In good manufacturing practice (GMP) and other GxP’s, the term validation has a formal, specific meaning. In this context, validation is a quality management tool used to confirm that a process or a piece of equipment satisfies its intended purpose through the use of objective data.
In highly regulated industries, validation is used when establishing new commercial manufacturing processes, installing and qualifying new equipment, implementing software, or any other event that could affect product quality. Validation is a core part of GxP, and is found in quality management standards like ISO 9001.
The FDA explains that validation of pharmaceutical processes involves the “collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product.” In this white paper, we’ll talk in detail about what that means in practice, and cover some of the core principles to follow when writing and executing a validation plan.
A Quick Primer on Validation
Formal validation is used in industries where product quality can impact consumer health and safety, particularly when quality cannot be verified. In other words, when every unit coming off the production line can’t be directly tested to confirm it is within spec. Instead, we rely on a thorough understanding, documentation, and control of the process to ensure consistency and quality of the product.
Practically, validation also provides a system or checklist for organizations to follow when setting up a new process. For example, validation will make sure questions like these are addressed:
- Is the equipment we received from our vendor configured properly?
- Does the equipment have the capability to operate within the limits we need to consistently hit quality targets?
- What are the important operational parameters we need to control to prevent process excursions, and how do we know when an excursion is taking place?
- How do we determine our raw material specifications?
- What changes do we need to make to the synthesis recipe when we transfer it from lab-scale to commercial scale?
- Does the overall manufacturing process generate the correct level of active ingredient in each dose, within an acceptable range?
- How can we make sure that our whole process is running in control at all times?
Validation is a meticulous, detail-oriented process that must be adapted on a case-by-case basis. In this document, we’ll cover the most important principles. If you’re interested in more detail, there are some links at the end of this document for resources provided by the FDA, WHO, and ISPE (International Society of Pharmaceutical Engineers). Since this is a dynamic area that doesn’t lend itself to one-size-fits-all solutions, for complex validation projects it can be helpful to engage with a third party consultant.
The Validation Process
As with most aspects of GxP, the heart of a successful validation project is thorough documentation. This begins with the creation of a validation master plan (VMP), which lays out the overall philosophy for the validation project, as well as more granular details like the definition of the process flow and a list of what specific elements of the process require validation. We’ll talk more about the validation plan in Principle #3 below.
Also in the early stages of validation, engineers design the commercial-scale manufacturing line using information gathered during smaller scale R&D. The overall process flow is defined, and the design space of each piece of production equipment (or “unit operation”) is mapped. The design space is how input variables, like operating conditions and raw material properties, affect the critical quality attributes (CQA’s) of the material produced in the unit operation. CQAs determine the quality of the final product. For example, an input variable in the design space of a biopharmaceutical reactor might be the operating temperature, which affects the yield of an active ingredient, a CQA.
In complicated processes, a design of experiment (DOE) approach is often needed to map the design space. This is a critical step, because the design space is used to select production equipment, operating conditions, and informs the process control strategy for the full production line.
In complex products like biopharmaceuticals, gene and cell therapies, it can be difficult to identify which attributes should be included as CQA’s, even at the point where commercial production has started. In those cases, the list of CQA’s can be reduced or changed over time, as more data becomes available.
The next steps are to install and qualify equipment, then test the fully commissioned production line. Here, reducing execution missteps is critical to staying within timelines and budgets. This is a central part of any validation project and follows a three-part IQ OQ PQ process:
- Installation Qualification (IQ): confirming and recording that equipment is configured and installed properly from the manufacturer, including hookup to any utilities in the plant. Additional documentation like maintenance SOPs, calibration plans, spare parts lists, and emergency procedures, are finalized during this step.
- Operational Qualification (OQ): verifying that the equipment stably operates at the conditions specified in the process design, and running initial tests of the scaled-up design. The equipment is operated at the extremes of the process window, to confirm the CQA’s follow the expected behavior. This information allows the process window to be refined, and to determine the parameters to be used for statistical process control and process analytical technology. The capability of each unit operation- a quantitative comparison of the natural process variability to the specification window for a given CQA- is also defined here.
- Performance Qualification (PQ): verifying that the overall process generates the desired end product, and further refining or retargeting the operating parameter windows for the equipment, if needed. Note that this stage of qualification includes not just the equipment, but the personnel and procedures that will be used for routine production also.
The FDA considers the last step in PQ to be successfully running commercial-scale process performance qualification (PPQ) batches with the fully commissioned equipment set, control systems, and personnel. A PPQ is required for commercial distribution of pharmaceuticals.
Keep in mind that complete, detailed documentation of the objective data generated at each step is the primary deliverable from this process.
