Newsmakers: Aseptic Processing
Q&A with PDA President Richard M. Johnson
By Gil Y. Roth
With the 2010 edition of the Parenteral Drug Assocation's annual meeting coming up this month, I sat down to talk with PDA president Richard M. Johnson about aseptic processing issues. A 30-year industry veteran, Mr. Johnson has witnessed a fundamental shift in processing technologies and regulatory expectations. —GYR
Contract Phama: Tell me a little about your history and background.
Richard M. Johnson: I’ve been in the industry for about 30 years now. Some of the major stops along the way included ophthalmic companies like Bausch & Lomb and Alcon. The majority of the products at those facilities are aseptically processed. I was heavily involved for years in both international and domestic operations at those companies.
I’ve also been at Abbott Laboratories in a corporate quality role, and at Wyeth more recently as a global head of quality.
In addition, I’m former co-chair of the ISO Aseptic Processing committee. I’ve been on aseptic processing committees at PDA for a number of years and, until taking on this new role as president, I was also the leader of PDA’s sterile processing interest group.
CP: That’s quite a pedigree! What macro-trends have you seen in aseptic processing in that span?
RJ: Over the 30 years that I’ve been involved, there have been dramatic changes in the level of technology, allowing less and less risk associated with producing an aseptic product. The risk has always been pretty low, but relative to a terminally sterilized product, it’s higher.
A lot of the advances and technologies have a lot to do with further reducing that risk. One of the primary methods that has seen wider and wider acceptance is automation and the use of robotics. The biggest source of contamination for aseptically processed products are the people who have to interact with it. If you can separate the people from the environment in which the products are being processed, then you reduce the risk of contamination. We’re seeing higher levels of automation in terms of processing equipment. There’s more use of robotics and other non-contact ways of doing everything from sampling online to processing components.
CP: Is there a PAT analog within aseptic processing?
RJ: I think that aseptic processing has always had examples of what we now call PAT or process control. We see use of that also increasing. Both by industry practice and regulatory expectation, there's much more online monitoring of particles that are in the air. They can now be measured continuously. Those particles aren't all bacteria, but the overall concentration of airborne particles correlates with the chance of bacteriological contamination. More particles, more bacteria.
It's a standard practice in a cleanroom setting to have continuous monitoring of particles in the air. Similarly, there's been a big increase in new techniques for monitoring bacteria that may be present. We've seen quite an evolution in rapid biological methods recently. It's not instantaneous, but it's much faster than the traditional sterility testing. That allows you to do many more control steps in the process, if you're getting the data before the product is too far along.
With new techniques, we can do more monitoring of the process in realtime and make adjustments as necessary. That's an element of PAT; it's not exactly the way it would be in solid dosage manufacturing.
Because the common concern in aseptic processing is biological contamination, a lot of the effort has been on improving rapid microbiological testing methods. Some of them have become much more chemical methods rather than traditional microbiological methods. They're looking for certain biochemicals as an indicator of whether there are living organisms present. I don't think the technology has advanced to the point that you could stick a probe in and measure continuously. But it certainly has allowed for an increase in monitoring and a more rapid response.
Many supporting processes have had advances in continuous monitoring. Water is a major component of all these products, and it's quite common to have continuous online monitoring of the attributes of water for injection or purified water via instrumentation. No one refers to that as PAT, but it fits the criteria.
It's very complex. It's not just looking at the operation on a set of chemicals in a blender. You have to look at a lot of different activities, be it the sterilization of the glass that comes in, and the sterilization of the liquid, and the environment in which processing will take place. There's a lot of focus now on the integrity of the glassware used in packaging the drug product. That's led to a conversation about using polymers instead, to reduce the risk of breakage and the like.
CP: Are there extractable issues with that?
RJ: That's always been the concern, and that's probably the barrier that's kept polymers from being used more widely. The glass used for packaging pharmaceutical products is of very high quality, and designed to have very minimal impact on the product. Plastics present a more challenging situation. But there are many sterile products that have been packaged in plastic for years. Every one has to be evaluated individually.
