Some 50 industry lyophilization experts and interested parties gathered at the PDA 2010 annual meeting in Orlando for a combined meeting of the organization’s Lyophilization and Sterile Processing interest groups.
Moderator Edward Trappler, president of Lyophilization Technology, Inc., opened the proceedings by soliciting ideas from the audience in terms of what issues were deserving of discussion. The audience then voted from a long list, and prioritized three topics: Non-destructive Testing of Finished Lyophilized Product, Raised Stopper Detection, and Drug Product Moisture Content.
Non-destructive Testing and the Great Oxygen Mystery
Trappler posed a question to the audience: How many of you are doing non-destructive, online testing of your sterilized products? Just three raised their hands. Nevertheless, many in the audience wanted to discuss the topic.
The discussion soon focused on the testing of vial closures. A member of the audience presented a dilemma—his firm had been manufacturing and packaging lyophilized product into sealed vials for several years, but only recently started to discover increased levels of oxygen in the headspace.
The man provided a bit more history. The company had first detected a possible moisture issue, and suspected that stopper moisture was to blame. It sent one of its problematic lots to a lab for non-destructive testing to inspect the moisture, but the lab found the presence of excess oxygen as well. Approximately 20% of the vials, in fact, had what the company considered to be unacceptable levels of oxygen content in the vial headspace. Clearly there was an issue of container closure integrity, but what to do? the man wondered.
Trappler put the scenario into context. “We really don’t have a good handle on container closure,” he noted, particularly after final capping. “In fact, we really don’t test and know the container closure integrity of the vials after they’ve gone through the capper,” he added. “Pretty scary, isn’t it?”
Returning to the man’s dilemma, Trappler suggested that the roots of the extra oxygen may lie in the stopper itself. Stoppers, he said, are compositions of various solids—types of rubbers, clay, plasticizers, titanium dioxide, and so on—which are compressed together and molded into “rubber” stoppers. As such, they have certain degrees of permeability.
But the permeation rates are minor compared to other materials, one member in the audience noted. “If 100% of your lot is showing elevated levels of oxygen, then that’s a good indication you’ve got a problem with your stoppers.” But in most other cases, stopper permeability will not be the problem, the person said.
Ken Muhvich, PhD, principal consultant with Micro-Reliance, Inc. joined Trappler at the front of the room. Muhvich suggested the stopper failure could be due to improper molding. “I’ve seen twice in the past few years defects in the stopper molds themselves, meaning the stoppers had small concave depressions, which when challenged with a dye ingress, let dye in.”
Another audience member chimed in. There are challenge tests manufacturers can run to see if stoppers are leaking. This testing may need to be done before and after crimping. “If they’re crimped, is it that process? If it’s before, you could have some air exchange prior to crimping and you need to do something—such as the Lighthouse method [i.e., laser-based, non-destructive monitoring popularized by Lighthouse Instruments]—to know if your headspace has changed prior to crimping.”
The original questioner with the oxygen issue then offered up another query. If you had, say, 2% oxygen in the headspace, is that a failed vial?
Several members of the audience emphasized that it really depends upon the product in question. “It’s a matter of stability,” one said. “Does the oxygen compromise the stability of your product?”
The man then wondered if the FDA was moving towards requiring real-time monitoring using these non-destructive methods? “It’s not in their purview to tell you what to do in this case,” said Muhvich. To which Trappler added jokingly, “Yeah, but they have their ways and preferences!”
Another audience member raised yet another possible reason for the oxygen dilemma—the quality of shelves in the freeze dryer. For example, he said, if the manufacturer of the shelves sanded the edges to smooth them down, “it may have made the shelf one millimeter thinner at the edge. And when you go to add the stopper, it may not seal properly and that may be where your 20% is coming from.”
Trappler added another potential factor—the quality of the vial neck finish, which may be inconsistent from vial to vial. “I’ll give you a homework assignment,” he suggested. “Go to your vial manufacturers and ask them about the quality of their neck finishes and how they’re manufactured.” The suggestion was that many manufacturers may not be able to verify the consistency of the vial necks, or know much about the issue.
