Following our Own Instructions

At a recent industry workshop, I heard an FDA speaker clarify the concept of "compliance" into four simple statements: Say what you do. Do what you say. Prove it. Improve it. Companies usually use their standard operating procedures (SOP) to show that they have control over their processes, thereby demonstrating compliance with regulatory expectations. The "say what you do" phrase equates to the written SOP that defines the steps taken to achieve compliance to a regulatory requirement. "Do what you say" equates to following the SOP. This concept seems simple enough to follow. However, for years, FDA has been citing industry for failure to follow SOPs. So, it was no surprise when I read Jeanne Moldenhauer's article in the April 2011 issue of Pharmaceutical Technology Europe, titled "Review of FDA Warning Letters," and found that many of the 483s and Warning Letter observations issued in 2010 began with the words, "Failure to follow procedures..." Digging a little further, I went to the FDA reading room (www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm) and started looking at the 2011 Warning Letters issued to date. Once again, the phrase, "Failure to follow procedures..." was prevalent throughout.

Susan J. Schniepp

This trend is disappointing. Numerous webinars, seminars, and workshops designed to train personnel in the art of writing and following SOPs are presented every year. A myriad of articles, books, and manuals discuss the who, what, when, where, and how of SOPs. There are numerous companies, consultants, and experts that a company can hire to write, review, and critique these procedures as well.

Every company in the pharmaceutical industry has training programs to ensure that employees are provided with—and understand—current SOPs. When considering the various tools available to the industry regarding such procedures, it's unclear why industry still has trouble following its own instructions.

One reason may be the need for customized SOPs, which are often required by clients of contract manufacturing organizations (CMOs). Contract organizations typically write SOPs to accommodate diverse opinions on how a particular process should be implemented in order to guarantee compliance. These SOPs are presented to prospective customers as a part of due-diligence activities. Occasionally, a customer will insist on supplying the CMO with its own version of the SOP activity and demand that the CMO implement the procedure when manufacturing its product. This approach can be disruptive to the CMO for several reasons. For starters, the CMO's employees need to be trained on two procedures for one activity, and they must understand when and why, and in what situations they should use one SOP over the other.

Consider the following scenario: CMO A has an established SOP for performing visual inspections on final filled vials before packaging them. The SOP indicates the predicted reject rate associated with various vial defects that might occur as a result of the manufacturing process. Examples of some of the indicated defects are cracked vials, misplaced stoppers, poor crimps, and so forth. Each defect has an established reject rate based on production capabilities. Company A, a new client, has just qualified CMO A as an alternate supplier for their life-saving medicine because its primary supplier is unable to keep up with market demand. Company A would like CMO A to use its inspection SOP for visual inspection purposes. There are major differences between the two SOPs, including the defect categories, the established reject rates for defect categories, and the inspection report forms. Company A's SOP has more defect categories, and the reject rates are tighter than CMO A's SOP, which prompts the use of the different inspection report form.

As a further example, an experienced, trained employee at the CMO is performing the vial inspection for Company A's product and forgets that there is a custom SOP for this process step. The employee completes the inspection and turns in the results to the manufacturing quality assurance (MQA), which detects the error and initiates an investigation. The lot in question must be reinspected using Company A's SOP, and the appropriate acceptable quality levels (AQLs) must be applied to the product lot in question. This reinspection delays the release of the product by several weeks, causing a stock-out situation in the field.

Another problem CMOs face when using customized SOPs is how to handle conflicting SOPs. Consider the following scenario: CMO B has just been selected by Company B to manufacture its product. CMO B has an SOP for identifying and investigating incoming raw materials for foreign matter. The SOP requires CMO B to characterize foreign matter as either inherent or aberrant. If the foreign matter is deemed inherent to the raw material, a description of the foreign matter is recorded as part of the raw-material release. The foreign matter is then removed and the raw material is used in product formulation. If the foreign material is determined to be aberrant, then the raw material in question is put on hold, and an investigation is initiated to determine the identification of the foreign material in question.

Most of CMO B's clients are comfortable with the SOP, but when manufacturing Company B's product, CMO B comes across some black particles in sucrose, a raw material used in the manufacture of Company B's product. CMO B uses its foreign material SOP to record the incident. The foreign-material report indicates, under high magnification, that the black material is burnt sucrose. Because burnt sucrose is inherent to sucrose (the raw material), it is deemed suitable for manufacture. CMO B releases the batch record and the associated product to Company B for review, approval, and release. Company B refuses to release the product because its internal SOP, which was not provided to CMO B, specifies that foreign matter found in raw materials must be sent for molecular identification. Until the discrepancies between the SOPs are resolved, product manufactured for Company B is required to be released by exception.

The practice of using customized SOPs also presents a logistical problem for the CMO: Which SOP should be presented to the regulatory authority during a cGMP inspection? For product-specific inspections, only those SOPs associated with the product should be presented to inspectors. However, when a general inspection is combined with a product-specific preapproval inspection, for instance, two SOPs for the same process must be provided to inspectors. Invariably, inspectors will investigate the areas where the firm may have internal challenges and in all likelihood, will leave the CMO or the company with a an observation that it "failed to follow written procedures..."

There are no easy solutions to the situations described. CMOs and their clients, however, can minimize these and similar types of circumstances through open communication. CMOs must seek to understand their clients' needs while clients must seek to understand their CMOs' quality systems. Although we are all in the same industry, we do not always share a common language with respect to describing our internal systems. Establishing a common language between the two parties makes it easier to determine what, if any, changes need to be made to a CMO's quality system to accommodate the client's needs. If the two parties can effectively communicate and eliminate the need for redundant SOPs, their chances of avoiding unfortunate compliance mishaps will greatly increase."

Susan J. Schniepp is vice-president of quality at OSO Biopharmaceuticals and a member of the PharmTech editorial advisory board, susan.schniepp@mac.com.