There's an evolution in packaging. One of the areas of interest right now is how the product gets delivered to the patient. On the one hand, there's a focus on controlling things through the distribution chain, maintaining the cold chain for biologics, in particular. On the other side, there's the issue of how the patient deals with the package. If it's in a vial, then the user needs to stick a syringe in and extract the contents. If you want to cut out that activity, which generally occurs in the healthcare setting offers far less microbiological control than you get in the manufacturing facility, then do you package it in a prefilled syringe?
At PDA, we have a very large annual conference on prefilled syringes. It's a big area of interest. It used to be a segmented part of the overall spectrum of products, but it's grown phenomenally in recent years. Partly, that's driven by the potential for self-delivery of a drug, not just the healthcare setting.
People are designing packages that are completely sterilized by gamma radiation, then get filled by a needle puncturing a membrane. A laser than seals the membrane back up, all in a closed environment. That's about as safe a concept as you can imagine.
CP: Why do you think harmonization has accelerated?
RJ: There's definitely been an increase in cooperation among regulators. They face the same increasing demands and decreasing resources that companies face. There's a recognition that this is a global marketplace and that cooperation becomes a force multiplier, allowing them to perform their mission more successfully.
In the short-term, I think we're seeing a phenomenon where, because some countries haven't been as active on the international scene and are now starting to harmonize, companies are seeing more inspections. In my last position at Wyeth, it was not uncommon to have an inspection from not only FDA, but multiple European authorities, one from Brazil, another from as far off as Uganda. Japan just recently started doing international inspections, so I think that's an ongoing trend.
It puts more resource constraints on both inspectors and the companies that are subject to inspection.
CP: Are contract manufacturers held to a different level of scrutiny than in-house facilities by inspectors?
RJ: I think the challenge for contract facilities is that they have different customers with different expectations. For a manufacturing site,there are some product-specific aspects that can be adjusted, but the systems-based aspects can get very complicated if there are multiple sets of expectations from clients.
With biologics and other new drugs, there's increased potential for cross-contamination, especially at CMOs.
CP: What's PDA's role in Asia?
RJ: We have several chapters in the Asia-Pacific region. We've run several meetings in China and are setting up programs there. We're discussing the possibility of running at least one program on aseptic processing in China this year. In India, we're talking about establishing a PDA chapter. In all these regions, we already have quite a few members.
Our largest single chapter is in Japan; we also have chapters in Korea, Taiwan and Australia. Latin America and Africa haven't been big areas. South Asia is obviously a growing market, but there's been more inroads in regards to API manufacture than biologics or finished dosage forms, especially sterile forms.
I think there's more finished dosage form manufacturing (for export) going on in India than in China. There's not a lot of contract manufacture of aseptically processed products going on in either of those regions.
The other important advance is in isolation technology. You can’t automate everything. You still need people to reach in at certain points and perform some manipulation. If you can totally enclose that so that there’s a barrier between the person and the product, you increase assurance.
Isolation is a reciprocal relationship. Just as we’re trying to reduce the possibility of microbiological contamination of product by people, we also need to protect the people from the more active and cytotoxic products. It works both ways.
The thing is, every one of these technologies represents an improvement but also a new set of challenges. When isolators first came into use, they were like glove-boxes. Over time, especially with different decontamination techniques, the gases that were used had an effect on the integrity of the gloves. In response, there’s been an evolution in the selection of materials for those gloves, as well as techniques that were developed to better measure glove-integrity. Otherwise you could end up with a new source of contamination.
Another example is in filtration. In aseptic processing, everything at some point in time has to be sterilized. Aseptically processed drug products tend to be liquid, and liquids get sterilized by passing them through a membrane that will exclude bacteria. As we’ve progressed, membrane technology has improved in terms of reliability and performance.
Risk is a statistical concept. In a typical sterilization process, the standard is that you should achieve a less-than-one-in-one-million chance of a failure. That doesn’t mean that one in every million products will fail, but that every product has that small a chance of having a bacteria or other microorganism that survives. That’s a very high level of assurance.
For aseptic processing, it’s much more complicated to assign that sort of value. What we have to do is establish that value for each individual process, then look at how they connect and make sure there are no gaps that could have a lower level of assurance.
