FDA Validation Regulations

By: Gerry Creaner B.Chem Eng and Donagh Fitzgerald B.Prod Eng. Last Updated: May 2022

The concept of validation was first considered in the late 1970s as a way to improve pharmaceutical quality after several notable quality issues. Before that, pharmaceutical quality was evaluated by testing samples from the finished medicine.

Over the next 10 years, the FDA began to introduce the concept of validation into manufacturing regulations.

It’s important to remember that the science of manufacturing safe medicines was well defined at that time e.g. mix A with B and you get C; ferment X for Y-days and you get Z.

However, to make safe medicines consistently every time, that science by itself is not enough (think back to the wine example from earlier). Validation would add the testing and documentation systems used to confirm that the final medicine is fit for use and function.

In May of 1987 the FDA announced its first validation guidance, in the document “Guideline on General Principles of Process Validation (the 1987 guidance)”.

Since then, the FDA has periodically updated this guidance to reflect current industry best-practices. Modernisation of manufacturing processes, developments in technology, and implementation of new risk management strategies are all reasons that original document has since been updated.

These days, a company’s compliance with validation guidance and consideration of their validation documentation is a key part of an FDA inspection.

The timeline was remarkably similar with the guidelines from the EMEA (the regulatory body in Europe) and other regulators around the world.

In 1990, the International Council for Harmonisation (ICH) was established to bring together regulators from the USA, Europe, and Japan to create a “harmonisation of regulatory requirements”.

This harmonisation of regulation was intended to make it easier for companies to sell their medicines between different international markets.

The ICH has now produced a series of guidelines and some of these are relevant to validation activities. We’ll reference a couple of these guidelines at the relevant points in our validation articles but you can also see this page for more information.

In both the European and US systems of regulation – validation is essential to meet regulatory requirements.

These regulations should be thought of as a set of tram-tracks that the company must prove it manufactures its medicines within, rather than being a single line that all companies must strictly walk along.

Neither set of regulations actually lay out the details of how a company should meet these requirements.

In doing so, the regulations leave significant room for individual circumstance. They deliberately don’t try to set out specific steps or templates that companies must follow.

The rest of this post takes a look at some of the specifics found within the FDA regulations. If that’s a bit much for you, there are 3 key takeaways:

• Validation is a regulatory requirement for pharmaceutical companies to confirm that they are consistently manufacturing safe medicines for the public
• Therefore, companies must be able to provide proof of validation activities when requested (during an audit by a regulatory agency like the FDA, EMEA etc.)
• Validation is a framework of guidelines rather than a specific set of fixed rules – allowing companies to adapt their validation activities to suit their specific manufacturing/product requirements

Or if you’re interested in some of the regulatory specifics, let’s take a look at some of the FDA regulations that deal with validation activities…

Validation is laid out as a requirement within the current Good Manufacturing Practices (cGMP) of the FDA.

The FDA regulations concerned with pharmaceutical manufacturing are 21 CFR parts 210 and 211. Process validation is required (generally and specifically) within both of these parts.

The general regulation that leads to a requirement for process validation is in subpart F “Production and Process Controls”, 211.100(a)…

“There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.” – FDA

Here we capture the essence of validation (i.e. documentation that proves a reliable outcome) in the regulations.

Other parts of the regulations are concerned with more specific parts of validation…

In the section “Sampling and testing of in-process materials and drug products” – 211.110(a):

“To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.” – FDA

Here we see the idea that not only should a final product be tested, but processes that might cause variation in critical quality attributes should also be subject to validation (we’ll talk more about critical quality attributes in the next section).

While this section gives a little more information about what should be recorded, there is still substantial room for the details of this to be different in different circumstances.

211.110(b):

“Valid in-process specifications for such characteristics shall be consistent with drug product final specifications and shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate. Examination and testing of samples shall assure that the drug product and in-process material conform to specifications.” – FDA

Here we see the concept of setting out specifications to control in-process material – not just final product quality.

211.180(e):

“Written records required by this part shall be maintained so that data therein can be used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures.” – FDA

In this section we see the need to keep and review documentation at regular intervals to see if any changes need to be made to the manufacturing processes.

211.68(a):

“Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product. If such equipment is so used, it shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained.” – FDA

This outlines the need for validation in automated, mechanical, and electrical equipment.

There are many other places where validation activities are referred to within regulations. The purpose of this article is not to give a full overview of every regulation concerned with validation, it is to provide the key takeaways previously outlined:

• Validation is a regulatory requirement for pharmaceutical companies to confirm that they are consistently manufacturing safe medicines for the public
• Therefore, companies must be able to provide proof of validation activities when requested (during an audit by a regulatory agency like the FDA, EMEA etc.)
• Validation is a framework of guidelines rather than a specific set of fixed rules – allowing companies to adapt their validation activities to suit their specific manufacturing/product requirements

You might also be interested in reading:

• What is pharmaceutical validation?
• The stages of process validation
• What is IQ OQ PQ?
• What is an equipment validation protocol?
• What is computer system validation or CSV?
• What is a Validation Master Plan?