Validation — Necessary, And Not Necessarily Evil

By Christina Meyer Dell Cioppia, Amec Foster Wheeler

1962 was a very significant year. It was the year of the Cuban Missile Crisis and the Second Vatican Council. It was the year that John Glenn became the first American to orbit the earth, and a seemingly innocent time when the Dick Van Dyke Show was a huge new television hit. Some very well-known people were born in 1962, including Garth Brooks, MC Hammer, Evander Holyfield, Tom Cruise, Jon Bon Jovi, and … me. All of us who were born in the U.S. in 1962 owe a tremendous debt of gratitude to Frances Kelsey of the FDA, who prevented thalidomide from entering the U.S. drug market.

In 1962, thalidomide was sold in Europe as a treatment for anxiety and gastritis, and later to treat morning sickness in pregnant women. The drug was advertised by its manufacturer as being completely safe, even for pregnant mothers. By 1960, thalidomide was marketed in 46 countries, with sales almost matching those of aspirin.¹ Tragically, as a result of mothers taking Thalidomide during pregnancy, over 5,000 infants in Europe — and over 10,000 infants worldwide — were born with phocomelia, a malformation of the limbs. Why not in the U.S.? Because Kelsey, an FDA medical officer, helped prevent approval and marketing of thalidomide in the United States. This decision led to great public support for the FDA and to stronger drug laws, including the Kefauver-Harris Drug Amendments, which required drug makers to prove that their product worked and was safe before the FDA could approve it for sale.²

Sadly, the tragic story of thalidomide is not an isolated event, and it can certainly be argued that the requirement to validate came in response to major drug disasters. U.S. drug validation seems to have its origins in the early 1970s, in response to some very well-publicized sterility problems in parenteral products.

With increased regulatory scrutiny and requirements, the onus was placed on drug manufacturers to prove that their processes resulted in products with the efficacy, purity, and strength claimed. Since FDA’s original objective focused on parenterals, manufacturers of non-parenteral products saw little value in validation and viewed it as more of an unnecessary regulatory burden that should be limited to parenteral manufacturers and sterilization processes. Furthermore, FDA’s definition of validation provided little direction to manufacturers on what needed to be done to meet regulatory requirements.

The oft-quoted definition of validation was put forth by Ted Byers in 1980: "Validation is the attaining and documentation of sufficient evidence to give reasonable assurance, given the state of science and the art of drug manufacturing, that the process under consideration does, and/or will do, what it purports to do."³ Great, we can do this! But what exactly has to be done to provide “sufficient evidence,” and what does “reasonable assurance” mean? The FDA’s intent was to avoid being overly prescriptive in dictating rigid requirements on how to provide this proof. It was up to individual manufacturers to ensure they built, operated, and maintained their facilities and quality systems to ensure that drug products were safe and effective. The process must “do what it purports to do.”

Under the Food, Drug, and Cosmetic Act, a drug is considered adulterated if the “methods used in its manufacture, processing, packing, and holding, and the facilities and controls” do not conform to cGMP requirement. In other words, even if the end product conforms to all specifications, if it was not manufactured under conditions that adhere to CGMP requirements, the product is adulterated and cannot be sold.

Validation originally pertained to process validation. However, a process cannot be proven to consistently produce an acceptable product if the equipment and systems used in its manufacture don’t perform consistently. Today, equipment qualification — including installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ) — are included under the broader umbrella of validation.

Unfortunately, qualification and validation are often thought of as an end point in the project lifecycle. However, inspecting, testing, and documenting a system alone will not validate it. Systems and processes must be designed, constructed, installed, operated, and maintained properly to allow for initial validation and ongoing maintenance in a compliant state. This translates to designing with the end in mind, which is the overarching philosophy in FDA’s Quality Systems Approach to Pharmaceutical CGMP Regulations: “Quality should be built into the product, and testing alone cannot be relied on to ensure product quality”.⁴

A lifecycle approach to regulatory compliance mandates that qualification and validation considerations be raised early in the project lifecycle. This begins at the conceptual, preliminary, and basic design phases, with quality input into critical project related deliverables such as:

• User requirement specifications
• Material, equipment, and personnel flow diagrams
• Classification, zoning, airflow, and room pressurization diagrams
• Vendor documentation requirements and factory acceptance testing (FAT) / site acceptance testing (SAT) protocols, if these will be referenced to support qualification
• Basis of design documents for CGMP critical areas
• Piping and instrumentation diagrams (P&IDs)

Does this mean that quality personnel should approve engineering deliverables? Absolutely not. However, if a system isn’t designed to be compliant and validate-able, no amount of documentation, inspection, or testing will make it compliant. Therefore, input from those who are ultimately responsible for defending the design before regulatory authorities (namely, validation and quality) is critical during the design phase. At a minimum, the quality organization should provide input into and approve user requirement specifications, since these form the foundation of later validation activities.

Do some companies go overboard with validation? Of course, but more often than not, it is in response to what they think is required rather than what is actually required. We’ve all seen 200-page installation qualification protocols for plant steam systems (or other systems) that don’t actually need to be qualified or validated. We’ve all been on projects where quality approval is required on every equipment specification, piping and instrumentation diagram, and basis of design document.

However, the tendency to overreact is understandable. Failure to comply with any regulation contained in FDA 21 CFR Part 210/211 render a drug product adulterated, as well as making the person responsible for failure to comply subject to regulatory action. Add this to the commercial losses of not gaining regulatory approval or being first to market, and it becomes very clear why we sometimes try to specify, document, inspect, and test every nut, bolt, and fitting that may have even the slightest connection with the manufacturing process and product quality.

Validation isn’t an easy, straightforward, painless, or in any way even slightly enjoyable task, but let’s not forget that there really is a purpose to all of this beyond what is often perceived as endless piles of paperwork. Would any of us want to give our children a vaccine, antibiotic, or aspirin if we didn’t feel completely confident that these were manufactured under a process that does “what it purports to do”? Providing this assurance means proving that the process is in a state of control, which means the equipment is designed properly, installed properly, functions properly, and is operated and maintained properly. That assurance can only be provided through validation.

References:

1. B. Fintel, A.T. Samaras, C. Edson, “The Thalidomide Tragedy: Lessons for Drug Safety and Regulation Introduction to Food Regulation in the United States,” Helix Magazine, July 28, 2009.
2. FDA, A History of the FDA and Drug Regulation in the United States, September 2013.
3. F. Carleton, J. Agalloco, Validation of Aseptic Pharmaceutical Processes, p. 1, Marcel Dekker (New York), February 1986.
4. FDA, Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulation, September 2006.

About The Author:

Christina Meyer Dell Cioppia is senior VP of validation and regulatory compliance with Amec Foster Wheeler. She has assisted firms worldwide in the areas of commissioning, qualification, validation, and worldwide regulatory compliance. Christina holds her BS in biochemical engineering from Rutgers University, and an MBA in industrial management from Fairleigh Dickinson University. She is a frequent industry speaker and contributing author to the ISPE Commissioning and Qualification Baseline Guide and the book Good Design Practices for GMP Pharmaceutical Facilities.