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Angie Drakulich was editorial director of Pharmaceutical Technology.
An industry roundtable on how users and makers can best assess and manage black specks.
In April 2012, industry experts discussed the issue of atypical visible particles in pharmaceutical raw materials, including excipients, at the joint International Pharmaceutical Excipient Council's (IPEC) Regulatory Conference and ExcipientFest-Americas Conference in San Juan, Puerto Rico. On the panel were Dr. Lucinda Buhse, director of the Division of Pharmaceutical Analysis in FDA's Office of Pharmaceutical Science at CDER; Ann Van Meter, chair of the IPEC GMP Committee and of the IPEC Atypical Visible Particles Working Group; Dave Schoneker, director of Global Regulatory Affairs at Colorcon and past IPEC–Americas Chairman; and Dale Carter, current chair of IPEC–Americas. The following pages include an edited excerpt of the transcribed roundtable, which was moderated by Pharmaceutical Technology Editorial Director Angie Drakulich. To listen to the complete and unedited discussion, click here.
A primary cause of drug recalls during the past year has been the presence of visible particles, that is off-colored particles or black or tan specs, in pharmaceutical products. The presence of visible particles affects both excipients manufacturers and users with regard to standard expectations for mitigating the atypical visible particles and with regard to decision-making about raw material acceptance criteria. The International Pharmaceutical Excipients Council (IPEC) is working to develop and fast-track a guideline on how to measure and properly assess the significance of these visible particles, particularly within white polymer powders. The guideline is meant to dispel any confusion around the presence of particles in excipients and to provide information for excipients users and makers on how to proceed when making decisions about these particles. The following is an edited transcript of a roundtable discussion that took place in April 2012 at the IPEC/ExcipientFest Americas conference in San Juan, Puerto Rico. Featured panelists are listed at left.
Q&A with panelists
PharmTech: When elevated temperatures are used with organic substances for drying or solvent removal, these temperatures, even though they're beneficial for solvent removal and reduction of bioburden, can actually char the white powder materials and leave the so-called black specs. Could you comment on this and what other manufacturing or processing techniques may cause these visible particles?
The Speakers Roundtable session on atypical visible particles at IPEC/ExcipientFest Americas 2012 in San Juan.
Schoneker (Colorcon): Probably the most common cause of the particles that everybody sees is charring. There are various points in the process where it's going to get charred and turn a little bit brown or black, and there are various points where there's motion, or compression, that over time will form such particles. It's important to understand that these particles are inherent to the excipient manufacturing process and always will be. There are also errant particles, particles that you don't typically see that show up and probably need a different level of assessment.
What IPEC really wants to talk about with the industry is zero tolerance (that is, absolutely no visible particles in the excipient material). Zero tolerance should not be the goal because it's unrealistic. What we're trying to do (with the IPEC guideline) is to figure out how to look at the particles that are inherent versus the particles that are not inherent, and how one can come up with procedures and controls to deal with each type. Right now, there is no regulatory guidance on this subject, and everybody is assuming that every particle is atypical—or not inherent—when in fact, they are. This is creating a lot of controversy throughout the industry.
Carter (IPEC): To add to that, if you have an abrasive product going through stainless-steel pipes and other things, you're going to scour that product. When you have big crystallizers and large dryers, there is buildup. Even in crystallizations, the color can be just how the crystal formed. It may appear slightly different in color than the next particle. Trying to remove these aesthetically unpleasing specks should not be the industry's main interest. What should be focused on is identifying the reasonable state of art for individual products, following GMP, and separating those occasional off-colored materials from real contamination.
PharmTech: Because there are no existing guidelines about how to handle these visible particles, the user's discovery of black specks in raw materials can in many cases lead to an entire batch of material being rejected. Currently, how does one distinguish between the normal specks that may be formed during the manufacturing process and potentially harmful foreign contaminants?
Van Meter (IPEC): From an excipient manufacturer point of view, we work very closely with customers to analyze the particles. About 80 to 90% of any particles that I have analyzed that are returned from a customer are off-colored polymer. Unfortunately, when you're dealing with pure white powders, it is common to have these very, very small dark particles, and even though they're very small in number, they do stand out. I understand that they cause alarm; but again, 90% of them are purely the listed polymer.
