Andy Teng10.20.06
The Proof Is in the Pudding
Process Validation Is Increasingly Part of the
End-to-End Service That Providers Offer to OEMs
Andy Teng
Contributing Writer
As the medical device industry increasingly embraces full-service, outsourced manufacturing, one of the value-added functions OEMs have come to expect from third-party service providers is product validation. From product conception to design transfer to sterilization, just about every step along the manufacturing continuum requires design and process validation, and vendors have responded by making validation services a regular part of their offerings.
While most engineering firms, manufacturing providers, testing labs and other vendors generally don’t offer validation as a standalone service, they will incorporate it as a part of a comprehensive package. That’s because medical OEMs have needs as diverse as the products they bring to market—some need a full spectrum of service and expertise, while others require only a narrow portion. Whatever the need, contract service providers say they increasingly are being called on in a consultative capacity as well as for their manufacturing capabilities and they must be able to validate, when necessary.
“As a contract manufacturer, you do pretty much what needs to be done,” said Scott Dentino, director of manufacturing at Santa Cruz, CA-based BC Tech, a medical device development and manufacturing house. “We have customers that come in with a wide range needs. I deal with some customers that already have products that are manufactured, and they are really savvy, and some customers have no idea.”
Like other manufacturing service providers who spoke with MPO, Dentino said most clients are not seeking process validation by itself but, instead, all the services around it. For instance, some OEM customers turn to BC Tech to reverse engineer a product that had been manufactured by another service provider. But because the customer no longer wants to work with the original manufacturer, BC Tech may be provided a finished product and asked to figure out how to manufacture it, he added.
Validation Explained
Validation is required under Quality System Regulations (QSR) on several fronts, but the mandates that outsourcing providers must comply with are design and process validation—the former of which is especially applicable to contract manufacturing providers. According to FDA regulations, process validation is defined as “…establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics.”
The aim of process validation is to set up effective processes and controls in device manufacturing. These cover a wide array of performance and process issues, including initial validation as well as re-validation. For manufacturing service providers as well as OEMs, process validation must meet the requirements specified under 21 CFR Section 820.100. Validation is required when manufacturing a new product—and also when a change is made in the manufacturing process that materially affects product characteristics such as uniformity and identity. This includes changes in equipment and process, and even packaging.
As both a regulatory mandate and an effective safeguard in an OEM’s risk management efforts, process validation is an absolute necessity. QSR clearly makes a case for product quality through validation programs, including greater product safety as well as improved manufacturing that can yield less scrap and establish validation files that can be used to support next-generation products.
What to Validate
Although the regulations are clear on validation requirements, contract manufacturing service providers say many clients—especially smaller OEMs—aren’t always certain about what needs to be validated. According to the FDA, validation must be performed when process results “can’t be fully verified during routine production by inspection and test.”
Andy Snow, vice president of quality and regulatory affairs for the Advanced Medical Operations of Boulder, CO-based HEI, a contract design and manufacturing firm, said, “There is a general underestimation of what really is required to validate a process. The more common areas where [OEMs] tend not to understand what the requirements are include validation of test methods as well as lack of understanding of automated processes.”
According to Snow, while bigger OEMs tend to be more sophisticated and have a clearer understanding of their validation obligations, they still look to their service providers to help in the process, especially as they become more comfortable with full-service outsourcing. He pointed out that some clients comfortable with outsourcing to a full-service firm will assign junior engineers to oversee the project, knowing that knowledge gaps will be tended to by the more experienced outsourced partners. This, he added, is indicative of the device industry’s growing comfort level with full-service outsourcing.
As part of the service it provides to clients, HEI may perform a gap analysis during design transfer. From that, the company can determine validation requirements, which helps to form the foundation of the validation master plan. Snow pointed out that most clients transitioning products into manufacturing ask that HEI help with the validation process.
For firms such as Proven Process, an East Walpole, MA-based contract manufacturing provider and process validation services firm, gap knowledge most often is found among the startups. According to Ken Fine, the company’s president, these smaller OEMs understand the basic requirements of process validation but fail to address the nuances.
