The primary objective of calibration is minimizing any uncertainty in measurements. It reduces errors in measurement to an acceptable level, which is critical for every stage of the FDA approval process. This article will demonstrate the importance of calibration inline with the FDA approval process.

What does the FDA do?

The U.S. Food and Drug Administration (FDA) is responsible for:

• Protecting public health by ensuring that foods are safe for consumption
• Ensuring food products are sanitary and labeled properly
• Regulating veterinary and human drugs, vaccines and other such biological products, including medical devices are safe and effective
• Protecting the public against exposure to radiation from electronic products
• Assuring cosmetic products, dietary supplements and other such products are safe for consumption and labeled properly
• Regulating tobacco products
• Advancing public health and safety by speeding up product innovations

What is FDA Approval and Why is it Required?

Any product that is FDA approved has been analyzed, examined and tested, and its benefits have been found to outweigh its potential risk.

What Products need FDA Approval?

Depending on the intended use and potential for risks associated with a product’s use, the FDA assesses and approves various things, like:

• New drugs, including over-the-counter (OTC)
• Biological products
• Medical devices
• Veterinary drugs
• Food additives and supplements
• Color and other additives in food products, drugs, cosmetics, etc.

Flow Chart of FDA Approval Process

When a new drug is being developed, it needs to go through certain procedures, before it can be approved for use/sale:

The drug sponsor must test the drug on multiple species of animals to gather basic information about the compound’s safety and efficacy. The results, along with the compounds and manufacturing process used, are submitted to the FDA via an Investigational New Drug (IND) application for clinical trials.

The FDA reviews the IND to ensure the proposed studies do not pose an unreasonable risk to human subjects. It also verifies if adequate informed consent and protection for the subjects is provided.

Once the IND is approved for clinical testing, there are three phases:

• Phase 1 generally has less than a hundred healthy volunteers to investigate common side effects and how the drug is processed by the human body.
• Phase 2 typically involves a few hundred patients. Preliminary data on the drug’s effectiveness is collected by comparing the response of test-groups given different treatments or placebos.
• Phase 3 involves thousands of patients, so more information can be gathered about safety, effectiveness, dosages, interaction with other drugs and even effects on different populations.

Post clinical trials, a New Drug Application (NDA) is submitted to ask for approval of the drug for marketing. This contains all the information gathered from human and animal testing, its behavior in the body and the manufacturing process.

The FDA has 60 days to decide if the NDA is to be filed for review. The FDA Review Team evaluates the research conducted by the sponsor and the manufacturing facilities are inspected. The drug labelling is also reviewed to ensure all the necessary information is printed.

Once the drug is approved, the sponsor is required to periodically submit safety updates, so the FDA can detect and take definitive action against unexpected adverse events.

Definition of Calibration

Calibration is basically comparing the measurements made by a device against a reference instrument or standard to check its precision, accuracy and limits.

Importance of Calibrated Equipment during FDA Approval

Over time and with repeated use, the accuracy and precision of every instrument tends to ‘drift’. To be confident about the reliability of the measurements being taken, regular service and maintenance are needed to ensure the performance of the instrument throughout its lifetime.
The primary objective of calibration is minimizing any uncertainty in measurements. It reduces errors in measurement to an acceptable level, which is critical for every stage of the FDA approval process.

FDA Requirements for Calibration

Calibration requirements for equipment are defined by Title 21 of the FDA’s Code of Federal Regulations. According to section 820.72:

• Manufacturers need to ensure inspection, measuring and test equipment is suitable for the intended purposes and capable of producing results that are valid. They must include proper provisions for handling, preserving and storing equipment.
• Calibration must be performed routinely and if there are any errors found, corrective action needs be taken and any adverse effects caused need to be evaluated and documented.
• Associated activities like maintenance, preservation and storage need to be recorded and documented. The procedures need to be easily accessible to the personnel performing the calibration and must include specific directions on how the calibration is to be performed and acceptable limits for accuracy and precision.
• The standards used to inspect, measure and test equipment should be traceable to national or international standards.

FDA Guidelines for Calibration

• Calibration must be performed routinely, as per written directions
• Document the calibration of every device that needs calibration
• Specify the acceptable limits for accuracy and precision
• Train calibrations personnel
• Use calibration standards that are traceable to the National Institute of Standards and Technology (NIST), other acceptable standards, or in-house standards if necessary
• Make provisions for evaluating adverse effects caused by malfunctioning equipment and procedures for remedial action

Importance and Role of Calibration Services

Calibration services provide a variety of services that help laboratories with attaining and maintaining FDA approval for production. Even in-house calibration requires the calibration standards to be periodically calibrated and certified for traceability. Additionally, it isn’t always feasible to perform calibration in-house, especially when there are just a few instruments of one type, or multiple instruments that need different types of calibration.

If equipment or standards are sent out of the laboratory for calibration, qualification becomes crucial, since different environmental conditions might cause incorrect readings. For sensitive, fragile or bulky equipment, calibration services can help prevent damage and eliminate the need for qualification.

Apart from preventing quackery, FDA approval ensures consumers and health-care professionals have the information they need to use drugs wisely. It also gives them the assurance that the drugs, brand-name or generic, have passed stringent quality checks, are effective and their benefits outweigh any risks.