Schoneker (Colorcon): From an excipient user perspective, we've learned that most companies don't talk to their suppliers about these particles. Instead, all kinds of analyses are done to prove that a charred particle is something it's not. Users then have tons of data and still don't know what to do about the particles and they end up rejecting the batch.
The supplier, however, could probably explain why the particles are there, what they are, and how they control them. For example, a supplier might say, 'If the particles are brown, that's normal and you probably don't have to do a whole lot of analyses unless you have some reason to think it's something else. If the specks are purple, however, you need to go to the next step in analysis.' The missing link here is communication.
PharmTech: When such a batch rejection occurs based on atypical visible particles, that decision affects not only cost but also the supply chain, and potentially can lead to a drug shortage. What are your thoughts on this?
Van Meter (IPEC): Yes, very few particles can cause the rejection of an entire batch of materials. But I'd like to clarify that when we're talking about these particles, we're not talking about something that is pervasive or gross, we're talking about just a very, very few micron-size particles in an entire batch of material. At a customer location, if those are seen at receipt, then the entire batch could be quarantined and shipped back. As an excipient manufacturer, that rejection incurs tremendous cost because the material has already been manufactured and shipped. Then you have to bring the material back and perform an appropriate disposition; there's often no rational thought as to why the material was rejected. Sometimes, the recipient decision is just visual— 'I see black specks; I can't accept this lot.' The alternative is for the user to take a controlled approach to call the material manufacturer, do the appropriate investigation, and release the material.
PharmTech: FDA does not have an official position on this subject yet, but are there any visible particles that are considered acceptable in raw materials today or should everything be ruled out?
Buhse (FDA): As an agency, we want to know that you understand what product you're making, so that you know what is or isn't acceptable.... There are risk-based, science-based decisions that you need to make as the manufacturer of the final drug about what you can tolerate in your incoming raw materials, including the excipients. So if you have particles, we would look to see that you understand what they are. Perhaps it's as simple as having a discussion with your supplier and being able to explain to the agency what the particles are and why they are not a risk to public safety or patient safety, which is our prime concern. Risk management, good science, and always keeping the safety of the patient in mind is what we're looking for.
Schoneker (Colorcon): In the food industry, there's a guideline on acceptable filth that specifically states how many insect parts are okay, how many wings are okay, and how much dirt can be present. Now we don't necessarily want to go there in the pharma industry, but, again, the concept that FDA can't find a particle to be acceptable is not true. FDA on the food side has been saying that for decades, and a certain amount of particles, if you will, is the reality. We just need to figure out for our industry what we can do in a reasonable way.
PharmTech: Can you provide some insight into the pending IPEC guideline on atypical visible particles in excipients and its goals?
Van Meter (IPEC): We have a subteam in which excipient manufacturers are looking at what a responsible manufacturer in full GMP compliance would need to do to provide a high degree of assurance to customers (excipient users). The manufacturer needs to be able to tell the customer that it has the issue under control, that it has minimized the particle occurrence to the greatest extent possible, and that it can communicate with them about this topic.
The next phase of our plan is the user phase. Users will need to have a subteam where they look at issues such as, 'What do we do upon receipt? If we see a black particle, do we automatically reject?' And in some cases, users will need to re-examine their decision-making procedures in this regard.
Ultimately, we hope to bring together the responsible manufacturing point of view from the maker's side and the responsible acceptance procedures on the user's side, all with the focus on patient safety. Once we have what we consider a good guideline, we hope to sit down with FDA and review it with them to gain acceptance and move forward.
Schoneker (Colorcon): To be clear, from the point of the IPEC Executive Committee, this guideline is not meant to give manufacturers the ability to avoid high quality standards. If you have a belt that is shearing pieces into the product—the resulting specks are not inherent. That problem needs to be fixed and GMP practice must apply.
PharmTech: The IPEC guideline may suggest taking a customer complaint about specks being found in excipient materials and using that complaint to perform a risk assessment. Can you provide some more detail on what's planned?