Motivation for Validation
The primary motivation to follow validation protocols is that it is the best known method to ensure consistent product quality, and therefore consumer safety, when direct verification is not possible. (This assumes that quality, safety, and efficacy are built into the product, which should always be the case.)
Furthermore, it is required to maintain regulatory compliance, avoiding fines, failed audits, and costly corrective actions. We’ll talk more about regulations in this area in the next section. Since FDA citations are public, pharmaceutical quality issues- including inadequate validation- can damage consumer confidence in a pharmaceutical manufacturer.
Proper validation also provides a strategy to make sure that your process is consistently running in control, protecting the product revenue stream by maximizing yield and reducing the need for troubleshooting shutdowns. It also helps to avoid delays in planning, scale-up, and commissioning a new manufacturing process.
Why Pharmaceutical Validation Is Especially Important
When validation is applied to something as complicated as pharmaceutical manufacturing, it can be labor intensive and time consuming. However, it is a critical part of protecting the health and safety of the consumer. This is reflected in the regulation around pharmaceutical validation, which is comprehensive and actively enforced.
The FDA is responsible to confirm that validation is carried out properly, as described in 21 CFR parts 210 and 211. In addition, the FDA publishes guidance documents which interpret the federal codes and provide more context and detail. In particular, the 2011 FDA guidance on process validation provides a practical framework, with an explanation of how the elements of the framework relate to the regulations.
For example, 21 CFR 211.100 requires “written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess”. Other parts of 21 CFR 211 address planning and IQ, requiring the facilities to be properly selected or built, and that equipment must be designed for intended use, and “calibrated, inspected, or checked according to a written program designed to assure proper performance” (21 CFR 211.68). Regulation also covers sampling of in-process material and the use of equipment monitoring and process control (211.110).
The net effect of these regulations is that validation is legally enforceable in pharmaceutical manufacturing. In fact, pharmaceuticals can be identified as “adulterated” if they aren’t manufactured according to these guidelines.
Regulatory compliance, however, should be thought of as a secondary (though necessary) goal of thoroughly following validation protocols. Particularly with complex products like biopharmaceuticals and gene therapies, where direct verification is impractical or impossible, validation is a key element to ensuring a consistently safe, effective final product. (In fact, in some cases the complete mechanism of how complex pharmaceuticals work is not fully known, making verification almost impossible.)
Modern pharmaceutical manufacturing processes can be complex and extremely sensitive to variations in processing conditions, so validation of the design space, the process control strategy, and the equipment at a precise level is needed. To illustrate this, consider a few examples:
- Ambient relative humidity can affect several aspects of tablet pressing, like powder handling, tablet properties, and even degradation of the active ingredients.
- For sterilization of packaging for parenterals, verification of sterilization is impossible, making full characterization and process control (i.e., validation) of the sterilization equipment critical.
- The extracellular pH of a bioreactor can determine the identity and amount of the generated products. Unfortunately, it can be quite difficult to control, partly because microorganisms can release chemicals to change the pH of their environment. Further complicating the situation, pH sensors can become fouled, making measurements unreliable. For this reason, characterization of the process window and the behavior of the measurement system are both critical.
6 Principles of Effective Pharmaceutical Validation
Validation is a fairly broad topic, and each individual project is different. So rather than a step-by-step guide, we’ll cover six principles that help to ensure successful validation across a range of pharmaceutical projects.
Understand the Relevant Regulatory Guidelines
Build a Cross-Functional Team
Have a Well-Documented Validation Plan Based in IQ OQ PQ Principles
Identify Organizational Gaps
Conduct Validation at All Stages of Product Life Cycle
Regularly Revisit and Update Validation Processes
The regulations in 21 CFR provide the framework and minimum requirements for validation activities. In the previous section, we discussed the parts of the code that are specific to pharmaceutical manufacturing. Any systems used to store and transmit data- including electronic signatures- should comply with 21 CFR Part 11, which is a general regulation on electronic record-keeping.
While the regulations around pharmaceutical manufacturing are comprehensive, they are not detailed, and are meant to cover a diverse range of situations. This means that some of the regulation in this area is left to the discretion of the FDA. For this reason, it can be helpful to work with a third party consultant with knowledge of the current regulation approach in your specific area.
The team responsible for planning and executing validation should have representation from all affected departments (operations, purchasing, testing, and others), as well as a diversity of technical expertise.
The FDA provides examples of the technical disciplines that should be considered, including “process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance”. R&D input is also helpful during scale-up of the process, definition of the design space, and identification of CQAs. Representation from departments that interact with equipment and raw material vendors can also speed up validation, for processes that are sensitive to incoming materials.
