Within pharmaceutical manufacturing, the goal of process validation is to build quality into the operation at every step. The result is consistent product quality. It seems straightforward but how does one achieve this when it involves a myriad of multiple systems (PLCs, HMIs, control systems, etc.) and requires a team effort that encompasses people from various disciplines within the plant? 

First and foremost, it is important to design processes that ensure product quality, safety and efficacy. Today’s software systems can help validate pharmaceutical manufacturing and steer the most appropriate design of processes in the right way. For instance, these systems can deliver clear documentation, provide version control for the multitude of systems in use and backup to ensure all risks are mitigated. 

Software systems have become instrumental as validation expands from analytical methods used for the quality control of drug substances and drug products to computerized systems for clinical trials, labeling or process control. Quality cannot be adequately assured merely by in-process and finished product inspection or testing. Validation must happen at each step of a manufacturing process, which involves lots of team members from engineers to quality control to compliance officers, etc. to assure that the finished product meets all quality attributes, including specifications. 
  
Documentation and traceability for compliance
Part of the validation process is in the documentation—there needs to be integrated support for documentation with 100% clarity and traceability. In addition to this, version control of all software systems used within the pharmaceutical manufacturing process are necessary to ensure compliance with the current good manufacturing practices (CGMPs). These regulations state that manufacturing processes must be designed and controlled to ensure that in-process materials and the finished product comply with quality requirements that have already been predetermined and assure consistency and reliability. 21 CFR Parts 210 and 211 encompass requirements for approving or rejecting processes and specifications that impact drug quality. 

In fact, 21 CFR 211.22 requires clear, written documentation for quality control and any anomies or deviations must be justified and documented as well. To meet such compliance regulations, it is critical to deploy a software specializing in version control, backup and documentation.  

In highly regulated industries like pharmaceuticals, the four eyes principle or otherwise known as the two-person rule, is a requirement that mandates two individuals must approve some action before it can be taken and this requirement is also usually managed by the same software system that ensures process validation.

The four eyes principle gives another reason for deploying a validation software systems that is able to integrate seamlessly with a full range of automation devices and equipment commonly in use by pharmaceutical manufacturers and not just tied to one single manufacturer. The version control system needs to be vendor-agnostic, which further safeguards validation is properly addressed. 

Pharmaceutical software systems for process validation
Validation software systems help manage and keep track of all types of activities that take place over the lifecycle of the product and process. Whether a piece of equipment designed to manufacture something, a process/recipe to make something, or a computer program to control something—the pharmaceutical industry has a need for validation, which is best done not manually but rather using a sophisticated system.

For instance, such software systems will automatically store the new versions or copies as they’re made. When a new staff member goes to log in, the system will know who last notated the file and everything is time-stamped, allowing for a clear audit trail. It also ensures all the right data is being captured. It can prompt the user to enter notes and/or comments, which are stored by the system and can be provided in real time. This way the user can easily reference why changes were made. Today, this is often still handled manually. In many instances, pharmaceutical companies will use external contractors and then realize thereafter the need for better controls to be put into place. Team leaders see the need for a smart version control and a backup system to safeguard them from any potential problems. Additionally, the system can let the user know that a contractor made changes that were saved to an external thumb drive. The system can alert the person in charge that they need to get a copy of the thumb drive. 

Such systems as described are typically used on a daily basis. They are especially helpful to developers who are making the code changes and often trying to get through a backlog of work. With automated validation in place, many issues related to tracking changes go away. For example, when using the validation system, the user would simply log in to the system and use the latest copy of the programming file from the central repository before beginning work. They wouldn’t worry about having the latest version and would need any notes or comments that may need to be addressed. Once done with the day of work, the user would simply save all the changes and essentially put the file back on the shelf and check it back into the system along with any notes or comments.  

Automating validation
The validation system can also act an automated backup or scheduler. It can connect to the control network with zero human involvement. It automatically reaches out to the devices in the network to obtain the current copy that’s running on a device and checks it against the central repository to ensure its correct. Nothing can happen that isn’t allowed to happen.

There is also flexibility because the user can choose how frequently they would schedule a backup. Most will do it on a daily or on a shift basis, so that any and all changes will be noted. For example, perhaps somebody walked up to a controller and put some code on it without letting anyone know. A validation system would pick up on that and flag it. Maybe it is a malicious attack or some sort of cybersecurity issue, the system will catch vulnerabilities through regular scanning intervals. 

Again, it’s just comparing what is actually running on the device to what is assumed or thinks should be running there. This is when a business process gets kicked off. For example, if changes are noted that aren’t running, the system will conduct a comparison to determine if there are any issues. It would take into account just the code differences. Let’s say, there are ten thousand lines running on a controller, the system will simply highlight what is changed and will send that information off to an email distribution list where a manager or decision-maker can then decide what action to take. 

This change control methodology focuses on managing change in order to prevent inadvertent consequences. Certain manufacturing changes (i.e changes that alter specifications of a drug or a critical device attribute or bioavailability) are mandated to have regulatory filings and prior regulatory approval. Change is an inherent part of the lifecycle of a pharmaceutical product. A change can be an addition to, deletion of, or modification to a manufacturing process, material, product, procedures or equipment.

Summary
Validation is used in the process design stage through commercial production and can provide the scientific evidence that a process can consistently result in delivering a quality product.  When manufacturing pharmaceutical drugs, there must a very accurate, repeated degree of certainty in obtaining consistent results. To best achieve validation, it is important to use the right software systems.

With validation, it is instrumental in making sure the process is repeated exactly step by step all the way through and is achieving the end result within the allowed tolerances. For instance, temperature set points for producing certain drugs such as stimulants—methamphetamine and Ritalin or antidepressants—or perhaps tolerances for thicknesses of insulin bags, as an example, would have its processes validated and assigned validation thresholds. For the threshold, each individual step would be assigned a certain range, such as the temperature could fluctuate from five to six degrees or anywhere in-between but if it crosses over and gets to seven, then that would cross the threshold. The process would be flagged and product considered bad. This can be costly and why a lot of engineering work goes into figuring out what are the validated process variables. 

A lot of time and money is spent on certifying one individual way of making a particular drug and why software systems have become key in the solution to help pharmaceutical companies get to that validated state. Then once they are running, the software ensures that if they need to audit or provide a guarantee, they have one. The system helps to set a protocol that requires review, signoff and signatures. The protocol is always checked and authenticated before the process can go into production. 

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Robert Glaser is the chief technical officer of Auvesy, Inc. (www.auvesy.us). Prior to this role, he worked for Auvesy Germany for over 10 years since the company’s founding in 2007. He most recently served as director of research and development for Auvesy. Robert holds a master’s degree in computer science.