In the end, the mystery of the headspace oxygen generated vibrant discussion and interesting theories, but no certainty as to what is likely causing the problem.
Raised Stopper Detection: What’s the Rationale?
Trappler asked the PDA members in the audience whether they were conducting tests for raised stoppers—i.e., stoppers which sit higher in their vials than usual. Five audience members raised their hands. Several more, however, said they were considering means of raised stopper detection. Still many more were not considering it at all.
Should we do raised stopper detection? Trappler surveyed the audience—just 10 believed that manufacturers should be doing raised stopper detection,
What is fundamentally being addressed by looking for raised stoppers? One audience member posed just that question. “I would guess it’s the sterility of the product? A lot of times a raised stopper really doesn’t tell you much about closure integrity. It’s just an issue with the way that the stopper was manufactured.”
Exactly, said Muhvich, a former member of the FDA. “When I was at the FDA I saw a lot of good studies where people sealed vials and did all kinds of challenges to them, but they didn’t have issues. Stuff happens all the time on the line. As long as your inspection process is good, I don’t think you’ll have a sterility assurance issue.
Muhvich noted that many manufacturers prefer to do stability testing in relation to container closure integrity. “If you have ensured integrity, you will only get false positives [if any positives] on your stability testing,” he said. “The only way it’s going to fail on stability is if it’s a seal integrity issue.”
“As of 2008, you can use seal-integrity testing in lieu of sterility testing on stability now,” he continued. “I wouldn’t dare use a sterility test on stability now.”
What is the rationale for concern about raised stoppers? Trappler asked.
One person suggested that ingress prior to crimping is the main concern. [E.U. regulation] Annex 1 says the vial is not integral until it is crimped, he said.
“I see that raised stopper as raising more of a stability and product quality issue,” said another participant from the crowd. “It may affect that product over the six months that it sits in distribution. The reason you’re freeze-drying your product is because it’s not stable as a liquid.”
Said another: “Yes, the probability of an oxygen or water molecule getting in [to vials] is much higher than a microbe getting in.”
And yet another member of the audience provided this final thought: “If you don’t have any control over the height of your stopper, how much control do you really have over your capping operations?”
Mastering Moisture within Vials
Trappler posed a trivia question: What is the most common moisture specification for freeze-dried drug products? The audience said 2%, or maybe 3%. It’s irrelevant, Trappler reminded. It really depends on the product, and noted that he has seen residual moisture specs as high as 11%.
Many manufacturers, in fact, performed stability studies simply as a means of justifying their high residual moisture specs, he noted. “One needs to consider how much active ingredient is in the product . . . you have to consider the molar ratio of moisture to the active ingredient of the compound.”
How to reduce moisture content? One approach is use a disaccharide in the formulation that has a strong affinity for water, said Trappler. “You may use it as a bulking agent, but it’s really a dessicant. Then you get bound water instead of free water.”
“You can also look at degradants,” an audience member added. Great point, said Trappler. “Very often we only look at the active ingredient,” he said. “You may also need to look at the toxicity profile of the degradant as well. I’m amazed at how many companies miss that. It’s kind of scary.”
The conversation again turned to stopper integrity, this time in terms of how it may impact moisture content. “We have to control the temperature through the supply chain all the way to the patient,” one person said. “Often the temperatures are very low, which could challenge stopper integrity.”
“It’s pretty easy to ship at 5 degrees,” Trappler said, “but minus 20 becomes more of a challenge. If so, what do you use to ship the product? You can use a eutectic mixture, but you can also use dry ice, which has a temperature of -76 degrees.”
But most stoppers are made to withstand temperatures to, perhaps, -50 degrees, he continued. “So what happens to stopper integrity? Is the seal still good? I don’t know.”
“We had a product like that, and we had to ship it in a cooler within a cooler,” remembered one participant. “We learned our lesson the hard way with dry ice. . . .We lost integrity. I’ve seen a lot of products now that need to be shipped at -20, and that really makes it difficult.”