Van Meter (IPEC): The way that we think a good manufacturer should behave in this regard is that you need both a feed-forward and a feed-back risk assessment. The feed-forward risk assessment involves having documentation of the process that details where these types of particles may be formed. Then a company can perform a review or a mitigation when they are found. We also want a feed-back risk assessment, which means that when a manufacturer gets a customer complaint, you can take the particles, analyze them, and look back in the manufacturing process to see where the particle may have been generated. That risk assessment should then be updated as necessary.
In addition, I'd like to make a comment about testing and how we can learn how to mitigate some of these issues. We get asked all the time about whether our sample plan covers visible particles. The answer is, you sample, and you evaluate your samples for particles of any kind that would be atypical. However, when you're looking at a performance level, even if you're generating off-color particles, in many cases, you're looking at performance levels of 6, 7, 9 Sigma, and beyond. So anything that you can grab a sample of, you can ensure yourself that if you have an off-color particle that may end up in a final product, you're going to catch it.
PharmTech: From FDA's perspective, what is your take on the IPEC approach discussed so far?
Buhse (FDA): This is a conversation that's going back and forth between manufacturers of excipients and the users of the excipients because perhaps the communication has not been there between those two groups, and I think this guideline will really help move that communication forward so people understand the excipients that they're using and then can use the good science they need to decide what to do moving forward.
And then they can have a better understanding of what 'out of normal' is because, obviously, if an excipient does come in and you are used to 2 particles in 200,000 kilos and one day it comes in as 10 particles out of 200,000 kilos, that raises a red flag. You need to have the ability to call your supplier and talk about it. And maybe they already know that the particles are there, or maybe it's something completely different, and you both need to go back and do a complete CAPA and take a look at perhaps that pipe that needs to be replaced because it's 25 years old, and so forth. And if you aren't communicating, then perhaps some material could get into the market that maybe should have been stopped had there been better communication.
Overall, it's a good place for both the suppliers and the users to start talking and figuring out what they want to put in this guideline. As an agency, we're happy to take a look at the guideline when a good draft exists and see what we think.
PharmTech: There is clearly frustration on both sides, user and maker, with this issue. What types of dialogue do you think need to happen beyond what's already taking place?
Carter (IPEC): There's got to be an understanding of how products are made, their capabilities, and how they are used. The makers of excipients have concerns over their own intellectual property. In making excipients, you don't typically, for equipment or certain processes, patent them. This confidentiality is what gives a certain company an ability to make a certain product of a certain quality. But companies have to get beyond this frame of mind in order to talk about sources. They have to build a quality partnership. This dialogue, however, needs to start in the development process when companies are choosing excipients. Early conversations are key.
Van Meter (IPEC): Having this guidance in place will provide the safe environment that not only says it's okay for these particles to exist, but that also encourages makers and users to talk about this issue because, as we have has alluded to, it's been there all along. When you have these discussions, not only do you build a much higher degree of trust, supplier to maker, but you also avoid panic.
Buhse (FDA): [These ideas about dialogue] support a lot of the initiatives that the agency has been pushing, such as quality by design and understanding better how raw materials affect the final product. So it can only help to be having that communication between manufacturers and users and being able to understand the variability in your raw material and how then you can make sure that that variability in your raw material can be taken care of in your own manufacturing process so that the end product is potentially less variable or at least will no longer have a high probability of being rejected down the road.
"Your write up on the visible particles conference was very useful, particularly hearing FDA's perspective. I also liked D. Schoneker's comment on FDA's acceptable level of particles (and filth) in food. It's extremely helpful that FDA says unequivocally that these particles don't present a health risk. Similarly, most particulates in drugs, particularly oral ones, don't present a health risk, they present a quality issue. From my experience, atypical matter from supplier excipients is less common than atypical matter that occurs during manufacturing. The latter are usually associated with manufacturing equipment or items, e.g., a piece of teflon or other polymer, particle of stainless steel, etc. The materials are usually present an extremely low hazard and don't present a risk to patients (I'm a toxicologist by training). However, we still must do toxicology assessments of each. The issue with the JNJ plant in Fort Washington also included this kind of particulate matter. Hence, it's a general challenge within industry." --Dave, Large Pharma Company, US