This blog discusses general principles of process validation for the commercial manufacture of drug products. Process validation involves a series of activities taking place over the lifecycle of the product.
What is process validation? - Process Validation is defined as the collection and evaluation of data, from the process design stage throughout commercial production (lifecycle), which establishes scientific evidence that a process is capable of consistently delivering quality products.
Stage 1 - Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through process development.
Stage 2 - Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
Stage 3 - Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.
Effective process validation contributes significantly to assuring good drug quality. Because let’s be fair, everybody wants a good quality drug which is fit for its intended use!
Stage 1: Process Design
Process development activities provide key inputs to the process design stage, such as the dosage form, product quality attributes (QA), process parameters (PP) and input material attributes (MA). This is discussed in the PR&D and QbD blog.
When designing a production process, the commercial manufacturing equipment should be considered. New sources of variability will be present versus a lab environment: input material lots from different suppliers, production operators, environmental conditions and measurement systems with larger systematic errors compared to lab equipment. Lab- or pilot-scale models designed to be representative of the commercial process can be used to estimate these extra sources of variability. For example:
Lab experiments can be conducted considering hot and humid environmental conditions e.g. running the reaction in “Asian summer conditions” at 35 °C and 75 % RH (relative humidity)
Computer-based or virtual simulations of certain unit operations can provide process understanding and help avoid problems at a larger scale.
Pilot scale batches can be performed on at least a 1/10 scale of the commercial process while using manufacturing equipment which is equivalent to the commercial equipment
Stage 2: Process Qualification
During the process qualification (PQ) stage of process validation, the process design is evaluated to determine if it is capable of reproducible commercial manufacture. This stage has two elements:
Design of the facility and qualification of the equipment and utilities
Process performance qualification (PPQ)
During stage 2 cGMP compliant procedures must be followed! And it speaks for itself: successful completion of the process qualification stage is necessary before commercial manufacturing and distribution.
2.1 Facility design and qualification of equipment and utilities
It is essential that activities performed to assure proper facility design and commissioning precede PPQ. Here, the term qualification refers to activities undertaken to demonstrate that utilities and equipment are suitable for their intended use and perform properly. Qualification of utilities and equipment generally includes the following activities:
Selecting utilities and equipment based on whether they are appropriate for their specific uses: User Requirement Specifications (URS)
Verifying that utility systems and equipment are built and installed in compliance with the design specifications: Design Qualification (DQ) and Installation Qualification (IQ)
Verifying that utility systems and equipment operate in accordance with the process requirements in all anticipated operating ranges. Operating ranges should be shown capable of being held as would be necessary during routine production: Operational Qualification (OQ) and Performance Qualification (PQ)
2.2 Process Performance Qualification (PPQ)
The PPQ combines the actual facility, utilities, equipment (each now qualified), and the trained personnel with the commercial manufacturing process and control procedures to produce commercial batches. The goal of this stage is to confirm the designed process and to show that the commercial manufacturing process performs as expected. Data from laboratory and pilot studies.
In most cases the PPQ batches are accompanied by a sampling plan which is more exhaustive than would be the case during routine commercial production. All analytical and process data gathered during PPQ are vital and can assist troubleshooting when problems should arise during routine commercial production.
In the past, the usual “3 golden batches” rule applied. However, with the introduction of QbD and the extensive focus on process understanding the number of batches can be determined via a risk-based approach. For instance, when PAT is employed the process is monitored continuously and can be adjusted in a timely control loop, so the process maintains the desired quality of output material. This would lead to lower risk and could warrant a different PPQ approach.
The FDA proposes to asses the following data from Stage 1:
Product knowledge. The assessment should focus on process variation that might impact product safety, efficacy or quality.
Process Understanding. Attempts to assess the relationship between material attributes, CQA’s, CPP’s and an estimation of their variability on the control strategy.
The Control Strategy itself. The factors that should be assessed include raw material specifications, equipment capability versus process requirements and experiences to date with process performance.
With these assessments completed, a residual risk level should be determined. This risk level is directly proportional to the confidence in the process performance and will help to justify the number of PPQ batches.
Figure 1. Determination of the number of PPQ batches through risk assessment.
The higher the residual risk, the more PPQ batches will be required to confirm the process capability for reproducible commercial manufacture, but again, the process should be fully understood and documented. Using a Quality by Design (QbD) approach during Stage 1 should ultimately result in a lower residual risk and minimize the number of PPQ batches.
Stage 3: Continued process verification (CPV)
The goal of the third stage of validation is to ensure that the commercial process remains in a state of control. It is a science and risk-based real-time approach which focusses on collecting and evaluating relevant data about the process to detect undesired variability. For instance, control charts can be used to map the process yield and the quality of the finished product. By means of statistical evaluation is then investigated whether the observed variability in yield and quality can be attributed to the variability in quality of the incoming raw materials or intermediate products.
Different lots of input raw materials are often the root cause of varying product quality, amongst other factors such as insufficient process parameter control. Variation can also be detected by the assessment of defect complaints, out-of-specification results, process deviation reports and batch records.
Data gathered during this stage might suggest ways to improve and/or optimize the process by altering some aspect of the process, such as the operating conditions (process parameter ranges and setpoints), process controls, input materials or components.
Continued process verification can even be an alternative approach to traditional process validation. The manufacturing process performance is continuously monitored and evaluated (ICH Q8). Continued process verification can be used in addition to, or instead of, traditional process validation. This means, however, that extensive in-line, on-line or at-line controls and monitoring process performance and product quality on each batch are required.
There is a lot more to say about each of the topics. However, space and time are limited (or aren’t they?).
Let’s end by summarizing some of the most impactful points:
From the start of development all throughout scale-up, process validation and/or continued process verification we cannot neglect the fact that risk assessments have become increasingly more important.
Continued process verification can be a sole entity and thereby completely skipping the traditional process validation. But you guessed it, this should be backed by a risk-based approach.
The number of PPQ batches can be determined by – indeed – a risk-based approach!
With a lifecycle approach to process validation that employs risk-based decision making it is imperative that product knowledge, process understanding, and a suitable control strategy are the number one priority from start to finish. It would be very hard to estimate risks about something you do not know or understand very well!
 Guidance for Industry: Process Validation – General Principles and Practices. FDA, January 2011, Current Good Manufacturing Practices (cGMP), Revision 1
 Guideline on process validation for finished products – information and data to be provided in regulatory submissions. EMA, 21 Nov 2016, Rev1, Corr.1
 ICH Q8 (R2)
Blog by Steve Clarisse