.
Data Integrity: QC laboratories need secure computerized systems with automated data captures and audit trails, this will comply with 21 CFR Part 11.

Microbiology laboratories are to include controlled environment areas for Media Preparation, Sterility Testing and Incubation, using Laminar Flow units and controlled access points.

11. Electronic Documentation Systems and Data Flow Systems

Electronic documentation systems are being used in today's industries as part of efforts to improve efficiency and data integrity.
Examples include:

• Building management systems (BMSs) that allow for direct monitoring of HVAC systems and utilities in real time.
• Manufacturing execution systems (MESs) that track all production activities and batch records.
• Laboratory information management systems (LIMSs) that manage all types of analytical data.

These systems and any other electronic systems used to manage and store documentation and data should be compliant with 21 CFR Part 11, which specifies how audit trails and electronic signatures will be maintained and managed, as well as how access to those systems and documentation will be controlled.

12. Validation and Qualification

The process of production begins with a systematic qualification and validation program of the facility; this includes:
1) Design qualification (DQ), which verifies that the design meets GMP and all project requirements.
2) Installation qualification (IQ), which is the verification of the correct installation of the systems and equipment.
3) Operational qualification (OQ), demonstrating that the systems operate according to their specified intended function.
4) Performance qualification (PQ), is the ongoing confirmation of the consistency of operation during the production process.

In addition to the above mentioned areas, validation will encompass HVAC systems, cleanroom environments, utility systems, cleaning methods and equipment. All validated systems must be shown to comply with applicable regulations and be reproducible through the use of standardized practices.

13. Environmental, Health and Safety Considerations

EHS (Environment, Health and Safety) is a major consideration for pharmaceutical plants. These plants must ensure that they meet GMP requirements as well as EHS requirements in order to maintain both the safety of workers and the environment.
Some examples include:
1. Proper ventilation and exhaust systems for all solvent handling areas.
2. Explosion proof electrical fittings installed in flammable zones.
3. Emergency exit routes, alarms and fire suppression systems provided.
4. Designing operations ergonomically to limit operator’s fatigue and strain on their bodies.

Appropriately managing waste generated by the facility to comply with state/local environmental regulations by ensuring safe disposal of effluents and hazardous wastes.

14. Future-Proofing and Scalability

Because the pharmaceutical industry changes very quickly, facilities need to be designed as flexible and modular so that changes can easily be adapted.
Futures-ready design features include:

• Easily configurable modular cleanroom systems to accommodate changing process requirements.
• Allocation of space directed toward eventual installation of equipment associated with the introduction of new product lines.
• Integration of automated and digitally monitored systems.
• HVAC and lighting systems designed for energy efficiency for sustainability.
• Flexibility at design stage will minimize long-term operational costs and facilitate upgrades to technology that ultimately generate returns during their life cycle.

15. Common Design Mistakes to Avoid

• Not considering the process flow during layout design.
• Not providing HVAC zoning and pressure balancing.
• Not using construction materials compliant with GMP.
• Not segregating the flow of materials from the flow of personnel.
• Not providing enough utility infrastructure to accommodate future growth.

By avoiding above mistakes you can achieve regulatory compliance and improved operations after start to commission manufacturing facility.

Frequently Asked Questions (FAQs) in Planning and Designing a Manufacturing Facility

Q1. What are the main objectives of pharmaceutical facility design?

Answer: The primary goals in pharmacy infrastructure modeling are to meet cGMP requirements, maintain product quality and provide "no-drug- contamination" working environments.

Q2. What regulations guide facility design?

Answer: The regulatory guidelines for pharmaceutical facilities are 21 CFR Parts 211 and 814, EU GMP guidelines, WHO guidelines and ISO 14644.

Q3. Why is material flow design important?

Answer: The flow of product from raw materials to finished goods at a pharmaceutical facility must be designed in a manner which does not permit cross-contact of impurities and maximizes the efficiency of product movement throughout the manufacturing process.

Q4. What are cleanroom classifications?

Answer: Clean room classification from ISO class 4 through ISO class 9 are determined by the number and size of air particles present in 1 cubic meter volume of air.

Q5. How is HVAC critical in pharma design?

Answer: The importance of a heating, ventilation and air conditioning (HVAC) system within a pharmaceutical facility model is that it enables the maintenance and control of the clean room air pressure, temperature and the size and quantity of the airborne particles.

Q6. What utilities are essential in pharmaceutical plants?

Answer: The utilities necessarily required for a pharmaceutical facility include purified water, HVAC system (air handling units), purified water, water for injection, clean steam and compressed air.

Q7. What is validation in facility design?

Answer: Validation of a pharmaceutical facility design is a demonstration that all systems function in compliance with all governing regulatory agencies in real-world operational conditions.

Q8. How can facilities be future-proofed?

Answer: By utilizing modular design layout, scalable utility source and automated digital automation system; all elements of a pharmacy facility can be made "future-proof."