Good Engineering Practices(GEP) in Pharmaceuticals – Examples of GEP in Action

Good Engineering Practice (GEP) in the pharmaceutical industry refers to established engineering methods and standards used to ensure that facilities, systems, and equipment are designed, built, and maintained in compliance with regulatory requirements and industry standards. GEP is crucial for maintaining product quality, safety, and operational efficiency.

GEP acts as a bridge between general engineering practices and the stringent requirements of the pharmaceutical industry, ensuring systems support the production of safe and effective products.

Examples of GEP in Action:

• Properly designing cleanrooms to control contamination.
• Selecting materials for equipment that are resistant to corrosion and compatible with cleaning agents.
• Designing HVAC systems to maintain required temperature, humidity, and air quality levels.
• Implementing proper utility systems, such as purified water and compressed air, to meet pharmaceutical-grade standards.

Key Aspects of GEP:

1. Compliance with Standards: GEP aligns with recognized industry standards such as ISO, ASME, ANSI, and regulatory requirements from agencies like the FDA or EMA.
2. Documentation: Comprehensive documentation is maintained for design, construction, testing, and maintenance. This ensures traceability and accountability.
3. Risk Management: GEP incorporates risk assessment to identify and mitigate potential issues that could affect product quality or safety.
4. Validation and Qualification:
   • Design Qualification (DQ): Ensures the design meets intended use and regulatory requirements.
   • Installation Qualification (IQ): Verifies that systems and equipment are installed correctly.
   • Operational Qualification (OQ): Confirms systems operate as intended within specified parameters.
   • Performance Qualification (PQ): Ensures systems perform consistently under actual operating conditions.
5. Sustainability and Efficiency: Emphasis on cost-effectiveness, energy efficiency, and minimal environmental impact while meeting quality and safety standards.
6. Interdisciplinary Coordination: Effective communication among engineers, quality assurance, operations, and project management teams is vital for implementing GEP.

Example of GEP in HVAC System Selection:

Scenario: Designing an HVAC system for a pharmaceutical cleanroom used for aseptic filling of injectable products.

Step 1: Defining Requirements

In compliance with Good Engineering Practice (GEP):

• The system must maintain a Grade B or Grade C environment as per EU GMP Annex 1 or equivalent regulatory guidelines.
• The temperature must be stable at 20-22°C, with humidity levels of 40-60%, to protect sensitive drug products and ensure employee comfort.
• The air quality must meet ISO 14644-1 Class 7 (or better) with a specific airflow pattern to prevent contamination.

Step 2: GEP-Compliant Selection

In GEP Framework:

1. Load Calculation: Proper heat load calculation is performed, accounting for:

1. • Equipment heat output.
   • Personnel heat loads.
   • Process-related heat generation.
   • External factors such as solar load.

2. System Capacity: Select a system that matches the calculated load with 10-15% overdesign for future scalability but avoids oversizing, which could cause inefficiency and control issues.
3. Material Selection:

1. • Use non-corrosive and cleanable materials for ducts and filters to avoid contamination.
   • Select stainless steel diffusers in critical zones to minimize particle shedding.

4. Airflow Design:

1. • Ensure a unidirectional (laminar) airflow in critical areas to protect sterile products.
   • Implement differential pressure zones (e.g., maintain +15 Pa between cleanroom and surrounding areas).

5. Filtration Levels:

1. • Use HEPA filters (≥99.97% efficiency for particles ≥0.3 µm) for terminal filtration.
   • Install pre-filters to reduce the load on HEPA filters and increase their lifespan.

6. Energy Efficiency:

1. • Choose energy-efficient components, such as variable frequency drives (VFDs) for fans, to save operational costs.

Step 3: Implementation Without GEP

Now, let’s imagine the HVAC selection ignores GEP:

1. Improper Load Calculation:
   The system is undersized due to incorrect heat load estimates. During peak operation, the HVAC fails to maintain required temperature and humidity, causing non-compliance with cleanroom standards.
2. Material Issues:
   Ductwork materials were not properly vetted. Corrosion occurs, leading to particulate shedding into the cleanroom and contamination risks.
3. Airflow Design Flaws:
   A non-unidirectional airflow pattern results in particle turbulence in critical zones, exposing sterile injectable products to contamination during filling.
4. Inadequate Filtration:
   Filters chosen do not meet ISO Class 7 standards. The cleanroom fails validation, delaying product manufacturing and regulatory approvals.

Step 4: Realistic Outcome of GEP Compliance

With GEP Practices:

• The HVAC system is sized to handle peak loads, maintaining precise temperature and humidity control.
• Proper filtration and airflow patterns ensure compliance with ISO standards, preventing contamination.
• Energy-efficient designs reduce operational costs by 15%, achieving long-term savings.
• Smooth facility qualification and regulatory approvals save time and resources, ensuring timely product release.