“Emerging companies often do not understand the extent of the effort for process validation. They understand the regulatory implications but often underestimate the need for statistical significance of sample sizes, the formal documentation with proper review and approval and the importance of applying risk management concepts to process validation,” he pointed out.
Proven Process, which offers risk assessment and management, design verification, process capability analysis and equipment and process performance qualification, typically receives requests for basic process validation services from both large and small companies. Customers often ask for validation planning, process failure modes and effects analysis, equipment installation qualification and operational qualification, process and product performance qualification (including design of experiments and process capability studies) as well as software validation for automated process equipment.
Fine pointed out that larger OEMs are more actively involved in their process validation efforts but may choose not to perform all functions internally; some pieces may be outsourced to his company. Smaller device OEMS, on the other hand, are more dependent on third-party expertise to ensure they meet their quality obligations.
Because the validation spectrum of medical devices is so broad, it extends not only to just finished goods manufacturers but component contractors as well. In many instances, OEMs and component makers look to third parties to validate those products, said Trabue Bryans, executive vice president and general manager for the Atlanta Division at AppTec, a contract testing lab. She noted that the company often is asked to validate components used in finished products as part of the overall process validation efforts.
For instance, validation might include bio-burden testing for bacterial load, closure viability and other assessments. Bryans said manufacturers—large or small—should realize that components, as much as finished goods, fall under the QSR requirements for process validation.
Where it become especially thorny is determining the right protocol and knowing what to validate. Among new technologies and even in existing products that are reprocessed, OEMs may need help in determining the right testing to validate. Disinfection efficacy, package integrity and pyrogenic claims are some of the product characteristics commonly tested by AppTec, but there are many emerging technologies that can confound OEMs when it comes to validation. In established but specialized technology, even some of the largest OEMs still may need outsourced services.
“When you start to get into areas such as bio-compatibility and viral clearance, they just can’t know it all,” Bryans said.
AppTec is one of the specialists in new technology validation, especially with products that incorporate tissue. Dean Enrooth, the executive vice president of business development, said because some products encompass tissue, pharmaceutical and device manufacturing, the company must observe good tissue practice, in addition to the usual GMP. These requirements can be lost on smaller manufacturers, he pointed out, because some are surprised when told that they must validate a number of processes.
One difficulty facing new technology developers is determining how to validate their products when no predicate devices exist. Bryans said that’s when companies sometimes turn to providers such as AppTec, because staffers like herself participate on a number of standards organizations that help to set up appropriate testing methods and protocol. By leaning on their expertise, OEMs stand a better chance to win market approvals when they submit premarket approval applications or investigational device exemptions.
“That’s a huge part of what we do—serving as advisors,” she said, adding that adhering to standards organizations’ visions also can help new technology win market clearance in the international markets.
Validating the manufacturing process also encompasses the equipment used to make components and finished products, and some vendors point out that this is an area where buyers often need help. Although they already know how to operate the equipment by the time an install is complete, validating the equipment adds another layer of complexity to the process, and buyers often look to third-party experts to help them ensure compliance with validation requirements.
Karen Greene, technical director at Eden Prairie, MN-based DDL, a package and product testing company, noted that some of her clients ask questions about the proper operations of equipment, how best to maintain package integrity and even establishing the proper protocol.
Greene explained that, among the clients served by DDL, some of the biggest deficiencies observed include knowledge of ISO 11607, the standard on packaging for terminally sterilized medical devices. The latest revisions to the standard—which calls for medical packaging to maintain its integrity for the shelf life of the medical device—are designed to harmonize it with EN-868-1. However, language used in the revision can be confusing to the uninitiated, with many clauses mandating steps for validating and testing the packaging. That’s why outsourced service providers with deep subject matter expertise have been in high demand; they are able to help OEMs develop test methods and protocols that will help them comply with the standard.
As OEMs continue to outsource more non-core activities, contract manufacturing service providers, engineering houses and sterilization firms likely will play a greater role in how medical device OEMs set up their validation efforts within their quality programs. As another value-added service these vendors provide, process validation is just one more function that can be outsourced and further proves that the medical device industry is growing more comfortable with end-to-end outsourcing.