When your facility is ready to put its methods to the test, validation demonstrates that your processes and equipment will consistently generate accurate results. The Food and Drug Administration’s (FDA’s) 1987 Guideline on General Principles of Process Validation defines process validation as “Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product, meeting its pre-determined specifications and quality attributes.”
The FDA created its initial validation guidelines in an effort to reduce errors and increase safety across the industry, and these guidelines, in combination with recent updates, are an important element of current good manufacturing practices (cGMPs) — for good reason. Tragic errors occurred before these validation guidelines were created, including the Therac-25 incident, in which patients received massive overdoses of radiation from radiation therapy machines. This incident highlighted the need for stricter validation requirements, as proper software and automation validation may have exposed the machine’s design flaws.
Proper testing is not only important for automated systems, but also for facilities, construction, packaging and more. Accomplishing accurate validation without breaking the bank can be challenging, but some facilities find that contract manufacturing organizations (CMOs) help take the weight off their shoulders. Validation service providers offer highly skilled personnel and wide range of specialized services, allowing manufacturers to pick the right provider for their process and budget. To find out more about what sets validation CMOs apart from the pack, how validation regulations are changing and how manufacturers can meet the requirements of a global market, Pharmaceutical Processing spoke with validation CMOs.
Some equipment and instrumentation providers include validation services with the cost of their equipment as a package deal. However, the existence of validation CMOs is a testament to manufacturers’ desire for more options.
Why do some companies choose to enlist the help of a CMO? Wai Wong, Vice President and General Manager at Pharmatech Associates Inc., which offers validation policy and program development; protocol and master plan development; and validation of laboratory systems, packaging, automation systems, software, facilities and construction, explains that packaged deal offerings’ protocols “tend to be generic and only test the functions of the equipment without taking into account the special requirements for each customer.” Enlisting the services of a CMO “allows the buyer to have validation protocols that are tailored specifically for the site and their requirements.”
Kenneth Christie, Chief Operating Officer at VTS Consultants Inc., which offers commissioning, qualification, regulatory consulting and GMP training on a global basis, adds that in addition to observing “cookie-cutter” offerings, he has witnessed documentation errors: “In many cases, I have reviewed such documentation only to find incorrect equipment descriptions, model numbers, etc. because no one bothered to verify that it was correct for the equipment ordered.”
Adjusting to Change
In 2011, the FDA updated its validation guidance. Wong explains how this update has impacted manufacturers: “With the release of the new FDA Guidance on Process Validation in January 2011, many companies have been requesting guidance on how to comply with the new regulations.” Wong explains that “The new guidance brought about a fundamental change to the way the FDA evaluates whether new and existing products are manufactured in a way that is both scientifically and statistically shown to be in a state of control.”
New manufacturing trends are also influencing validation. “Single-use disposable systems are becoming more and more commonplace in aseptic manufacturing,” says Wong. “They have several advantages in that they don’t require large capital outlay tanks and do not require cleaning validation as they are sterile. The tradeoff is you typically have to do some leachables and extractables testing.” The increased industry use of restricted access barrier systems (RABS) is also influential. Wong says that while RABS “reduce the initial capital outlay, there is added complexity on the qualification and validation side when it comes cleaning and sterilization validation.”
Software validation is also undergoing changes: “Enterprise Resource Planning (ERP) has exploded over the past two years,” explains Valarie King-Bailey, Chief Executive Officer at OnShore Technology Group Inc., which offers software validation services for ERP, ECM and Enterprise compliance management systems. “As life sciences companies seek to automate their quality and supply chain processes, ERP adoption is growing.”
The Bare Bones of Revalidation
If a change is made to a process or output product, or if a process is no longer working in a state of control, revalidation must occur. We asked the experts if manufacturers sometimes shy away from revalidation. “To a certain point … manufacturing companies are weighing the costs of revalidation when it comes to changes to their facilities,” says Wong. “Typically, revalidation is performed per a routine schedule … and is not as complicated as the initial validation.” Wong explains that “If changes are made to the plant, then more extensive validation is then required depending on the modifications.” He notes that “some companies take this opportunity while making changes to the plant to also improve their previous validation activities to bring them up to the current standards.”
King-Bailey explains that although companies sometimes attempt to delay revalidation, “there is no need to fear this process.” In OnShore’s experience, “regression testing is always the biggest problem with revalidation.” Sometimes, in an effort to fully comply, companies have gone overboard: “They test everything ‘just to be safe’— there is no need to do this.” OnShore recommends that “users spend time conducting a risk assessment and basing test decisions on the level of risk.”
If It’s Not Documented, It Didn’t Happen
The service providers agreed that proper documentation of validation processes is vital. In the industry, “If qualification results are not documented, then they never happened,” says Christie. “Companies must be able to develop a system whereby results are readily retrievable and assure the integrity of the information, whether it is in paper or electronic formats. Documentation deficiencies are found in the top 10 most cited observations by both the FDA and the MHRA of the UK.”
King-Bailey believes that electronic documentation formats are an ideal solution: “Document management systems are now a commodity technology and have the ability to support validation change control processes. This should not be a manual process.” She says that automated processes can help increase efficiency: “OnShore has pioneered the use of Raltus ProcedureCapture to streamline validation testing,” a test script automation tool that “allows users to capture IQ/OQ test scripts, execute validation testing and summarize the results.” According to King-Bailey, “Use of this software has resulted in up to 80 percent testing efficiencies.”
Acceptance on Every Shore
According to the experts, the industry’s move to international markets is influencing the shape of things to come. “Since many companies sell their products globally, they must make sure they meet the regulatory requirements for each country,” Christie explains. “To think that meeting the U.S. GMPs automatically assures compliance to other countries’ regulations is a myth.”
Wong agrees: “The global supply chain is here to stay, so companies will have to make sure their validation programs can address multiple compliance standards and be able to demonstrate process understanding and control.” Wong believes that “multi-use facilities overseas can expect continued scrutiny of their cleaning validation program,” and that “analytical method validation will continue to be a sore point with overseas developers seeking to come to the U.S., largely because of the misperception that the USP is the standard for methods. USP represents the minimum standard,” and “it is still incumbent on the developer to demonstrate the method is adequate for their product’s needs.”
Consistency Is Key
Christie has observed some validation confusion from manufacturers, who sometimes go overboard with validation in an effort to comply.
“I think the trend today … is the attempt by industry to make a risk analysis of what is proposed for qualification protocols and to assure that the extent of testing and nature of the test challenges really prove the ability of the equipment or utility to meet its defined specifications,” says Christie. “I have seen protocols where the level of detail was far beyond what was needed and little effort was made to evaluate the adequacy of test challenges. I think some companies believe the more pages in a protocol, the better it is.”
“Regulations today tell you what you have to demonstrate but not the method. If you can prove what is required and have it based on logic and/or scientific methods, then the agency should accept it.” According to Christie, consistency would help companies better understand what is expected: “Auditors don’t seem to be consistent in their approach or what they consider to be deficient,” he explains, and that inconsistency “impacts why companies are afraid to change from past and overkill practices.”