Failure to adhere to Good Engineering Practice (GEP) during a pharmaceutical project can result in significant issues that affect regulatory compliance, system performance, operational costs, and product quality. The implications become especially evident in critical utilities like chillers, boilers, and facility design. Below are the potential consequences:

1. Impact on Chiller Systems:

Chillers are crucial for maintaining controlled temperatures in pharmaceutical processes and storage areas. Deviating from GEP can lead to:

a. Performance Failures:

• Undersized Chillers: May fail to meet cooling demands, causing fluctuations in temperature-sensitive environments like cleanrooms, storage areas, and process cooling.
• Oversized Chillers: Lead to inefficient operation, excessive cycling, increased energy consumption, and unnecessary wear and tear.

b. Contamination Risks:

• Poor selection of materials (e.g., corrosion-prone metals) can lead to contamination in clean utilities.
• Incorrect piping design may cause stagnant water zones, increasing the risk of microbial growth.

c. Compliance Issues:

• Inadequate temperature control can result in non-compliance with regulatory requirements for product storage, leading to batch rejections or recalls.

2. Impact on Boiler Systems:

Boilers generate steam for sterilization, heating, and other processes. Without GEP, the following problems may arise:

a. Inadequate Steam Quality:

• Poorly designed systems may produce wet steam or contain impurities, compromising sterilization processes and equipment reliability.
• Improper material selection may lead to scaling, corrosion, or contamination of steam used in processes.

b. Inefficiency and High Costs:

• Oversized boilers can increase fuel consumption, operating costs, and emissions.
• Undersized boilers may fail to supply sufficient steam during peak demand, causing operational disruptions.

c. Safety Hazards:

• Absence of appropriate safety valves, controls, or monitoring systems can lead to dangerous conditions like overpressure or steam leaks, posing risks to personnel and equipment.

3. Impact on Facility Design:

Facility design plays a pivotal role in ensuring compliance and operational efficiency. Ignoring GEP can result in:

a. Non-Compliance with cGMP:

• Inefficient layouts may allow for cross-contamination between clean and non-clean areas due to improper segregation of material and personnel flows.
• Lack of proper airlocks or HVAC systems can compromise cleanroom classifications, risking product contamination.

b. Operational Inefficiency:

• Poor design may lead to bottlenecks in workflows, increasing downtime and reducing productivity.
• Oversized or improperly located equipment can waste valuable space and resources.

c. Increased Costs and Delays:

• Rectification of design flaws after construction can lead to costly modifications and project delays.
• Non-compliance with regulatory standards can result in expensive penalties, rework, or project rejection by authorities.

Case Example:

Let’s imagine a scenario:

• Chiller Issue: A chiller system without GEP oversight was installed with insufficient capacity. During peak summer months, it fails to maintain the 2–8°C range in a pharmaceutical warehouse. This results in the spoilage of heat-sensitive raw materials and finished products, leading to millions in losses and regulatory scrutiny.
• Boiler Issue: A boiler system is installed without proper consideration of steam quality standards. Impurities in steam used for sterilization lead to non-sterile equipment, forcing the rejection of an entire production batch.
• Design Issue: The facility lacks proper personnel and material flow segregation. Contaminated materials inadvertently enter clean zones, leading to product recalls and potential legal action.

Audit Failure due to GEP:

Several pharmaceutical companies have been notified by the U.S. Food and Drug Administration (FDA) for failing to adhere to Good Engineering Practice (GEP) standards, leading to significant regulatory actions. Notable examples include:

1. Amman Pharmaceutical Industries: In February 2024, the FDA issued a warning letter to Amman Pharmaceutical Industries in Jordan, citing violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. The inspection revealed significant deficiencies in aseptic processing areas, including inadequate facility design and equipment that did not conform to CGMP standards, compromising product sterility and quality. FDA

1. Aurobindo Pharma Limited: In June 2019, the FDA issued a warning letter to Aurobindo Pharma Limited in India, highlighting deviations from CGMP for active pharmaceutical ingredients (APIs). The inspection identified issues such as inadequate facility design, insufficient equipment maintenance, and failure to establish appropriate written procedures, all of which are integral components of GEP. Wikipedia

1. Ranbaxy Laboratories Ltd.: In September 2008, the FDA issued warning letters to Ranbaxy Laboratories Ltd. in India, citing serious manufacturing deficiencies, including falsified data and test results. These violations were linked to failures in GEP, particularly in equipment qualification and facility design, leading to adulterated drugs entering the U.S. market. Wikipedia

These cases underscore the critical importance of adhering to GEP in pharmaceutical manufacturing to ensure product quality, patient safety, and regulatory compliance.

Failure to implement GEP during project execution significantly impacts the performance, safety, and compliance of chillers, boilers, and facility design. Adhering to GEP ensures that systems are efficient, reliable, and compliant, minimizing risks and ensuring the smooth operation of pharmaceutical processes. Neglecting GEP leads to operational inefficiencies, financial losses, and reputational damage, which can be far costlier than practicing it from the outset.