Destin A. LeBlanc

Cleaning Validation Technologies

Technical Consulting Services

SEPTEMBER 1999

Validation and equipment qualification; when "identical" really isn't.

Reference: 21 CFR 211.100, Written procedures, deviations; Guideline On General Principles of Process Validation, May, 1987

As explained in the 1987 validation guideline, the general requirement for process validation is contained in section 211.100 of the CGMP regulations which states that "[T]here 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."

The validation guideline addresses several general principles of equipment suitability. For example, installation qualification is described as establishing confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. Installation qualification includes examination of equipment design, determination of calibration, maintenance, and adjustment requirements, and identifying critical equipment features that could affect the process and product. Another principle is that equipment is evaluated and tested to verify that it is capable of operating satisfactorily within the required process operating limits and that actual production conditions, including "worst case" situations, are simulated. The guideline cautions that "[I]n assessing the suitability of a given piece of equipment, it is usually insufficient to rely solely upon the representations of the equipment supplier…"

The guideline further states that each specific process should be appropriately qualified and validated, noting the inherent danger in relying on perceived similarities between products, processes, and equipment.

The following case illustrates the importance of performing adequate equipment qualification on each piece of processing equipment, and the problems that may result when firms fail to verify equipment supplier representations.

A pharmaceutical firm used two blenders to produce a tablet. Both blenders were from the same equipment manufacturer, had the same model number and same design. Although one blender was older than the other, the supplier told the drug manufacturer that the units were "identical." The drug manufacturer took the claim at face value and did not include the older blender as part of its process validation.

The drug company marketed about 100 lots of tablets made using the old blender. In testing retain samples, the company found that some lots failed the content uniformity specification.

The firm's investigation traced the out of specification lots to one of the two "identical" blenders, namely the old one. The pharmaceutical firm's own investigation found the older blender to have a slightly smaller capacity and different RPM (revolutions per minute) operational characteristics when run at the same settings as the newer blender.

Subsequently, the firm recalled its total production of the product it made using the older blender. This extensive recall involved multiple strengths of product totaling approximately one half million bottles from U.S. and foreign consignees. The firm plans to qualify the old blender using production size lots.

In light of this case study, during your audits of a firm's process validation, it would be appropriate to determine if the firm's validation protocol includes equipment qualification for all units of significant equipment, even where multiple units are supposedly "identical." Moreover, as explained in the validation guideline, the validation should reflect production size lots.