One of the things about aseptic processing that I think is both so challenging and fascinating is that it’s more of a journey than a destination. Intrinsically, there’s no way to disprove a negative. The only way to tell if a product is contaminated is by doing destructive testing on it.
CP: With increased technology, I assume we’re also seeing increased regulatory demands?
RJ: Absolutely! FDA has had a specific guidance for aseptic processing for about 20 years now. In 2004, after a lot of public discussion (of which PDA was a very prominent participant), they revised their aseptic guidance. The revision represented a lot of new and updated requirements. What we’ve seen in the past six years is that many of the international regulatory requirements have been updated to come into harmony with FDA. We’ve probably come closer to a harmonized international standard now than ever.
That said, Europe has its Annex 1 for its Manufacturing Practice Directive, which covers aseptic processing and its expectations. Most of it’s in harmony with the U.S., but they’ve increased the requirements for monitoring of non-viable particulates.
CP: What other countries or regions are pushing new regulations?
RJ: Japan also has a guidance that came out relatively recently. There’s ISO, the International Standards Organization, which also has an aseptic processing guidance. Then there’s a group called Pharmaceutical Inspection Cooperation Scheme (PIC/S), that consists of international regulatory agencies and promotes cooperation and exchange among agencies. This group puts out guidance documents and has a wide international scope. Europe, Australia, Canada and other countries are members. (The U.S. isn’t in yet, but they’re applying to join.)
CP: What do you think accounts for differences among regions? Is real harmonization possible, or are there issues that pre-empt it?
RJ: With regard to aseptic processing, the vast majority of the regulatory expectations and requirements have become harmonized. The FDA update really detailed a lot of specific areas, and the EU and other documents have come into harmony with most if not all of them.
But each of these groups, based on past experiences or perceptions about their home markets or the like, sometimes have areas that are on the margin of those topics, and may diverge.
For example, the EU not only requires monitoring particles of half a micron or larger, they also require measurement of particles that are five microns or larger in size. They want a little more detail than other regulatory bodies require.
From an industry standpoint, most companies these days are manufacturing product for more than one market, so people take all the harmonized expectations and the additional ones that individual regulatory bodies require. For convenience, many companies adopt those across the board. It doesn’t make sense to have one set of expectations on the day you’re making product for the U.S., and a different set so that on another day you can make the product for Sweden.
I believe that far more aspects have been harmonized among regulators than there are aspects that are different.
CP: What’s new on the regulatory front?
RJ: There’s an increased focus on combination products, and that impacts aseptic processing. A pre-filled syringe falls in that category. FDA recently published for comment a new GMP requirement for combination products that will require more application of both device quality system requirements and drug GMP requirements. That’s a relatively new concept.
CP: Is that just codifying something that companies had been previously doing?
RJ: No, it’s new. I’ve done a lot of prefilled syringes with drug product, and the syringe was basically treated like a packaging component. Now it’ll be considered a device, and that raises the regulatory expectations.
CP: How would you describe PDA’s role in all this?
RJ: PDA’s role is the primary, worldwide scientific organization promulgating guidance positions and training with regard to aseptic processing. We’ve published a number of technical documents that are widely used throughout the industry. We comment on regulatory proposals and hold a lot of conferences and training programs.
PDA actually has a training facility at its headquarters that includes an aseptic processing area. It lets people get hands-on training in good practices in a setting that doesn’t risk product. These are very intensive 80- to 100-hour courses with expert instructors.
Aseptic processing is always a key area of our annual conference. We also have a prefilled syringe conference, a parenteral conference in Europe, as well as microbiological conferences in the U.S. and Europe. Education’s a core area of PDA’s activity.
CP: What do you consider biggest industry shifts during your 30 years?
RJ: Certainly, those advances in technology have been huge. Gone are the days when people would have an interaction with virtually every aspect of the product, thanks to automation and isolation.
But the biggest change is consolidation, both of major companies and of manufacturing sites. A lot of that started when some of the export/import barriers for drug products eroded. You no longer needed a plant in each European country, so there’s much fewer facilities. The result of that is that it’s much easier to invest in new technologies. Plants are putting out much more product. Having fewer facilities means that those remaining have to be much better at what they do.