Life Sciences Q&A
by Mark A. DeSorbo
The cancellation of Federal Standard 209 (FED-STD 209) and the rise of cleanroom protocols handed down by the International Organization for Standardization (ISO) has raised many questions among contamination-control professionals on just where the U.S. Food and Drug Administration (FDA) stands.
Richard L. Friedman, a compliance officer with the FDA's Center for Drug Evaluation and Research (CDER) recently sat down with CleanRooms magazine to discuss the proverbial changing of the cleanroom protocol guard.
How will the sun-setting of 209 and the rise of ISO cleanroom standards impact the pharmaceutical industry?
The vast number of firms will likely use these generic documents as references when developing their programs to evaluate airborne particulate cleanliness. The documents not only impact multiple world regions, but also various industries, including aerospace, microelectronics and, of course, pharmaceuticals.
In my opinion, one well harmonized, baseline document on the topic of air-cleanliness classification is better than five with small, but difficult-to-reconcile differences.
A lot less reading for the industry professional to do on this issue as well.
So overall, I think it will be beneficial for the industry by providing a standard that helps one in the qualification of a cleanroom or clean zone's air cleanliness.
Of course, these standards should not be misunderstood or misapplied as conferring compliance on sterile drugs. FDA's regulations and guidance provide information to facilitate pharmaceutical industry compliance and their standing is not affected by ISO documents.
How should end users perceive ISO documents?
The two ISO documents, like their 209E predecessor (developed solely to set the lowest acceptable standard for a government contract for multiple industries), are simply key references one may consult when conceiving the program for qualifying and testing particulate quality for a given pharmaceutical clean area. As routinely acknowledged by ISO documents, a drug firm will need to assure that protocols and procedures are adapted to fully conform to requirements of the relevant industry and regulatory agency. So ISO clearly recognizes the impracticality of providing absolute, one-size-fits-all qualification requirements for varied industries with myriad unique designs and applications. They contain an implicit understanding that there may be need for departures from the minimal ISO advisements.
Will the FDA draft a position on the ISO cleanroom standards? If yes, when will the agency do so?
We will most likely communicate internally via our Human Drug cGMP Notes publication (available via FOI) and/or training courses.
We'll share our thoughts with the industry by continuing to answer the many e-mails and phone calls we've been receiving since the changeover in November as well as through larger forums, such as industry conferences.
What do you see as the main differences between 209 and the ISO standards?
The documents are largely the same, although there are a few major exceptions. To name a few, ISO now uses the metric system. Also, calculations may permit less sampling to qualify a Class 100 area.
ISO also has added new recommendations on data handling. It will be important for firms to be sure that any data generated during qualification studies and ongoing monitoring is properly handled and interpreted in a manner that meets current Good Manufacturing Practices (cGMPs).
How does the FDA plan on handling the exclusive use of the metric system in the ISO documents?
For the first time, we will be including the metric system in our FDA guideline that addresses aseptic processing cleanroom classification. In our revision of the 1987 guideline on Sterile Drug Products Produced By Aseptic Processing, we plan to put air classification in terms of both the English and metric systems. This will allow for interchangeability with our revised guidelines and international guidelines in terms of converting clean area classifications from English to metric or visa versa.
Do the ISO documents provide a comprehensive baseline cookbook for qualifying and monitoring a cleanroom?
That is an important clarification that should be made on the scope of these documents.
For pharmaceutical applications that we usually see at FDA, classification of a clean area is based not only on particle concentration, but also microbiological data. And, while these ISO documents do not include the concept of surveying various locations that are considered “worst-case positions” in the given clean zone, this type of hazard analysis approach is a necessary compliment to the more grid-like monitoring method that one might follow using ISO.
In other words, if a firm compliments use of the ISO documents with a risk-based identification of sampling sites, it will likely be well on its way to classifying and monitoring a clean zone. Naturally, as with any qualification or validation exercise, these HVAC studies must convincingly demonstrate robustness of the system and reproducibility of results. Along with a sufficient data foundation to make such conclusions, a firm will want to ensure that the particle and microbiological monitoring methods used to produce this data were reliable ones. For example, these methods need to include a sufficient sample size to produce an accurate result.
What is the FDA's opinion of the value of standards and recommended practices penned by the many international and industry organizations?
We welcome them. The diversity of opinions expressed by different organizations is part of a positive process. The technical documents that they produce serve to advance thought on issues that are otherwise often debated, but rarely pursued to the point of reaching a clear written consensus. Inevitably, the document is then the impetus for more discussion and often enhances understanding of the given issue by both its primary industry audience as well as the regulatory agency charged with interpreting the relevant regulatory requirements. One example I can think of is an ambitious and laudable effort by one organization to gather European and American industry specialists to reach agreement on steam sterilization issues. This single issue has taken considerable time to address because of its complexities, but I think that an excellent technical document will ultimately be produced. I think any process that is in place to try and come up with a consensus statement is positive as long as it is science and experience based.
One of the fascinating things that comes out of the existence of so many industry and international organizations is the existence of multiple documents that address one particular issue.
Because these documents often differ in some respects, a manufacturer might have difficulty choosing which one is the ideal one to use. In fact, a firm with a successful cGMP approach will probably find concepts in each and every one of these technical publications to mix and match in order to develop their cGMP programs. The bottom line is the opinions expressed in these documents are fruitful, but the reader has the responsibility to properly tailor their programs to meet cGMP. Usually, reading a variety of references is invaluable in getting them there.