Taking a cross-functional approach, where each team member approaches the project from a different angle helps to ensure a complete plan is developed, with no critical parts missing.
It’s also important that the validation team has the support of management, so that it has the time and resources needed to thoroughly work through complicated validation issues.
The VMP is critical for two reasons. First, it is the guiding document for the entire project. Second, it is likely to be closely reviewed during regulatory audits. So it should be comprehensive and understandable. The plan should be developed with input and approval from all of the members of the validation team, approved by the team, and updated as needed.
Since the document will be referenced often and reviewed outside the organization, it should be organized into easy to follow sections. The detailed structure of the document may differ depending on the project, but major components typically include:
- Basic information on the company, and a space for the members of the team to approve the document
- Statement of the company’s general policy on validation and how it applies to risk management
- Overall definition of the intended product and the process flow
- List of the equipment and procedures that will be qualified through IQ OQ PQ and validated, and how (an equipment matrix or checklist can be used here)
- An explanation of the selection criteria for which equipment and procedures are subject to validation (in other words, a description of the risk-based approach used to select components for validation), and a timeline for validation
- References to ancillary documents including SOPs, maintenance schedules, training manuals, and documents describing any other element of the process that could affect product quality
- A plan for ongoing process monitoring and process control
Some organizations, such as small businesses or businesses that do not routinely conduct validation activities, may not have the in-house expertise or resources to efficiently carry out a validation.
Even in organizations with deep technical expertise in process engineering, QA, and in the chemistry and biology involved in the manufacturing of their products may lack institutional knowledge and experience in the more nuanced details of pharmaceutical validation.
If there are knowledge gaps in your organization, it’s important to recognize and address them early on. To fill these gaps, businesses often engage third party validation experts to fill these gaps. These experts can simplify and speed up the validation process, through:
- Current knowledge of the relevant regulations and guidance, which can sometimes be vague and open to interpretation. In these cases, an experienced validation consultant can clarify the text and spirit of the regulations, reducing the amount of time spent by in-house personnel and reducing the risk of misinterpretation.
- Risk assessment, to ensure that your validation resources are concentrated in the most critical areas, and that all potential sources of risk are identified.
- Templates to speed up the extensive documentation that regulators will be looking for on audits.
Validation is a critical part of commissioning a new process, which is why we’ve focused on that. However, validation activities continue through the life cycle of a product.
In fact, an important aspect for process validation is the strategy for managing changes to the process. The procedures used for change control should be addressed in the VMP, and any time there is a change to the process that could affect a CQA, that change should be validated. For example, a new raw material supplier, new piece of production equipment, or moving the manufacturing line to a different building could all trigger validation.
The criteria for which events trigger validation should be risk-based, and clearly spelled out in the VMP.
Re-validation could also be triggered by data generated by QA testing or statistical process control. For example, in-process analysis could indicate changes in the variability of a CQA, or repeated out of spec batches or customer complaints could indicate that some element of the process has changed. In this case, resolving the issue may require re-qualifying parts of the process.
The importance of this is reflected in 21 CFR 211.180, which requires periodic reviews of product quality and process control data, to determine whether any changes should be made.
The validation team should decide on regular intervals for reviewing and updating all of the processes used for validation, annually, for example, and include this in the VMP. The plan itself should be considered a living document, re-examined and revised periodically.
The plan should also identify triggering events for reviewing validation processes, like major changes in regulation, to the manufacturing line, personnel, facilities, or the structure of the organization.
An Example of Pharmaceutical Validation in Practice
Now that we’ve covered the basic principles of validation, let’s look at how they would be applied in a hypothetical situation. Consider a new pharmaceutical product developed through R&D, made in lab-scale quantities, and is now ready for scale-up to commercial production. This new product is a mixture of an active ingredient and excipients, delivered as a tablet.
The first step of the validation process is for management to form the cross-functional validation team, and make sure they have the time and resources to complete the project. The team should then evaluate whether there is sufficient in-house expertise to execute the project, or whether third party consulting is needed.
The team can begin drafting the VMP, preferably from a template so that no critical information is missed. Some of the details of the process will still be unknown at this point, but this can be added during process design.
Next, let’s step through the three execution stages of validation, as defined by the FDA.
Stage 1: Process Design
In this stage, engineers will develop a scaled-up process for the product. This involves defining the process flow and unit operations. For example, this process would require a reactor to synthesize the active ingredient, a spray dryer, a mixing unit to combine the active ingredients with excipients purchased from a vendor, a tablet press, and an operation to package the tablets.
Next, the operating windows for each step will be defined through well-documented, systematic experiments. These windows would include the temperature of the reactor, average particle size of a vendor-supplied excipient powder, and the pressure used to press tablets, for example. Operating windows would be selected to meet CQA’s identified during R&D, which might be the amount of active ingredient in each tablet and the hardness of the tablet.
