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. Many of the 483s and Warning Letter observations issued in 2010 began with the
words, "Failure to follow procedures..." (1). Digging a little further, I went to the FDA reading room 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 and can cause 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.