Process Validation Requirements for Drugs and Devices

Robert L. Spencer, associate attorney with Hogan & Hartson LLP and former FDA compliance officer, who now assists the medical device industry in interpreting agency regulations, explains the differences between process validation for drugs and for medical devices.

What are the differences between drug and device process validations? Are there source materials that address the question?

Validation of manufacturing processes is required by both the good manufacturing practice (GMP) regulations for finished drug products and the new quality system regulation for medical devices. While the definitions of process validation for drugs and devices differ slightly, both emphasize documenting that a process will consistently produce products that meet predetermined specifications.

The major difference between process validation requirements for drugs and devices is not in process validation standards (which are the same for both drugs and devices) but in how validations are considered during marketing application approval decisions. During premarket approval (PMA) inspections for both drugs and devices, FDA reviews the manufacturer's process validations. However, the Center for Drug Evaluation and Research (CDER) will generally approve a new drug application even if the manufacturer has not completed all required process validations, simply requiring the manufacturer to complete the studies before the drug is commercially distributed. The Center for Device and Radiological Health (CDRH), on the other hand, will generally not approve a PMA application until all required process validations have been completed.

CDER considers process validation a field responsibility to be addressed after approval (Compliance Program Guidance Manual 7346.832­Preapproval Inspections/Investigations Program). It will not withhold approval of an application if process validation has not been attempted, if a validation protocol is not available, or if a protocol is available but does not adequately test all process parameters. CDER will withhold approval of an application, however, if validation has been attempted and significant data integrity issues arise or if the process cannot be validated, as noted in Human Drug GMP Notes (vol 2, no 1, March 1994). Moreover, although CDER does not require manufacturers to complete process validations before an application may be approved, completing such validations is a GMP requirement that must be met before any shipments of the product are made.

Devices are treated somewhat differently. Before approving a PMA, CDRH will normally determine the firm's ability to manufacture the product (Compliance Program Guidance Manual 7383.0001­Medical Device Premarket Approval and Postmarket Inspections Program). CDRH has instructed district offices to recommend against a PMA application if the manufacturer has not completed the required validation studies. When a district office recommends that approval of a PMA be withheld because validation studies have not been completed, the manufacturer may attempt to correct problems and request a follow-up inspection. The district office may require the manufacturer to certify in writing that the validation studies have been completed before it initiates a follow-up inspection.

The different approaches taken by CDRH and CDER apparently relate to each center's interpretation of the applicable provisions of the Federal Food, Drug, and Cosmetic (FD&C) Act. Section 515(d)(2)(C) of the FD&C Act specifically states that approval of a PMA application must be denied if the device is not manufactured in conformance with good manufacturing practice requirements, which include process validation. However, section 505(d)(3) of the FD&C Act, relating to approval of marketing applications for drugs, does not specifically require compliance with the drug GMP regulations as a condition for marketing approval. CDRH appears to be regulating according to the former section and CDER according to the latter.