In addition to setting process windows, these experiments are important to determine the sensitivity of the CQA’s to the operational parameters. Here, that might include the yield of the active ingredient from the reactor as a function of reactor temperature.
Data from the process design stage should be organized and complete. This is important for several reasons. First, the data is used to spec and purchase equipment. It will also be used for scale-up experiments and in the future to troubleshoot manufacturing issues. The data can also later be audited to confirm you have a thorough understanding of the effect of process variability on product quality at all steps.
Stage 2: Process qualification
Once the unit operations and process windows are defined, equipment can be ordered and installed. During the IQ process, the identity, configuration, and specified operating limits of the equipment will be confirmed and documented. Any measurement equipment, like thermocouples, pH meters, or level sensors, would also be checked or calibrated here.
An issue that could be caught during IQ is a part made from the wrong material. In this process, it is important that the punch tip in the tablet press is made from a specific, hard material to avoid wear. If the manufacturer built the press with the wrong punch material, the punches could wear quickly, causing tablet dimensions to go out of spec. Engineers and technicians should check the documentation for the equipment to make sure the specified material was included.
Next, OQ is performed by running each piece of equipment independently, under simulated production conditions. For the reactor, OQ could involve running simulated batches of varying sizes, confirming that the heaters and impeller motor have enough capacity to operate within the specified window for any batch size.
In PQ, the full process is run to make a test batch of tablets, by the staff who would normally run the process. Here, poor or inconsistent product quality could indicate a source of variability that was not previously known. For example, if pressed tablets are not holding together, this could indicate poor humidity control in the facility. This fix for this might be installing humidity monitoring and control, and using humidity as a controlled process parameter.
Stage 3: Continued Process Verification
Once the process is qualified, ongoing monitoring of process conditions, in-process intermediate material, and testing of final products are used to continuously validate and periodically verify the process. In this stage, statistical process control techniques can be used to continually refine and improve the operating windows.
Monitoring at this stage can also help to catch new sources of variability that would not exist during qualification. For example, switching to a new supplier of a powder excipient might reveal that particle size distribution of that ingredient is important when initial qualification batches are out of spec. Or adding a new reactor with a slightly different impeller design could lead to issues with mixing efficiency that would be caught during OQ or PQ of the new design.
Potential Consequences of a Validation Misstep
Formal validation using the framework we’ve discussed here is the best known method for ensuring a process that consistently generates high quality product. So any deviation from that framework risks product quality, and all of the consequences that arise from that, which in the case of pharmaceuticals includes risks to public health.
Following validation guidelines also reduces the financial risk of product loss and production delays by providing a proven, systematic approach for qualifying new processes and equipment.
In terms of regulatory compliance, if the FDA finds problems with your validation process, it can issue a public warning letter or Form 483 (“Inspectional Observations”). Issues can then be addressed through corrective actions. Ongoing, un-corrected problems can result in recalls, product seizures, or even civil penalties.
FDA auditors pay close attention to validation and GMP issues in general, as shown by the high number of citations issued in this area. Note that these citations are also public, so they can result in a loss of consumer confidence that can be difficult to rebuild.
Pharmaceutical process validation is a systematic process that confirms and documents that a process will consistently deliver a high-quality product. It is resource and time-intensive, but is an important tool for ensuring health and safety of consumers. This is reflected in the regulations around process validation, which are comprehensive and thoroughly enforced.
The six key principles for successful validation that we covered were:
- Understand the Relevant Regulatory Guidelines
- Build a Cross-Functional Team
- Have a Well-Documented Validation Plan Based in IQ OQ PQ Principles
- Identify Organizational Gaps
- Conduct Validation at All Stages of Product Life Cycle
- Regularly Revisit and Update Validation Processes
Validation can be a daunting project for businesses that do not conduct it regularly. For more information, or for assistance on your validation project, contact the experts at Dickson.
We covered the key principles here, but if you’re interested in more detail, here are some additional references on pharmaceutical process validation:
FDA: Quality System Regulation: Process Validation (2015)
FDA: Guidance for Industry Q8(R2) Pharmaceutical Development (2009)
FDA: Facilities & Equipment: CGMP Requirements (2015)
FDA: Guidance for Industry Process Validation: General Principles and Practices (2011)
FDA: Guidance for Industry Formal Dispute Resolution: Scientific and Technical Issues Related to Pharmaceutical CGMP (2006)
ISPE: Good Practice Guide: Process Validation (2019)
Global Harmonization Task Force: Quality Management Systems - Process Validation Guidance (2004)
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