By Scott Brunner, CAE
Chief Executive Officer
Alliance for Pharmacy Compounding

If you've read the book of Job in the Bible, you may recall the final scene: Job, having asserted that God owes him an explanation for why he's suffered loss of all he holds dear, finally gets a rise out of the Almighty. "Where were you," thunders God, "when I made the earth? Tell me since you know so much! Who decided its size ... came up with its blueprints and measurements ... set its cornerstone?" Job cowers, humbled finally to understand the vast power of the Almighty. "I am of small account," says Job. "I'll put my hand over my mouth."

I was reminded of that story last autumn when the United States Pharmacopeial Convention, Inc. (USP) released its revised United States Pharmacopeia (USP) Chapter <797>, including new restrictions that will have profound implications on how pharmacies that do sterile compounding operate and whether patients can continue to access and afford life-enhancing compounded medications.

In short, it was as if God had spoken. And trouble is, this god offered no more explanation than did Job's.

While the USP is not a governmental or regulatory body, it does manage to exercise extraordinary power and influence over pharmacy compounding in the U.S. The USP standards are the foundation, the measurement, the cornerstone for compounding pharmacy practice in the U.S. Every single state in the nation incorporates some version of the USP standards into its pharmacy law or regulation. And that's generally a really good thing for everyone because the purpose of USP's standards is not just consistency in compounding practice but assuring patient safety.

Usually, when the USP adopts a standard, there's abundant science — evidence — that supports the standard. The USP is not known for being cavalier. So when we lowly Jobs seek to understand what's being required of us under the USP standards, God ... in the form of the USP ... provides evidence, context, and rationale that demonstrate how the standard enhances patient safety. We may not always like what this god says or does, but we usually find few reasons to argue with it.

That's precisely why the recent release of the revised USP Chapter <797> is unusual. More precisely, the new chapter's restrictions on beyond-use dates and batch sizes are unusual — because they come with no evidence that they make patients safer and no evidence that they reduce rather than potentially increase the risk of contamination of sterile preparations.

It's as if our compounding god — the one whose decrees have long been rooted in science — has gone arbitrary on us. It makes no sense. That's why this time we lowly Jobs aren't ready to put our hands over our mouths.

We have questions — not just about how the new restrictions enhance patient safety, but other more scientific questions as well. Maybe we risk getting from the USP the sort of thundering, all-knowing, how-dare-you-question-me sort of response Job got from God. At least that would be a response, right? In any case, a response is needed because patient access to life-enhancing medications is at risk here. If that access is to be constrained, the least the USP can do is demonstrate why it's necessary.

QUESTIONS FOR THE USP:

• Has the USP performed any analysis or assessment of the benefits to patient safety the new sterile item beyond-use date (BUD) and batch-size restrictions offer? In other words, what data has the USP used to determine if these new BUD and batch-size requirements will improve the quality of compounded preparations?
• Does the USP have information or examples of quality issues associated with sterile compounds made in full compliance with the previous USP Chapter <797> standards?
• Has the USP performed any analysis or assessment of the potential downside, or unintended patient safety risks, associated with pharmacies making more frequent, smaller batches of sterile compounds in order to meet current patient needs?
• These sterile item BUD and batch-size restrictions seem to indicate the USP's concern that, even when followed, the standards in the new USP Chapter <797> are not themselves sufficient to ensure a high level of quality for sterile compounds, and therefore the amount of sterile compounding performed by state-licensed pharmacies must be limited to protect the public. What information does the USP have to support this concern? Can the USP explain why it would publish updated standards that it feels are insufficient enough that it must implement these restrictions?
• If the batch-size limit of 250 units was chosen because at that batch size, there is a certain percent chance in catching a sterility failure when 10 vials are sent for testing, why not simply increase the number of vials to be tested?
• Products that start sterile stay sterile, as long as they are packaged in appropriate dispensing containers (based on a container-closure integrity study and antimicrobial effectiveness testing). If a compounded sterile preparation (CSP) is sterile at 60 days, it is still sterile at 180 days. The focus of the Chapter is on achieving sterility of a CSP — but still pharmacies will have to perform stability studies to prepare these Category 3 items. The idea that somehow the longer BUD increases risk does not make sense with the appropriate data in place for the longer BUD. If the CSP is stable and sterile up to 180 days (or longer — whatever the science shows using the stability study), why cap the BUD — the effect of which will be to limit patient access by increasing costs to consumers?
• The USP does comment on the 250-unit batch limit in their FAQs on the revised Chapter <797>, as follows:

