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 (
http://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
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, firstname.lastname@example.org