FDA Process Validation in the Pharmaceutical Industry: A Basic Guide

The U.S. government has diligently monitored the safety of drugs and pharmaceuticals to protect public health. Medicine is inherently a high-risk industry, so basic testing of the final product alone is insufficient.

The U.S. Food and Drug Administration (FDA) continues to emphasize process validation for medical manufacturing organizations, including those in the pharmaceutical, biotechnology, medical device, and cosmetic industries.

What Is the Validation Process in the Pharmaceutical Industry?

What’s the Right Data to Collect For Premarket Validation?

What Are the 3 Main Stages of Pharmaceutical Process Validation?

What Other FDA Regulatory Requirements Are Worth Knowing?

What is the Importance of Process Validation Training?

The primary mindset behind process validation is that quality assurance must be built into the manufacturing process rather than just the final pharmaceutical product. It looks at quality control throughout the entire lifecycle of a drug, covering initial planning and development all the way to full-scale commercial production.

The concept arose in the mid-70s, though the first official guidance from the FDA began in 1987. Today, official documentation from the FDA details how medical businesses can keep their internal production systems compliant with the agency’s current Good Manufacturing Practices (cGMP). The document focuses on collecting data and evaluating standard operating procedures to show that a manufacturing process consistently meets quality standards.

But the importance of process validation goes beyond the safety and efficacy of the final drug. It’s instead a proactive approach that looks at every step of the manufacturing process

individually and ensures that product quality and design specifications match compliance obligations at every stage. Even minor variations in the Active Pharmaceutical Ingredients (APIs) can significantly compromise drug quality, so plan to assess variations and implement controls for them.

Companies must have these considerations figured out before scaling up manufacturing to a commercial level. Those that do not, risk FDA audits, increased scrutiny from regulatory agencies, forced recalls, and even facility closures

The premarket phase occurs when a drug candidate goes from development to production. This is a critical step in pharmaceutical process validation, as obtaining FDA approval for mass manufacturing involves proving that your production protocols are both safe and replicable.

It’s easy to collect too much data in the premarket phase. Even the most experienced medical professionals occasionally have trouble extracting valuable insights from the massive amount of information available, so how do you collect the right data for validation?

You need careful planning and rigorous reporting procedures at every stage of drug development. Use software-powered reporting tools to focus on the correct data that matters at that stage. You can also consult the FDA’s guidance document on balancing premarket and postmarket data collection, which covers devices but can also apply to drugs and other medical products.

The FDA recommends businesses instill process validation strategies into these 3 stages of the drug manufacturing process.

• Process design stage defines the commercialized manufacturing procedure.
• Process qualification looks at that design and determines whether it’s reproducible in the field.
• Process verification is the continued assurance that the validated process is controllable.

These three steps contribute to more consistently performing drugs, higher customer loyalty and trust, and a more reliable finished product to help you compete in the market. You’ll also help avoid FDA audits and improve your compliance posture.

Manufacturing Process Design Stage

Designing a process for the mass production of medical products is a complicated task. You must:

• Guarantee regular and consistent quality at every stage for every unit of output.
• Consider the limitations of your critical equipment and machinery.
• Take into account potential variations in the final product due to manufacturing tolerances.
• Implement process controls to address potential variations and avoid process failure.
• Provide documentation of the process, especially for studies on how each step in the procedure contributes to the final product.

While the early stages of process design don’t necessarily have to follow cGMP requirements or undergo thorough testing, the FDA still recommends facilities follow sound scientific principles.

Process Qualification (PQ)

Once you have a manufacturing process in mind, it’s time to qualify it by checking whether it’s ready for commercial production use. Doing so involves designing the facility itself and selecting the right piece of equipment.

Progress Performance Qualification (PPQ) occurs at this stage, as the business continually checks for cGMP compliance. All departments must be on board, including the quality assurance team. From there, the company can start moving products into commercial distribution.

The FDA mandates cGMP principles for designing the manufacturing facility and its equipment and systems. The company must verify objectively that equipment runs within acceptable specifications. Written documentation of protocols and expected outcomes is also necessary to record data collection policies, manufacturing conditions, and required testing methodologies.

Ongoing Process Verification

This stage is primarily for maintenance - preventing unexpected mistakes during production and ensuring that the process remains valid and compliant throughout the commercial manufacturing run.

Ongoing verification proactively searches for problems and addresses them before they impact the finished product. For instance, the facility must keep the quality of raw materials in check at all times.

The FDA once again calls for cGMP compliance during process verification. An ongoing effort is necessary to collect and analyze data regarding product quality and identify variability in the final product. Businesses perform these steps by sampling data obtained from the process qualification stage and maintaining the facility and equipment accordingly.

It’s also worth investing in a change management system to supplement the three stages of process validation above. If the manufacturing process ever needs to adapt, change management overlaps with ongoing verification to assess the potential impact of new changes and oversee their implementation.

Process changes can come from many sources:

• New steps in the manufacturing process
• New manufacturing equipment
• Switching suppliers that provide the raw materials
• New specifications of the final product
• Corrective management due to previous compliance audits

cGMP is a recurring theme of the FDA’s process validation guidance. The current Good Manufacturing Practices touch on many legally enforceable requirements from the FDA. A few of them are below for your reference.

• Data handling. Always review your data collection policies, particularly those involved in quality assurance and improving manufacturing practices.
• Facilities and equipment. The FDA specifically mentions that production facilities and equipment must be “of acceptable size, construction, and location to meet required needs.” Regular inspections and calibrations are then necessary to stay within industry standards.
• Written documentation. Process verification and control require written procedures and detailed documentation to keep track of processes.
• Stability testing. Testing for stability is vital throughout the drug development process. Have a well-documented stability testing program in place to ensure pharmaceuticals are both consistent and not impacted by cross - contamination.
• Sample testing. Facilities must also have controls in place for sample testing. Use statistics so that a sample is representative of a whole batch during analysis.
• Adulterated drugs. The FDA considers a drug “adulterated” when it no longer meets minimum standards for consistency or reliability. Being able to identify adulterated products is an important skill to have for a medical manufacturing organization.

Regarding process validation, the FDA recommends that businesses take a team-based approach, where representatives from various departments and groups within the company collaborate to decide on policies and best practices.

Process controls must also be a focus, including controls over the quality of product output, raw materials, major equipment, and operating procedures appropriate for the associated level of risk.

Pharmaceutical validation is a team effort, and empowering your teams with relevant training will assist you in upgrading your process validation efforts. Quality assurance staff, factory floor workers, and management teams need the right knowledge to focus properly on process design, process qualification, and ongoing verification.

CfPIE’s “Process Validation for Drugs and Biologics” course is perfect for any medical professional involved in process-validation-related fields like drug manufacturing, process development, or quality assurance. Even those in related fields, like risk and supplier management, will benefit from knowing how process validation integrates with other parts of the business.

Anyone from operational personnel who conduct process validations to individuals in management will learn everything they need to establish comprehensive process validation programs and ensure that their organizations comply with requirements from the FDA, the European Medicines Agency, and other regulatory bodies.