Validation Of Manufacturing Process

[Denisha Cerniglia]

Manufacturersin the highly competitive pharmaceutical industry always need to show consumers and regulators that they can provide consistently high-quality products that do exactly what they are supposed to.

As earlier stated, validation in the pharmaceutical industry is all about ensuring that relevant production processes adhere to established guidelines, resulting in a consistent, high-quality, and safe product that meets consumer demands. In essence, validation is an accepted methodology when key quality metrics can not be measured, tested, and verified.

Many of the top pharmaceutical and medical device manufacturers across the globe use our GXP-qualified platform to guide operator activities and business processes while automating data collection, providing a detailed record of all actions taking place throughout the product lifecycle.

For example, with Tulip's electronic batch records, manufacturers can make data collection and validation a continuous, seamless part of the manufacturing process with streamlined, automated documentation as operators and machines work.

When it comes time for a batch record review, the necessary information is easily accessible, legible, and accurate. This means manufacturers are able to spend more time ensuring the quality of their product and less time worrying about human-based transcription errors.

Process validation is the analysis of data gathered throughout the design and manufacturing of a product in order to confirm that the process can reliably output products of a determined standard. Regulatory authorities like EMA and FDA have published guidelines relating to process validation.[1] The purpose of process validation is to ensure varied inputs lead to consistent and high quality outputs. Process validation is an ongoing process that must be frequently adapted as manufacturing feedback is gathered. End-to-end validation of production processes is essential in determining product quality because quality cannot always be determined by finished-product inspection. Process validation can be broken down into 3 steps: process design (Stage 1a, Stage 1b), process qualification (Stage 2a, Stage 2b), and continued process verification (Stage 3a, Stage 3b).

In this stage, data from the development phase are gathered and analyzed to define the commercial manufacturing process. By understanding the commercial process, a framework for quality specifications can be established and used as the foundation of a control strategy. Process design[2] is the first of three stages of process validation. Data from the development phase is gathered and analyzed to understand end-to-end system processes. These data are used to establish benchmarks for quality and production control.

Design of experiments is used to discover possible relationships and sources of variation as quickly as possible. A cost-benefit analysis should be conducted to determine if such an operation is necessary.[3]

Quality by design is an approach to pharmaceutical manufacturing that stresses quality should be built into products rather than tested in products; that product quality should be considered at the earliest possible stage rather than at the end of the manufacturing process. Input variables are isolated in order to identify the root cause of potential quality issues and the manufacturing process is adapted accordingly.

Process analytical technology is used to measure critical process parameters (CPP) and critical quality attributes (CQA). PAT facilitates measurement of quantitative production variables in real time and allows access to relevant manufacturing feedback. PAT can also be used in the design process to generate a process qualification.[4]

Critical quality attributes (CQA) are chemical, physical, biological, and microbiological attributes that can be defined, measured, and continually monitored to ensure final product outputs remain within acceptable quality limits.[6] CQA are an essential aspect of a manufacturing control strategy and should be identified in stage 1 of process validation: process design. During this stage, acceptable limits, baselines, and data collection and measurement protocols should be established. Data from the design process and data collected during production should be kept by the manufacturer and used to evaluate product quality and process control.[7] Historical data can also help manufacturers better understand operational process and input variables as well as better identify true deviations from quality standards compared to false positives. Should a serious product quality issue arise, historical data would be essential in identifying the sources of errors and implementing corrective measures.

In this stage, the process design is assessed to conclude if the process is able to meet determined manufacturing criteria. In this stage all production processes and manufacturing equipment is proofed to confirm quality and output capabilities. Critical quality attributes are evaluated, and critical process parameters taken into account, to confirm product quality. Once the process qualification stage has been successfully accomplished, production can begin. Process Performance Qualification [8] is the second phase of process validation.

Continued process verification is the ongoing monitoring of all aspects of the production cycle.[9] It aims to ensure that all levels of production are controlled and regulated. Deviations from prescribed output methods and final product irregularities are flagged by a process analytics database system. The FDA requires production data be recorded (FDA requirements ( 211.180(e)). Continued process verification is stage 3 of process validation.

The European Medicines Agency defines a similar process known as ongoing process verification. This alternative method of process validation is recommended by the EMA for validating processes on a continuous basis. Continuous process verification analyses critical process parameters and critical quality attributes in real time to confirm production remains within acceptable levels and meets standards set by ICH Q8, Pharmaceutical Quality Systems, and Good manufacturing practice.

First, I want to note that process verification and validation are not the same thing as design verification and validation. The latter are performed as part of design controls, and have their own specific definitions and steps.

What you need to remember here is that process verification requires some sort of quantitative proof that specifications have been met. In the simplest terms, if you specified that a part should be exactly 20 mm in length, you could verify that by measuring the parts that your process produces against the specification of 20 mm.

At first glance, this looks very similar to the definition for verification. However, process validation does not measure or test a final product against specifications, like when you verify a process is working correctly.

Some processes may be verifiable, but from a business perspective, it may make more sense to validate them instead. The guidance document offers these examples for processes in which you might choose validation over verification:

Installation Qualification (IQ) - Installation qualification is used to ensure that the installation of any necessary equipment, piping, services, or instrumentation has been executed in accordance with the manufacturer's requirements.

Operational Qualification (OQ) - During operational qualification, the equipment should be tested to determine process control limits, potential failure modes, action levels, and worst case scenarios.

Performance Qualification (PQ) - In the performance qualification phase, the goal is to demonstrate that the process will consistently produce acceptable results under normal operating conditions.

Etienne Nichols is a Medical Device Guru and Mechanical Engineer who loves learning and teaching how systems work together. He has both manufacturing and product development experience, even aiding in the development of combination drug-delivery devices, from startup to Fortune 500 companies and holds a Project...

In 2011, the FDA released Guidance for Industry Process Validation: General Principles and Practices. This guidance emphasizes that, as the FDA puts it, the validation process of manufacturing and commercialization are critical to the quality assurance of the product itself.

The ultimate objective is to assist readers in understanding how their organizations can successfully manage the challenges of FDA-compliant large-scale commercialization while maintaining drug quality, effectiveness, and safety.

Need project or staffing assistance for process validation within your facilities? We help thousands of life science companies develop scalable resource plans to support validation efforts throughout the project lifecycle. Whether it's drafting protocols to execution and compilation of data packs, our resources have you covered. Learn more and connect with us: Commissioning, Qualification, and Validation.

A foundational tenet of this FDA guidance document is the lifecycle concept. The lifecycle approach is concerned not only with the initial drug development processes; but also, the establishment of commercial manufacturing and routine commercial production until the discontinuation of the product.

It's important to note that prior to manufacturing and commercialization activities, manufacturers should be able to confirm that the products that they plan to commercialize can meet the required quality standards and that the designed manufacturing procedures can accommodate mandates related to safety and efficacy.

Manufacturers should also understand potential variations in Active Pharmaceutical Ingredient (API) and drug products that could occur during commercialization and scale-up activities. They need to make every effort to understand the source, degree, and impact of the variation.

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