  153. Why is there a maximum batch size of 250 units for CSPs requiring sterility testing? Sterile compounding within 503A facilities is largely a manual process. The chapter sets a minimum standard for quality assurance that encompasses a wide variety of practice sites. These quality assurance parameters are not intended for outsourcing facilities or pharmaceutical manufacturers, as they were created to accommodate the equipment and processes normally performed by 503A facilities. The risk of contaminating a CSP is likely to increase as the batch size increases, especially for a manual process. For example, equipment limitations (such as the size of a PEC [primary engineering control]) may only permit a portion of a large batch to be packaged in one continuous process. If 25 units are packaged in one continuous process, a batch of 250 units would require repeating this process 10 times. A batch of 1000 units would require repeating this process 40 times. Smaller batches reduce the potential for operator error due to fatigue. To help ensure sterility assurance, the batch size is limited to 250 final dosage units for CSPs that require sterility testing. Sterility testing does not guarantee that an entire batch is sterile, only the units tested. The possibility of detecting a contaminated preparation is about 10% for batch sizes between 10 and 100 but drops to about 4% for a batch size of 250 and only 2% for a batch size of 500.

  1. The example provided mentions potential issues ranging from fatigue to the number of times that the packaging process would have to play out. There is no acknowledgement, however, that if 1000 vials are needed, the weighing of components, mixing of components, and staging of items for each batch of 250 from anteroom to buffer room will now have to occur four times instead of one.

  2. The example notes that if 10 vials out of 500 are tested, that's only 2% of the batch. However, 10 out of 500 is exactly the number required for testing by USP Chapter <71>. In the case of small batches, the USP will now require fewer units to be tested, thus conflicting with USP Chapter <71>. Since the USP is choosing to deviate from USP Chapter <71> and requires 4% of the batch to be tested, why is the USP requiring that 20 vials out of 500 be tested or 40 of 1000 vials be tested rather than instituting an arbitrary restriction on batch size?

  3. What is the relevance of pointing to the sterility test as important while also noting that the sterility test does not guarantee sterility? The USP mentions ensuring sterility assurance, but USP Chapter <1207>, Sterility Assurance, states that "It is the controls that provide the desired assurance from microbiological risk rather than the results of any in-process or finished goods testing. The verification of safety of products labeled sterile is generally known as "sterility assurance". In other words, it's the process and not the testing.

  4. If the USP felt that the overall system created for Category 3 was not sufficient to allow for larger batches and longer BUDs, why did it not stop and redesign its approach to Category 3 CSPs?

  5. What is the logic of monthly testing of anything? Specifically, what is the value of monthly air sampling for Category 3? Certainly, it is more data compared to testing every six months, but what is the value of a monthly data point to the overall state of control? If this monthly data is generated and graphed out over time, a trend will not be observed for 3 to 5 months. This is not productive. If pharmacies are going to perform monthly air sampling, they will most likely need to buy their own equipment to do it. If they've bought the equipment, then the future cost is in media, which is not expensive. Why not have the pharmacies use that equipment and generate more data to understand their state of control as opposed to requiring a monthly frequency that doesn't provide timely trends?

  6. If the USP wants to pursue an option for Category 3 that is a more robust system, it could have included routine fingertip monitoring for each sterile compounder. As is in the revised USP Chapter <797>, only fingertip monitoring for initial qualification and q3 month media fills is required.

Whether it's BUD limits or batch-size limits, compliance with these restrictions in Chapter <797> will result in compounders having to prepare more frequent CSP batches. That means an increase in the frequency of critical compounding steps — weighing ingredients, mixing of components, transferring of materials and personnel into and out of cleanrooms, personnel garbing and gloving, transferring of materials into International Organization for Standardization 5 critical areas, connecting sterilization filters, setting sterilization cycles on autoclaves — that are manual processes essential for achieving sterility assurance. And yet the more compounders have to perform those steps, the greater the potential for a misstep. That's precisely what USP's new restrictions introduce into the process: increased risk of error or contamination.

Ultimately, via the BUD and batch-size restrictions in Chapter <797>, USP is conceding that the other standards in the revised USP Chapter <797> are not themselves sufficient to ensure an acceptable level of sterility assurance for sterile compounds. And that raises a question for state boards of pharmacy, each of whom will surely consider adopting some or all of the new chapter: Will adopting revised USP Chapter <797> be sufficient to ensure patient safety in their state, given the doubt cast by USP on its own standards?

So yes, there's a lot we lowly Jobs want to know, more we need to understand. Are the compounding gods listening?

Scott Brunner, CAE
Chief Executive Officer
scott@a4pc.org