Your Guide to Pharmaceutical Validation

In GxP and GMP environments, validation ensures that processes, equipment, or software consistently meet their intended purpose using objective, scientific data. It’s a critical quality management tool in regulated industries like pharmaceuticals, helping maintain product quality and compliance. In this blog, we’ll explore key principles of pharmaceutical validation and how to effectively write and execute validation documentation.

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.  

Pharmaceutical 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 using pharmaceutical equipment validation, 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 refines or retargets 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, as well.
  
  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 validation documentation in pharmaceuticals regarding the objective data generated at each step is the primary deliverable from this process.

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 ensure successful validation across a range of pharmaceutical projects.

1. Understanding the Relevant Regulatory Guidelines

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.  

2. Building a Cross-Functional Team

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.  

3. Having a Well-Documented Validation Plan Based in IQ OQ PQ Principles

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.

4. Identifying Organizational Gaps

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

5. Conducting Validation at All Stages of Product Life Cycle

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.

6. Regularly Revisiting and Updating Validation Processes

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.

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 products. 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 pharmaceutical 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.

Pharmaceutical validation ensures operations consistently produce high-quality products, safeguarding consumer health and meeting strict regulatory standards. For guidance or support with your validation project, contact our team at Vivamet.